Article

Multimodal imaging of striatal degeneration in Amish patients with glutaryl-CoA dehydrogenase deficiency

August 2007
Brain 130(Pt 7):1905-20

August 2007
130(Pt 7):1905-20

DOI:10.1093/brain/awm058

Source
PubMed

Authors:

Kevin Strauss

Clinic for Special Children

Jelena Lazovic

Clinical Centre of Montenegro

Max Wintermark

University of Virginia

Despite early diagnosis, one-third of Amish infants with glutaryl-CoA dehydrogenase deficiency (GA1) develop striatal lesions that leave them permanently disabled. To better understand mechanisms of striatal degeneration, we retrospectively studied imaging results from 25 Amish GA1 patients homozygous for 1296C>T mutations in GCDH. Asymptomatic infants had reduced glucose tracer uptake and increased blood volume throughout gray matter, which may signify a predisposition to brain injury. Nine children (36%) developed striatal lesions: three had sudden motor regression during infancy whereas six had insidious motor delay associated with striatal lesions of undetermined onset. Acute striatal necrosis consisted of three stages: (1) an acute stage, within 24 h of motor regression, characterized by cytotoxic oedema within the basal ganglia, cerebral oligemia, and rapid transit of blood throughout gray matter; (2) a sub-acute stage, 4-5 days after the onset of clinical signs, characterized by reduced striatal perfusion and glucose uptake, and supervening vasogenic oedema; and (3) a chronic stage of striatal atrophy. Apparent diffusion coefficient maps revealed that at least two of the six patients with insidious motor delay suffered striatal injuries before or shortly after birth, followed by latent periods of several months before disability was apparent. Thus, acute and insidious presentations may occur by similar mechanisms, and differ only with regard to the timing of injury. Intravenous fluid and dextrose therapy for illnesses during the first 2 years of life was the only intervention that was clearly neuroprotective in this cohort (odds ratio for brain injury = 0.04, 95% confidence interval = 0.01-0.34; P < 0.001).

Recommendations for diagnosing and managing individuals with glutaric aciduria type 1: Third revision

Article

Full-text available

Oct 2022
J INHERIT METAB DIS

Glutaric aciduria type 1 is a rare inherited neurometabolic disorder of lysine metabolism caused by pathogenic gene variations in GCDH (cytogenic location: 19p13.13), resulting in deficiency of mitochondrial glutaryl-CoA dehydrogenase (GCDH) and, consequently, accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine detectable by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Depending on residual GCDH activity, biochemical high and low excreting phenotypes have been defined. Most untreated individuals present with acute onset of striatal damage before age three (to six) years, precipitated by infectious diseases, fever or surgery, resulting in irreversible, mostly dystonic movement disorder with limited life expectancy. In some patients, striatal damage develops insidiously. In recent years, the clinical phenotype has been extended by the finding of extrastriatal abnormalities and cognitive dysfunction, preferably in the high excreter group, as well as chronic kidney failure. Newborn screening is the prerequisite for pre-symptomatic start of metabolic treatment with low lysine diet, carnitine supplementation and intensified emergency treatment during catabolic episodes, which, in combination, have substantially improved neurologic outcome. In contrast, start of treatment after onset of symptoms cannot reverse existing motor dysfunction caused by striatal damage. Dietary treatment can be relaxed after the vulnerable period for striatal damage, i.e. age 6 years. However, impact of dietary relaxation on long-term outcome is still unclear. This third revision of evidence-based recommendations aims to re-evaluate previous recommendations 1-3 and to implement new research findings on the evolving phenotypic diversity as well as the impact of non-interventional variables and treatment quality on clinical outcomes. This article is protected by copyright. All rights reserved.

Glutaric acidemia type 1: Treatment and outcome of 168 patients over three decades

Article

Full-text available

Oct 2020

Glutaric acidemia type 1 (GA1) is a disorder of cerebral organic acid metabolism resulting from biallelic mutations of GCDH. Without treatment, GA1 causes striatal degeneration in >80% of affected children before two years of age. We analyzed clinical, biochemical, and developmental outcomes for 168 genotypically diverse GA1 patients managed at a single center over 31 years, here separated into three treatment cohorts: children in Cohort I (n = 60; DOB 2006–2019) were identified by newborn screening (NBS) and treated prospectively using a standardized protocol that included a lysine-free, arginine-enriched metabolic formula, enteral l-carnitine (100 mg/kg•day), and emergency intravenous (IV) infusions of dextrose, saline, and l-carnitine during illnesses; children in Cohort II (n = 57; DOB 1989–2018) were identified by NBS and treated with natural protein restriction (1.0–1.3 g/kg•day) and emergency IV infusions; children in Cohort III (n = 51; DOB 1973–2016) did not receive NBS or special diet. The incidence of striatal degeneration in Cohorts I, II, and III was 7%, 47%, and 90%, respectively (p < .0001). No neurologic injuries occurred after 19 months of age. Among uninjured children followed prospectively from birth (Cohort I), measures of growth, nutritional sufficiency, motor development, and cognitive function were normal. Adherence to metabolic formula and l-carnitine supplementation in Cohort I declined to 12% and 32%, respectively, by age 7 years. Cessation of strict dietary therapy altered plasma amino acid and carnitine concentrations but resulted in no serious adverse outcomes. In conclusion, neonatal diagnosis of GA1 coupled to management with lysine-free, arginine-enriched metabolic formula and emergency IV infusions during the first two years of life is safe and effective, preventing more than 90% of striatal injuries while supporting normal growth and psychomotor development. The need for dietary interventions and emergency IV therapies beyond early childhood is uncertain.

Impact of newborn screening and quality of therapy on the neurological outcome in glutaric aciduria type 1: a meta-analysis

Article

Full-text available

Sep 2020

Purpose Glutaric aciduria type 1 (GA1), a rare inherited neurometabolic disorder, results in a complex movement disorder (MD) with predominant dystonia if untreated. Implementation into newborn screening (NBS) programs and adherence to recommended therapy are thought to improve the neurological outcome. Methods Systematic literature search for articles published from 2000 to 2019 was performed using the PRISMA protocol. Studies reporting on more than one individual identified by NBS were included. We investigated effects of interventional and noninterventional variables on neurological outcome. Results Fifteen publications reporting on 647 GA1 patients were included. In the NBS group ( n = 261 patients), 195 patients remained asymptomatic (74.7%), while 66 patients (25.3%) developed a MD. Compared with the NBS group, a much higher proportion of patients (349/386; 90.4%; p < 0.0001) diagnosed after the manifestation of neurologic symptoms had a MD and an abnormal motor development (285/349; 81.7%; p < 0.0001). For NBS patients, deviations from the recommended diet increased the risk of insidious onset MD, while delayed start of emergency treatment increased the risk of acute onset MD. Conclusions This meta-analysis demonstrates that NBS programs for GA1 have an overall positive effect on the neurological outcome of affected individuals but their success critically depends on the quality of therapy.

Orthopaedic manifestations of glutaric acidemia Type 1

Article

Full-text available

Aug 2020

Purpose Glutaric acidemia type 1 (GA1), a rare hereditary metabolic disease caused by biallelic mutations of GCDH, can result in acute or insidious striatal degeneration within the first few years of life. We reviewed the orthopaedic sequelae and management of 114 neurologically injured patients with a confirmed molecular diagnosis of GA1. Methods We performed a retrospective chart review spanning 28 years identifying 114 GA1 patients, most from the Old Order Amish population of Lancaster County, Pennsylvania, who were homozygous for a pathogenic founder variant of GCDH (c.1262C>T). We collected demographics, medical comorbidities, muscle tone patterns, Gross Motor Function Classification System level, gastrostomy tube status, seizure history, inpatient events, orthopaedic diagnoses and operative characteristics. Results Over an average follow-up of 4.7 ± 3.4 years, 24 (21%) of 114 patients had musculoskeletal problems requiring orthopaedic consultation. Scoliosis (n = 14), hip dislocation (n = 8/15 hips), hip subluxation (n = 2/three hips), and windswept hip deformity (n = 2) in the spine and hip joint were most common. In total, 35 orthopaedic surgeries were performed in 17 (71%) patients. The most common primary operations were one-stage procedures with proximal femoral varus derotation osteotomy and/or pelvic osteotomy (n = 8/14 hips) for subluxation or dislocation. In all, 11 patients had posterior spinal fusion for severe scoliosis. With the recommended metabolic management, there were no disease-specific complications in this cohort. Conclusions Children with GA1 who have static striatal lesions are at risk for musculoskeletal complications, especially scoliosis and hip dislocation, and appropriate operative management requires consultation with a metabolic specialist with specific considerations for fluid management and nutrition. Level of Evidence IV

Pericytes in Neurometabolic Diseases

Article

Full-text available

Sep 2020

Purpose of Review Since brain pericytes guarantee appropriate development and maintenance of the cerebrovascular system, we reviewed their role in neurometabolic diseases (NMDs), a subclass of inborn errors of metabolism that selectively cause neurological sequels and widespread cerebrovascular alterations. Recent Findings Main findings about pericyte involvement in NMDs arise from glutaric acidemia type I (GA-I) models. In this regard, we found that (i) a single intracisternal injection of the main accumulated metabolite (glutaric acid, GA) in rat neonates disturbed the neurovascular unit (NVU) as evidenced by blood-brain barrier hyperpermeability, and altered immunoreactivity of pericyte and astrocyte markers surrounding brain microvessels; (ii) GA-elicited capillary constriction near pericyte somata likely inducing reduced brain blood flow as reported in GA-I patients; (iii) GA-elicited pericyte contraction probably results from a defective interplay among NVU components and could be relevant in case of metabolic decompensation or energetic deficiency. Summary Although pericyte pathological features have been studied in few NMDs, their involvement in NMD pathophysiology is largely unknown. Thus, further studies are needed to identify their roles and therapeutic potentiality.

Glutaric Acid Affects Pericyte Contractility and Migration: Possible Implications for GA-I Pathogenesis

Article

Full-text available

Nov 2019
MOL NEUROBIOL

Glutaric acidemia I (GA-I) is an inherited neurometabolic childhood disease characterized by bilateral striatal neurodegeneration upon brain accumulation of millimolar concentrations of glutaric acid (GA) and related metabolites. Vascular dysfunction, including abnormal cerebral blood flow and blood-brain barrier damage, is an early pathological feature in GA-I, although the affected cellular targets and underlying mechanisms remain unknown. In the present study, we have assessed the effects of GA on capillary pericyte contractility in cerebral cortical slices and pericyte cultures, as well as on the survival, proliferation, and migration of cultured pericytes. GA induced a significant reduction in capillary diameter at distances up to ~ 10 μm from the center of pericyte somata. However, GA did not affect the contractility of cultured pericytes, suggesting that the response elicited in slices may involve GA evoking pericyte contraction by acting on other cellular components of the neurovascular unit. Moreover, GA indirectly inhibited migration of cultured pericytes, an effect that was dependent on soluble glial factors since it was observed upon application of conditioned media from GA-treated astrocytes (CM-GA), but not upon direct GA addition to the medium. Remarkably, CM-GA showed increased expression of cytokines and growth factors that might mediate the effects of increased GA levels not only on pericyte migration but also on vascular permeability and angiogenesis. These data suggest that some effects elicited by GA might be produced by altering astrocyte-pericyte communication, rather than directly acting on pericytes. Importantly, GA-evoked alteration of capillary pericyte contractility may account for the reduced cerebral blood flow observed in GA-I patients.

Patterns, evolution, and severity of striatal injury in insidious- vs acute-onset glutaric aciduria type 1

Article

Feb 2019

Background Striatal injury in patients with glutaric aciduria type 1 (GA1) results in a complex, predominantly dystonic, movement disorder. Onset may be acute following acute encephalopathic crisis (AEC) or insidious without apparent acute event. Methods We analyzed clinical and striatal magnetic resonance imaging (MRI) findings in 21 symptomatic GA1 patients to investigate if insidious‐ and acute‐onset patients differed in timing, pattern of striatal injury, and outcome. Results Eleven patients had acute and ten had insidious onset, two with later AEC (acute‐on‐insidious). The median onset of dystonia was 10 months in both groups, and severity was greater in patients after AEC (n = 8 severe, n = 5 moderate) than in insidious onset (n = 4 mild, n = 3 moderate, n = 1 severe). Deviations from guideline‐recommended basic metabolic treatment were identified in six insidious‐onset patients. Striatal lesions were extensive in all acute‐onset patients and restricted to the dorsolateral putamen in eight of ten insidious‐onset patients. After AEC, the two acute‐on‐insidious patients had extensive striatal changes superimposed on pre‐existing dorsolateral putaminal lesions. Two insidious‐onset patients with progressive dystonia without overt AEC also had extensive striatal changes, one with sequential striatal injury revealed by diffusion‐weighted imaging. Insidious‐onset patients had a latency phase of 3.5 months to 6.5 years between detection and clinical manifestation of dorsolateral putaminal lesions. Conclusions Insidious‐onset type GA1 is characterized by dorsolateral putaminal lesions, less severe dystonia, and an asymptomatic latency phase, despite already existing lesions. Initially normal MRI during the first months and deviations from guideline‐recommended treatment in a large proportion of insidious‐onset patients substantiate the protective effect of neonatally initiated treatment.

Patterns, evolution, and severity of striatal injury in insidious- versus acute-onset glutaric aciduria type 1

Article

May 2018

Background: Striatal injury in patients with glutaric aciduria type 1 (GA1) results in a complex, predominantly dystonic, movement disorder. Onset may be acute following acute encephalopathic crisis (AEC) or insidious without apparent acute event. Methods: We analyzed clinical and striatal magnetic resonance imaging (MRI) findings in 21 symptomatic GA1 patients to investigate if insidious- and acute-onset patients differed in timing, pattern of striatal injury, and outcome. Results: Eleven patients had acute and ten had insidious onset, two with later AEC (acute-on-insidious). The median onset of dystonia was 10 months in both groups, and severity was greater in patients after AEC (n = 8 severe, n = 5 moderate) than in insidious onset (n = 4 mild, n = 3 moderate, n = 1 severe). Deviations from guideline-recommended basic metabolic treatment were identified in six insidious-onset patients. Striatal lesions were extensive in all acute-onset patients and restricted to the dorsolateral putamen in eight of ten insidious-onset patients. After AEC, the two acute-on-insidious patients had extensive striatal changes superimposed on pre-existing dorsolateral putaminal lesions. Two insidious-onset patients with progressive dystonia without overt AEC also had extensive striatal changes, one with sequential striatal injury revealed by diffusion-weighted imaging. Insidious-onset patients had a latency phase of 3.5 months to 6.5 years between detection and clinical manifestation of dorsolateral putaminal lesions. Conclusions: Insidious-onset type GA1 is characterized by dorsolateral putaminal lesions, less severe dystonia, and an asymptomatic latency phase, despite already existing lesions. Initially normal MRI during the first months and deviations from guideline-recommended treatment in a large proportion of insidious-onset patients substantiate the protective effect of neonatally initiated treatment.

A review of patients with glutaric aciduria type 1 at Inkosi Albert Luthuli Central Hospital, Durban, South Africa

Article

Full-text available

Feb 2017
SAMJ S AFR MED J

Glutaric aciduria type 1 (GA1) is an organic acidaemia. The objective of this study was to describe the profile of patients diagnosed with GA1 at Inkosi Albert Luthuli Central Hospital, Durban, South Africa from 2007 to 2015. We identified 6 children (4 girls, 2 boys) in a retrospective review. The mean age at diagnosis was 12 months. Clinical findings on presentation were encephalopathic crises (n=4), hypotonia (n=4) and macrocephaly (n=5). Other complications included seizures (n=4), dystonia (n=3) and bulbar dysfunction (n=4). Urine organic acid screens showed elevated glutaric acid levels (n=6). Five patients tested positive for the A293T mutation on the glutarylco-enzyme A (CoA) dehydrogenase gene. Abnormalities on magnetic resonance imaging screening included hyperintense basal ganglia (n=6), widened perisylvian fissures (n=6), and an abnormal signal in the cerebral peduncles (n=5) and central tegmental tract (n=4). All patients were treated with L-carnitine and dietary modification. Two patients had a static clinical course, 1 patient gained milestones, and 3 have shown further neuroregression.

Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision

Article

Nov 2016
J INHERIT METAB DIS

Glutaric aciduria type I (GA-I; synonym, glutaric acidemia type I) is a rare inherited metabolic disease caused by deficiency of glutaryl-CoA dehydrogenase located in the catabolic pathways of L-lysine, L-hydroxylysine, and L-tryptophan. The enzymatic defect results in elevated concentrations of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutaryl carnitine in body tissues, which can be reliably detected by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Most untreated individuals with GA-I experience acute encephalopathic crises during the first 6 years of life that are triggered by infectious diseases, febrile reaction to vaccinations, and surgery. These crises result in striatal injury and consequent dystonic movement disorder; thus, significant mortality and morbidity results. In some patients, neurologic disease may also develop without clinically apparent crises at any age. Neonatal screening for GA-I us being used in a growing number of countries worldwide and is cost effective. Metabolic treatment, consisting of low lysine diet, carnitine supplementation, and intensified emergency treatment during catabolism, is effective treatment and improves neurologic outcome in those individuals diagnosed early; treatment after symptom onset, however, is less effective. Dietary treatment is relaxed after age 6 years and should be supervised by specialized metabolic centers. The major aim of this second revision of proposed recommendations is to re-evaluate the previous recommendations (Kölker et al. J Inherit Metab Dis 30:5-22, 2007b; J Inherit Metab Dis 34:677-694, 2011) and add new research findings, relevant clinical aspects, and the perspective of affected individuals.

Newborn Screening for Glutaric Aciduria Type I: Benefits and limitations

Article

Full-text available

Jul 2015

More than 15 years ago glutaric aciduria type I has been included in newborn screening programmes and pilot studies evaluating the potential benefit of early diagnosis and start of metabolic treatment for patients with this disease have been initiated. At that time many important questions on epidemiology, diagnostic quality, natural history, treatment, and cost effectiveness were not sufficiently answered. In particular, it was rather unknown whether early treatment improves the outcome. After implementation of glutaric aciduria type I in an increasing number of countries, and with careful evaluation of disease course and impact of early treatment, there is now solid evidence that affected individuals do have substantial benefit and that newborn screening for this disease is a cost-effective diagnostic intervention. Despite this success, there are still limitations concerning diagnostic sensitivity for patients with a low excreting phenotype and knowledge on long-term disease outcome. In conclusion, it has become evident that tandem mass spectrometry-based newborn screening for glutaric aciduria type I is a powerful and cost-effective tool to prevent the manifestation of prognostically-relevant movement disorders in the majority of early diagnosed patients.

Identification of effective drug targets in treating Glutaric aciduria type 1 disease

Thesis

Jan 2018

Raga Deepthi Ediga

Glutaric aciduria type I (GA‐I) is an autosomal recessive cerebral organic aciduria,caused by a defective GCDH enzyme. This protein lies in the common final catabolic pathway of L‐lysine, L‐hydroxy lysine and L‐tryptophan. Individuals possessing GCDH enzyme deficiency are biochemically characterized by the accumulation of neurotoxic metabolites glutaryl‐CoA, GA, 3‐OH‐GA as well as non‐toxic C5DC in their tissues and body fluids. If untreated, most of the individuals develop an acute encephalopathic crisis causing striatal damage during a finite period of brain growth, resulting in complex movement disorder with predominant dystonia, most commonly between 3 months to 3 years of age. Individuals, diagnosed before the onset of irreversible neurologic symptoms can be prevented from striatal damage, if they are treated with a special diet consisting of low L‐lysine content,supplementation with carnitine and essential amino acids as well as emergency treatment on demand. Even though the currently followed metabolic treatment is predicted to be safe and effective, a significant number of patients still suffer from striatal damage despite early diagnosis and treatment. In addition, recent findings report on extra‐striatal, extra cerebral and non‐neurologic abnormalities despite the current regimen followed. This highlights the prerequisite for the discovery of novel,safe and more efficient long‐term treatment strategies. In this thesis, we hypothesize that pharmacological inhibition of upstream enzymatic steps of the lysine degradation pathway, prior to GCDH, will prevent toxic metabolite accumulation and, consequently, induction of clinical disease phenotype in Glutaric aciduria Type I. To this end, Dehydrogenase E1 and transketolase domain containing 1 (DHTKD1)(approach1) and Aminoadipate amino transferase (AADAT) (alternate approach 2) are targeted and our hypothesis is tested in genetically modified cell models,Glutaric aciduria type I patient cell lines, and knockout mouse models. We therefore,developed a Dhtkd1‐/‐/ Gcdh‐/‐ mouse model and studied its characteristics biochemically and clinically after giving high lysine (4.7% (w/w) or 235mg of Llysine in food) in diet. Our studies showed that DHTKD1 knockout was unable to rescue GA‐I phenotype in Dhtkd1+/+/ Gcdh‐/‐ mice as seen by the accumulated GA levels on GCMS measurement. Since our in vivo data strongly suggested that DHTDK1 is not a suitable drug target in GA‐I, we did not proceed with drug testing.Next, we evaluated the commercially available, patented AADAT inhibitor PF04859989 in GCDH‐deficient cells. Indeed, the inhibitor treatment significantly reduced GA accumulation in these cells. Overall this thesis suggests that,pharmacological inhibition of AADAT is a novel therapeutic strategy for GA‐I.

Impact of age at onset and newborn screening on outcome in organic acidurias

Article

Full-text available

Dec 2015

Background and aim: To describe current diagnostic and therapeutic strategies in organic acidurias (OADs) and to evaluate their impact on the disease course allowing harmonisation. Methods: Datasets of 567 OAD patients from the E-IMD registry were analysed. The sample includes patients with methylmalonic (MMA, n = 164), propionic (PA, n = 144) and isovaleric aciduria (IVA, n = 83), and glutaric aciduria type 1 (GA1, n = 176). Statistical analysis included description and recursive partitioning of diagnostic and therapeutic strategies, and odds ratios (OR) for health outcome parameters. For some analyses, symptomatic patients were divided into those presenting with first symptoms during (i.e. early onset, EO) or after the newborn period (i.e. late onset, LO). Results: Patients identified by newborn screening (NBS) had a significantly lower median age of diagnosis (8 days) compared to the LO group (363 days, p < 0.001], but not compared to the EO group. Of all OAD patients 71 % remained asymptomatic until day 8. Patients with cobalamin-nonresponsive MMA (MMA-Cbl(-)) and GA1 identified by NBS were less likely to have movement disorders than those diagnosed by selective screening (MMA-Cbl(-): 10 % versus 39 %, p = 0.002; GA1: 26 % versus 73 %, p < 0.001). For other OADs, the clinical benefit of NBS was less clear. Reported age-adjusted intake of natural protein and calories was significantly higher in LO patients than in EO patients reflecting different disease severities. Variable drug combinations, ranging from 12 in MMA-Cbl(-) to two in isovaleric aciduria, were used for maintenance treatment. The effects of specific metabolic treatment strategies on the health outcomes remain unclear because of the strong influences of age at onset (EO versus LO), diagnostic mode (NBS versus selective screening), and the various treatment combinations used. Conclusions: NBS is an effective intervention to reduce time until diagnosis especially for LO patients and to prevent irreversible cerebral damage in GA1 and MMA-Cbl(-). Huge diversity of therapeutic interventions hampers our understanding of optimal treatment.

Glutaric Aciduria Type 1: Comparison between Diffusional Kurtosis Imaging and Conventional MR Imaging

Article

Jul 2023
AM J NEURORADIOL

Background and purpose: Routine MR imaging has limited use in evaluating the severity of glutaric aciduria type 1. To better understand the mechanisms of brain injury in glutaric aciduria type 1, we explored the value of diffusional kurtosis imaging in detecting microstructural injury of the gray and white matter. Materials and methods: This study included 17 patients with glutaric aciduria type 1 and 17 healthy controls who underwent conventional MR imaging and diffusional kurtosis imaging. The diffusional kurtosis imaging metrics of the gray and white matter were measured. Then, the MR imaging scores and diffusional kurtosis imaging metrics of all ROIs were further correlated with the morbidity scores and Barry-Albright dystonia scores. Results: The MR imaging scores showed no significant relation to the morbidity and Barry-Albright dystonia scores. Compared with healthy controls, patients with glutaric aciduria type 1 showed higher kurtosis values in the basal ganglia, corona radiata, centrum semiovale, and temporal lobe (P < .05). The DTI metrics of the basal ganglia were higher than those of healthy controls (P < .05). The fractional anisotropy value of the temporal lobe and the mean diffusivity values of basal ganglia in glutaric aciduria type 1 were lower than those in the control group (P < .05). The diffusional kurtosis imaging metrics of the temporal lobe and basal ganglia were significantly correlated with the Barry-Albright dystonia scores. The mean kurtosis values of the anterior and posterior putamen and Barry-Albright dystonia scores were most relevant (r = 0.721, 0.730, respectively). The mean kurtosis values of the basal ganglia had the best diagnostic efficiency with area under the curve values of 0.837 for the temporal lobe, and the mean diffusivity values of the basal ganglia in glutaric aciduria type 1 were lower than those in the control group (P < .05). The diffusional kurtosis imaging metrics of the temporal lobe and basal ganglia were significantly correlated with the Barry-Albright dystonia scores. The mean kurtosis values of the anterior and posterior putamen and Barry-Albright dystonia scores were most relevant (r = 0.721, 0.730, respectively). The mean kurtosis values of the basal ganglia had the best diagnostic efficiency with area under the curve values of 0.837. Conclusions: Diffusional kurtosis imaging provides more comprehensive quantitative information regarding the gray and white matter micropathologic damage in glutaric aciduria type 1 than routine MR imaging scores.

Glutarik Asidemi Tip1 ve Beslenme Tedavisi

Chapter

Full-text available

Dec 2021

Neuromonitoring in Rare Disorders of Metabolism

Article

Full-text available

Dec 2021

Inborn errors of metabolism (IEM) are a unique class of genetic diseases due to mutations in genes involved in key metabolic pathways. The combined incidence of IEM has been estimated to be as high as 1:1000. Urea Cycle disorders (UCD), one class of IEM, can present with cerebral edema and represent a possible target to explore the utility of different neuromonitoring techniques during an hyperammonemic crisis. The last two decades have brought advances in the early identification and comprehensive management of UCD, including further understanding of neuroimaging patterns associated with neurocognitive function. Nonetheless, very important questions remain about the potential acute neurotoxic effects of hyperammonemia to better understand how to treat and prevent secondary brain injury. In this review, we describe existing neuromonitoring techniques that have been used in rare metabolic disorders to assess and allow amelioration of ongoing brain injury. Directions of future research should be focused on identifying new diagnostic approaches in the management of metabolic crises to optimize care and reduce long term morbidity and mortality in patients with IEM.

Glutaric Acidemia, Pathogenesis and Nutritional Therapy

Article

Full-text available

Dec 2021

Glutaric acidemia (GA) are heterogeneous, genetic diseases that present with specific catabolic deficiencies of amino acid or fatty acid metabolism. The disorders can be divided into type I and type II by the occurrence of different types of recessive mutations of autosomal, metabolically important genes. Patients of glutaric acidemia type I (GA-I) if not diagnosed very early in infanthood, experience irreversible neurological injury during an encephalopathic crisis in childhood. If diagnosed early the disorder can be treated successfully with a combined metabolic treatment course that includes early catabolic emergency treatment and long-term maintenance nutrition therapy. Glutaric acidemia type II (GA- II) patients can present clinically with hepatomegaly, non-ketotic hypoglycemia, metabolic acidosis, hypotonia, and in neonatal onset cardiomyopathy. Furthermore, it features adult-onset muscle-related symptoms, including weakness, fatigue, and myalgia. An early diagnosis is crucial, as both types can be managed by simple nutraceutical supplementation. This review discusses the pathogenesis of GA and its nutritional management practices, and aims to promote understanding and management of GA. We will provide a detailed summary of current clinical management strategies of the glutaric academia disorders and highlight issues of nutrition therapy principles in emergency settings and outline some specific cases.

Siblings with Glutaric Aciduria Type 1 with Atypical Phenotype with Novel Pathogenic Variant in GCDH Gene

Article

Full-text available

Jun 2021
J Pediatr Neurosci

Glutaric aciduria type 1 (GA1) is caused by a deficiency of the enzyme glutaryl CoA dehydrogenase. It generally presents with developmental delay, dystonia, and large head. We are reporting siblings of GA1, presenting with an atypical phenotype with novel pathogenic variant. Thirteen-year-old boy presented with global developmental delay and stiffness of limbs. Examination revealed normocephaly and generalized dystonia. MRI T2WI was suggestive of symmetrical posterior putaminal atrophy. Tandem mass spectroscopy (TMS) and urinary gas chromatography-mass spectrometry (GCMS) were normal. Genetic analysis revealed a novel pathogenic homozygous missense variant in GCDH gene. An 8-year-old girl younger sibling of above child also had developmental delay and dystonia, posterior putamen atrophy in the MRI of brain, and same pathogenic variant in GCDH gene. Parents screening showed heterozygous status in both parents of same pathogenic variant. Any child who presents with global developmental delay with dystonia even with normocephaly, isolated symmetrical posterior putamen changes, with normal TMS and GCMS, a possibility of glutaric aciduria type 1 has to be considered.

Low excretor glutaric aciduria type 1 of insidious onset with dystonia and atypical clinical features, a diagnostic dilemma

Article

Full-text available

Nov 2020

A 4‐year‐old girl was referred for reassessment of dyskinetic cerebral palsy. Initial investigations in her country of birth, India, had not yielded a diagnosis. MRI brain in infancy revealed bilateral putamen hyperintensity. She had generalized dyskinesia predominantly bulbar and limbs. Motor and speech development were most affected with preservation of cognitive development. There was no history of acute encephalopathic crisis or status dystonicus. Initial urine organic acids and amino acids and acylcarnitine profile (ACP) were normal. A dystonia genetic panel showed compound heterozygosity with a pathogenic variant and a variant of uncertain significance in the GCDH gene. The latter is hitherto undescribed and is indicative of a potential diagnosis of glutaric aciduria type 1 (alternatively glutaric acidemia type 1) (GA‐1), an autosomal recessive disorder of mitochondrial lysine/hydroxylysine and tryptophan metabolism. Repeat urine organic acids showed isolated slightly increased 3‐hydroxy glutarate excretion consistent with GA‐1 and characterizing the patient as a “low excretor,” a diagnostic sub‐group where diagnosis is more challenging but prognosis is similar. Repeat MRI Brain at age 4 showed volume loss and symmetric T2 hyperintensity in the posterior putamina bilaterally. This case highlights the diagnostic dilemma of GA‐1 where differing clinical courses, genetic variants, neuroradiological findings, and biochemical excretion patterns may lead to a later diagnosis. The presence of newborn screening for GA‐1 should not dull the clinician's suspicion of the possibility that GA‐1 may present with a complex movement disorder. Timely diagnosis and treatment is essential, as neurological sequelae are largely irreversible.

Organic acidurias: Major gaps, new challenges, and a yet unfulfilled promise

Article

Full-text available

May 2020

Organic acidurias (OADs) comprise a biochemically defined group of inherited metabolic diseases. Increasing awareness, reliable diagnostic work-up, newborn screening programs for some OADs, optimized neonatal and intensive care, and the development of evidence-based recommendations have improved neonatal survival and short-term outcome of affected individuals. However, chronic progression of organ dysfunction in an aging patient population cannot be reliably prevented with traditional therapeutic measures. Evidence is increasing that disease progression might be best explained by mitochondrial dysfunction. Previous studies have demonstrated that some toxic metabolites target mitochondrial proteins inducing synergistic bioenergetic impairment. Although these potentially reversible mechanisms help to understand the development of acute metabolic decompensations during catabolic state, they currently cannot completely explain disease progression with age. Recent studies identified unbalanced autophagy as a novel mechanism in the renal pathology of methylmalonic aciduria, resulting in impaired quality control of organelles, mitochondrial aging and, subsequently, progressive organ dysfunction. In addition, the discovery of post-translational short-chain lysine acylation of histones and mitochondrial enzymes helps to understand how intracellular key metabolites modulate gene expression and enzyme function. While acylation is considered an important mechanism for metabolic adaptation, the chronic accumulation of potential substrates of short-chain lysine acylation in inherited metabolic diseases might exert the opposite effect, in the long run. Recently, changed glutarylation patterns of mitochondrial proteins have been demonstrated in glutaric aciduria type 1. These new insights might bridge the gap between natural history and pathophysiology in OADs, and their exploitation for the development of targeted therapies seems promising.

What are the information needs of parents caring for a child with Glutaric aciduria type 1?

Article

Full-text available

Oct 2019
BMC Pediatr

Background: Newborn screening has enabled the early diagnosis of Glutaric aciduria type 1, with the possibility of improving neurological outcomes in affected children. Achieving those outcomes requires parents to effectively manage their child's condition by adherence to a strict dietary regime and responding to situations that may trigger decompensation. The specific information and support needs of this group of parents are unknown. Methods: A focus group with five parents was conducted to gain insights into the information that parents needed and the ways in which they accessed and used information to manage their child's condition. A topic guide was used to direct the discussion which was recorded and fully transcribed. All participants gave informed consent. Data were analysed using thematic analysis, a structured approach that contributes to transparency and validity of results while allowing the integration of predetermined and emerging themes. To ensure rigour, two researchers were involved in initial coding of data and key analytic decisions. Results: Two main themes were identified. 'Understanding the condition' explored parent's needs to understand the scientific complexity of the condition and to be aware of the worst case scenario associated with loss of metabolic control. 'Managing the condition' explained how parents co-ordinated and controlled the involvement of other carers and parents' need to be active partners in medical management to feel in control of the situation. Conclusions: The study highlights the importance of addressing parents' initial and ongoing informational needs so they can fulfil their role and protect their child from metabolic harm.

Acute lysine overload provokes marked striatum injury involving oxidative stress signaling pathways in glutaryl-CoA dehydrogenase deficient mice

Article

May 2019
NEUROCHEM INT

Glutaric acidemia type I (GA I) is a neurometabolic disorder of lysine (Lys) catabolism caused by glutaryl-CoA dehydrogenase (GCDH) deficiency. Patients are susceptible to develop acute striatum degeneration during catabolic stress situations whose underlying mechanisms are not fully established. Thus, in the present work we investigated the effects of a single intrastriatal Lys administration (1.5-4 μmol) to 30-day-old wild type (WT) and GCDH deficient (Gcdh-/-) mice on brain morphology, neuronal injury, astrocyte reactivity and myelin structure, as well as signaling pathways of redox homeostasis. We observed a marked vacuolation/edema in striatum and at higher doses also in cerebral cortex of Gcdh-/-, but not of WT mice. Lys also provoked a reduction of NeuN and synaptophysin, as well as an increase of astrocytic GFAP, in the striatum of Gcdh-/- mice, indicating neuronal loss and astrocyte reactivity. Furthermore, we verified an increase of Nrf2 and NF-κB expression in the nuclear fraction, and a decrease of heme oxygenase-1 (HO-1) content in the striatum of Lys-injected Gcdh-/- mice, implying disruption of redox homeostasis. Finally, it was found that Lys provoked alterations of myelin structure reflected by decreased myelin basic protein (MBP) in the cerebral cortex of Gcdh-/- mice. Taken together, the present data demonstrate neuronal loss, gliosis, altered redox homeostasis and demyelination caused by acute Lys overload in brain of Gcdh-/- mice, supporting the hypothesis that increased brain concentrations of glutaric and 3-hydroxyglutaric acids formed from Lys may be responsible for the acute brain degeneration observed in GA I patients during episodes of metabolic decompensation.

Long Lasting High Lysine Diet Aggravates White Matter Injury in Glutaryl-CoA Dehydrogenase Deficient (Gcdh−/−) Mice

Article

Full-text available

Jan 2019
MOL NEUROBIOL

Glutaric acidemia type I (GA-I) is a neurometabolic disease caused by deficient activity of glutaryl-CoA dehydrogenase (GCDH) that results in accumulation of metabolites derived from lysine (Lys), hydroxylysine, and tryptophan catabolism. GA-I patients typically develop encephalopatic crises with striatal degeneration and progressive white matter defects. However, late onset patients as well as Gcdh−/− mice only suffer diffuse myelinopathy, suggesting that neuronal death and white matter defects are different pathophysiological events. To test this hypothesis, striatal myelin was studied in Gcdh−/− mice fed from 30 days of age during up to 60 days with a diet containing normal or moderately increased amounts of Lys (2.8%), which ensure sustained elevated levels of GA-I metabolites. Gcdh−/− mice fed with 2.8% Lys diet showed a significant decrease in striatal-myelinated areas and progressive vacuolation of white matter tracts, as compared with animals fed with normal diet. Myelin pathology increased with the time of exposure to high Lys diet and was also detected in 90-day old Gcdh−/− mice fed with normal diet, suggesting that dietary Lys accelerated the undergoing white matter damage. Gcdh−/− mice fed with 2.8% Lys diet also showed increased GRP78/BiP immunoreactivity in oligodendrocytes and neurons, denoting ER stress. However, the striatal and cortical neuronal density was unchanged with respect to normal diet. Thus, myelin damage seen in Gcdh−/− mice fed with 2.8% Lys seems to be mediated by a long-term increased levels of GA-I metabolites having deleterious effects in myelinating oligodendrocytes over neurons.

Induction of Neuroinflammatory Response and Histopathological Alterations Caused by Quinolinic Acid Administration in the Striatum of Glutaryl-CoA Dehydrogenase Deficient Mice

Article

Full-text available

Apr 2018
NEUROTOX RES

Glutaric acidemia type I (GA I) is an inherited neurometabolic disorder caused by a severe deficiency of the mitochondrial glutaryl-CoA dehydrogenase (GCDH) activity. Patients usually present progressive cortical leukodystrophy and commonly develop acute bilateral striatal degeneration mainly during infections that markedly worse their prognosis. A role for quinolinic acid (QA), a key metabolite of the kynurenine pathway, which is activated during inflammatory processes, on the pathogenesis of the acute striatum degeneration occurring in GA I was proposed but so far has not yet been evaluated. Therefore, we investigated whether an acute intrastriatal administration of quinolinic acid (QA) could induce histopathological alterations in the striatum of 30-day-old wild-type (WT) and GCDH knockout (Gcdh−/−) mice. Striatum morphology was evaluated by hematoxylin and eosin, T lymphocyte presence (CD3), and glial activation (GFAP and S100β) by immunohistochemistry and 3-nitrotyrosine (YNO2) by immunofluorescence. QA provoked extensive vacuolation, edema, and especially lymphocyte infiltration in the striatum of Gcdh−/−. QA also enhanced CD3 staining and the number of YNO2 positive cells in Gcdh−/− mice, relatively to WT, indicating T lymphocyte infiltration and nitrosative stress, respectively. QA-treated WT mice also showed an increase of GFAP and S100β staining, which is indicative of reactive astrogliosis, whereas the levels of these astrocytic proteins were not changed in Gcdh−/− QA-injected mice. The present data indicate that QA significantly contributes to the histopathological changes observed in the striatum of Gcdh−/− mice.

Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of long-term neurotoxicity

Article

Full-text available

Dec 2017
ORPHANET J RARE DIS

Background Without neonatal initiation of treatment, 80–90% of patients with glutaric aciduria type 1 (GA1) develop striatal injury during the first six years of life resulting in a complex, predominantly dystonic movement disorder. Onset of motor symptoms may be acute following encephalopathic crisis or insidious without apparent crisis. Additionally, so-called late-onset GA1 has been described in single patients diagnosed after the age of 6 years. With the aim of better characterizing and understanding late-onset GA1 we analyzed clinical findings, biochemical phenotype, and MRI changes of eight late-onset patients and compared these to eight control patients over the age of 6 years with early diagnosis and start of treatment. Results No late-onset or control patient had either dystonia or striatal lesions on MRI. All late-onset (8/8) patients were high excretors, but only four of eight control patients. Two of eight late-onset patients were diagnosed after the age of 60 years, presenting with dementia, tremor, and epilepsy, while six were diagnosed before the age of 30 years: Three were asymptomatic mothers identified by following a positive screening result in their newborns and three had non-specific general symptoms, one with additional mild neurological deficits. Frontotemporal hypoplasia and white matter changes were present in all eight and subependymal lesions in six late-onset patients. At comparable age a greater proportion of late-onset patients had (non-specific) clinical symptoms and possibly subependymal nodules compared to control patients, in particular in comparison to the four clinically and MR-wise asymptomatic low-excreting control patients. Conclusions While clinical findings are non-specific, frontotemporal hypoplasia and subependymal nodules are characteristic MRI findings of late-onset GA1 and should trigger diagnostic investigation for this rare disease. Apart from their apparent non-susceptibility for striatal injury despite lack of treatment, patients with late-onset GA1 are not categorically different from early treated control patients. Differences between late-onset patients and early treated control patients most likely reflect greater cumulative neurotoxicity in individuals remaining undiagnosed and untreated for years, even decades as well as the higher long-term risk of high excretors for intracerebral accumulation of neurotoxic metabolites compared to low excretors. Electronic supplementary material The online version of this article (doi:10.1186/s13023-017-0612-6) contains supplementary material, which is available to authorized users.

Glutaric Acidemia Type 1: A Case of Infantile Stroke

Article

Full-text available

Apr 2017

Background: Glutaric acidemia Type 1 (GA-1) is an autosomal recessively inherited metabolic disorder which is associated with GCDH gene mutations which alters the glutaryl-CoA dehydrogenase, an enzyme playing role in the catabolic pathways of the amino acids lysine, hydroxylysine, and tryptophan. Clinical findings are often encephalopathic crises, dystonia, and extrapyramidal symptoms. Case Report: A 9-month-old male infant referred to our department with focal tonic-clonic seizures during rotavirus infection and acute infarcts in MRI. Clinical manifestation, MRI findings, and metabolic investigations directed thoughts towards GA-I. Molecular genetic testing revealed a homozygous c.572T>C (p.M191T) mutation in GCDH gene which confirmed the diagnosis. Application of protein restricted diet, carnitine and riboflavin supplementations prevented the progression of Magnetic Resonance Imaging (MRI) and clinical pathologic findings during the 1 year of follow-up period. Conclusion: This case is of great importance since it shows possibility of infantile stroke in GA-1, significance of early diagnosis and phenotypic variability of disease.

A rare inborn error of metabolism masquerading as meningitis

Article

Full-text available

Jan 2016

We hereby describe a 7-month-old female baby, born to first-degree cousins, who was initially diagnosed as meningitis based on the features of seizures and dystonia with fever. Detailed review of brain imaging and high urinary 3-hydroxy (3-OH) glutaric acid level confirmed the diagnosis of glutaric aciduria Type I. There is a high probability of these cases getting misdiagnosed as meningitis. Persistent rigidity and dystonia precipitated by a febrile illness and the typical brain imaging picture are clues to the diagnosis of glutaric aciduria Type I, which can be confirmed by raised 3-OH glutaric acid level in body fluids.

Astrocyte Dysfunction in Developmental Neurometabolic Diseases

Chapter

Full-text available

Oct 2016
ADV EXP MED BIOL

Astrocytes play crucial roles in maintaining brain homeostasis and in orchestrating neural development, all through tightly coordinated steps that cooperate to maintain the balance needed for normal development. Here, we review the alterations in astrocyte functions that contribute to a variety of developmental neurometabolic disorders and provide additional data on the predominant role of astrocyte dysfunction in the neurometabolic neurodegenerative disease glutaric acidemia type I. Finally, we describe some of the therapeutical approaches directed to neurometabolic diseases and discuss if astrocytes can be possible therapeutic targets for treating these disorders.

Role of Dietary Amino Acids on Parkinson's Disease

Chapter

Full-text available

Jul 2016

Parkinson disease (PD) is a progressive neurological disorder which mainly affects the motor system of Central Nervous System (CNS). Oxidative stress implicates major pathogenesis of neurological disorders like PD. The nutrients and dietary supplements play an important role in the health of an individual and there are several lines of evidences suggesting the role of dietary factors in the development or pathogenesis of PD. The amino acids supplement has been found to reduce symptoms, as they act as the precursors of neurotransmitters which in turn may extenuate the mental disorders. The biosynthesis of amino acids in thebrain is regulated by the concentration of amino acids in plasma. Amino acids are also considerable entities, as they themselves or peptides consisting of them have profound antioxidant activities e.g., glycine and glutathione. The dietary constituents have an effect on the transport of amino acids across Blood Brain Barrier (BBB) thus indirectly modulating the therapeutic value of amino acids. The intricate biochemical and molecular machinery contributing to the neurological disorders is still unknown. Here we discuss the prophylactic role of dietary amino acids against PD.

Neurological Disorders Associated with Striatal Lesions: Classification and Diagnostic Approach

Article

Full-text available

Apr 2016
CURR NEUROL NEUROSCI

Neostriatal abnormalities can be observed in a very large number of neurological conditions clinically dominated by the presence of movement disorders. The neuroradiological picture in some cases has been described as “bilateral striatal necrosis” (BSN). BSN represents a condition histo-pathologically defined by the involvement of the neostriata and characterized by initial swelling of putamina and caudates followed by degeneration and cellular necrosis. After the first description in 1975, numerous acquired and hereditary conditions have been associated with the presence of BSN. At the same time, a large number of disorders involving neostriata have been described as BSN, in some cases irrespective of the presence of signs of cavitation on MRI. As a consequence, the etiological spectrum and the nosographic boundaries of the syndrome have progressively become less clear. In this study, we review the clinical and radiological features of the conditions associated with MRI evidence of bilateral striatal lesions. Based on MRI findings, we have distinguished two groups of disorders: BSN and other neostriatal lesions (SL). This distinction is extremely helpful in narrowing the differential diagnosis to a small group of known conditions. The clinical picture and complementary exams will finally lead to the diagnosis. We provide an update on the etiological spectrum of BSN and propose a diagnostic flowchart for clinicians.

2015 update on triple therapy for pyridoxine-dependent epilepsy

Article

Full-text available

May 2015

& Objectives: Of patients with pyridoxine-dependent epilepsy (PDE) due to ATQ deficiency, 75% suffer intellectual disability despite adequate seizure control with high dose pyridoxine. We aimed to assess the safety and efficacy of two novel therapeutic strategies to reduce accumulation of toxic intermediates in this cerebral lysine degradation defect. Methods: In two open-label observational studies, seven children with confirmed ATQ deficiency were started on dietary lysine restriction with regular nutritional monitoring, and outcome evaluation pipecolic acid, AASA levels in body fluids; development/cognition via age-appropriate tests and parental observations; epilepsy). Subsequently additional arginine supplementation was initiated to reduce cerebral lysine flux (cation transporter competitive inhibition).. Results: Lysine-restriction was well tolerated and diet is safe, resulted in reduction of lysine intermediates in all body fluids in all patients (up to 80% reduction AASA in cerebrospinal fluid), with beneficial effects on seizure control and psychomotor development. Additional arginine fortification resulted in normalization of biomarkers and dramatic improvement of psychomotor development. Discussion: Triple therapy is effective, especially if implemented early; studies for PDE newborn screening have been initiated. For dissemination and evidence generation, our PDE Consortium published Recommendations, developed a Digital Diet App and established a RedCap study database ( www.pdeonline.org ).

Morphological evidence of the protective effects of a synthetic chalcone against the striatal myelin damage induced by glutaric acid

Article

Apr 2023
INT J DEV NEUROSCI

Ultrastructural features of striatal white matter and cells in an in vivo model of glutaric acidemia type I created by intracerebral injection of glutaric acid (GA) were analyzed by transmission electron microscopy and immunohistochemistry. To test if the white matter damage observed in this model could be prevented, we administered the synthetic chemopreventive molecule CH38 ((E)-3-(4-methylthiophenyl)-1-phenyl-2-propen-1-one) to newborn rats, previous to an intracerebroventricular injection of GA. The study was done when striatal myelination was incipient and when it was already established (at 12 and 45 days post-injection [DPI], respectively). Results obtained indicate that that the ultrastructure of astrocytes and neurons did not appear significantly affected by the GA bolus. Instead, in oligodendrocytes, the most prominent GA-dependent injury defects included endoplasmic reticulum (ER) stress and nuclear envelope swelling at 12 DPI. Altered and reduced immunoreactivities against heavy neurofilament (NF), proteolipid protein (PLP), and myelin-associated glycoprotein (MAG) together with axonal bundle fragmentation and decreased myelin were also found at both ages analyzed. CH38 by itself did not affect striatal cells or axonal packages. However, the group of rats that received CH38 before GA did not show evidence neither of ER stress nor nuclear envelope dilation in oligodendrocytes, and axonal bundles appeared less fragmented. In this group, labeling of NF and PLP was similar to the controls. These results suggest that the CH38 molecule is a candidate drug to prevent or decrease the neural damage elicited by a pathological increase of GA in the brain. Optimization of the treatments and identification of the mechanisms underlying CH38 protective effects will open new therapeutic windows to protect myelin, which is a vulnerable target of numerous nervous system diseases.

How guideline development has informed clinical research for organic acidurias (et vice versa)

Article

Jan 2023

Organic acidurias, such as glutaric aciduria type 1, methylmalonic, and propionic aciduria (GA1, MMA, PA) are a prominent group of inherited metabolic diseases involving accumulation of eponymous metabolites causing endogenous intoxication. For all three conditions guidelines for diagnosis and management have been developed and revised over the last years, resulting in three revisions for GA1 and one revision for MMA/PA. The process of clinical guideline development in rare metabolic disorders is challenged by the scarcity and limited quality of evidence available. The body of literature is often fragmentary and where information is present, it is usually derived from small sample sizes. Therefore, the development of guidelines for GA1 and MMA/PA was initially confronted with a poor evidence foundation that hindered formulation of concrete recommendations in certain contexts, triggering specific research projects and initiation of longitudinal, prospective observational studies using patient registries. Reversely, these observational studies contributed to evaluate the value of newborn screening, phenotypic diversities, and treatment effects, thus significantly improving the quality of evidence and directly influencing formulation and evidence levels of guideline recommendations. Here, we present insights into interactions between guideline development and (pre‐)clinical research for GA1 and MMA/PA, and demonstrate how guidelines gradually improved from revision to revision. We describe how clinical studies help to unravel the relative impact of therapeutic interventions on outcome and conclude that despite new and better quality of research data over the last decades, significant shortcomings of evidence regarding prognosis and treatment remain. It appears that development of clinical guidelines can directly help to guide research, and vice versa. This article is protected by copyright. All rights reserved.

Nutrition Management of Glutaric Acidemia Type 1

Chapter

Jun 2022

Laurie E. Bernstein

Glutaric acidemia type-1 (GA-1) is an autosomal recessive disorder of lysine, hydroxylysine, and tryptophan metabolism.A defect of glutaryl-CoA dehydrogenase results in the accumulation of 3-hydroxyglutaric acid and glutaric acid.Nutrition management of GA-1 consists of restricting lysine and tryptophan, supplementing L-carnitine and providing sufficient energy to prevent catabolism.Patients with GA-1 have a particularly high risk of permanent cerebral damage from a metabolic crisis. Glutaric acidemia type-1 (GA-1) is an autosomal recessive disorder of lysine, hydroxylysine, and tryptophan metabolism. A defect of glutaryl-CoA dehydrogenase results in the accumulation of 3-hydroxyglutaric acid and glutaric acid. Nutrition management of GA-1 consists of restricting lysine and tryptophan, supplementing L-carnitine and providing sufficient energy to prevent catabolism. Patients with GA-1 have a particularly high risk of permanent cerebral damage from a metabolic crisis.

Mitochondrial dysfunction in inborn errors of metabolism

Chapter

Jan 2021

Inborn errors of metabolism (IEM) result in metabolic blockage and accumulation of substrate and metabolites, with subsequent shortage of metabolic products. IEM are responsible for developmental deficiencies in childhood and also death of affected patients. The pathophysiological mechanisms of most of these diseases are still unclear, resulting in poor or unsatisfactory therapies. Mitochondrial dysfunction has been consistently implicated as a key factor in the pathophysiology of many IEM. Even discrete disruptions of mitochondrial homeostasis may lead to cellular damage and ultimately cell death. Possible mechanisms in IEM pathology include energy metabolism disturbance, calcium dyshomeostasis, redox imbalance, and alterations in mitochondrial dynamics. Many of these events may act together and even synergistically to exacerbate the disabilities seen in patients affected by different IEM. We herein summarize evidence of mitochondrial involvement in the pathophysiology of IEM, spanning from primary mitochondrial deficits to cell damage elicited by secondary mitochondrial involvement.

Evaluation of the Clinical, Biochemical, Neurological, and Genetic Presentations of Glutaric Aciduria Type 1 in Patients From China

Article

Full-text available

Jul 2021

Purpose To characterize the phenotypic and genotypic variations associated with Glutaric aciduria type 1 (GA1) in Chinese patients. Methods We analyzed the clinical, neuroradiological, biochemical, and genetic information from 101 GA1 patients in mainland China. Results 20 patients were diagnosed by newborn screening and the remaining 81 cases were identified following clinical intervention. Macrocephaly was the most common presentation, followed by movement disorders and seizures. A total of 59 patients were evaluated by brain MRI and 58 patients presented with abnormalities, with widening of the sylvian fissures being the most common symptom. The concentration of glutarylcarnitine in the blood, glutarylcarnitine/capryloylcarnitine ratio, and urine levels of glutaric acid were increased in GA1 patients and were shown to decrease following intervention. A total of 88 patient samples were available for genotyping and 74 variants within the GCDH gene, including 23 novel variants, were identified. The most common variant was c.1244-2A > C (18.4%) and there were no significant differences in the biochemical or clinical phenotypes described for patients with the four most common variants: c.1244-2A > C, c.1064G > A, c.533G > A, and c.1147C > T. Patients identified by newborn screening had better outcomes than clinical patients. Conclusion Our findings expand the spectrum of phenotypes and genotypes for GA1 in Chinese populations and suggest that an expanded newborn screening program using tandem mass spectrometry may facilitate the early diagnosis and treatment of this disease, improving clinical outcomes for patients in China.

Metabolic Crises

Chapter

Mar 2021

Kevin A. Strauss

Intermediary metabolism comprises the set of chemical conversions that provides energy for vital activities and assimilates nutrients into tissues; it includes anabolic (energy-consuming syntheses) and catabolic (energy-generating degradation) processes. Catabolic pathways originate with macromolecular aggregates (glycogen, triacylglycerol, and protein), channel substrates into mitochondrial energy production, and adapt to biological stress under autonomic and endocrine control. “Inborn errors of metabolism” (IEMs) encompass a diverse spectrum of heritable monogenic conditions that interfere with one or more intermediary chemical reactions. Various physiological threats (e.g., infection, dehydration, perinatal transition) entrain catabolism of protein and energy reserves and, in a child with an IEM, can precipitate acute “metabolic crisis” characterized by deficiency of one or more vital fuels (e.g., glucose, β-hydroxybutyrate) and/or accumulation of cytotoxic proximal substrates (e.g., ammonia, leucine, acyl-CoA thioesters). Metabolic disorders present in nonspecific ways that overlap with more common disease states such as sepsis, severe gastroenteritis, and child abuse; their timely diagnosis is, therefore, predicated on a high index of suspicion and informed interpretation of laboratory data. Effective management depends on understanding metabolic adaptations to stress and clinical variables that affect glucose metabolism, acid-base homeostasis, and protein turnover. The principal aims of treatment are to provide energy from exogenous sources (e.g., dextrose) and reduce cytotoxins in the circulation and vital organs; the latter is achieved by shifting fuel metabolism toward an anabolic state and, when applicable, implementing active clearance strategies (e.g., chemical conjugation, hemodialysis). Comorbidities such as cerebral edema, acute liver failure, coagulopathy, cardiomyopathy, and rhabdomyolysis often accompany metabolic crises and are major determinants of clinical outcome.

Clinico-Radiological Correlation in 26 Egyptian Children with Glutaric Acidemia Type 1

Article

Full-text available

Jan 2021

Background Glutaric acidemia type 1 (GA1) is an inherited neurometabolic disease with significant morbidity. However, neuro-radiological correlation is not completely understood. Objective The study aimed to characterize the neuroimaging findings and their association with neurological phenotype in GA1 children. Methods Twenty-six Egyptian children (median age ¼ 12 months) diagnosed with GA1 underwent clinical evaluation and brain magnetic resonance imaging (MRI). We objectively assessed the severity of neurological phenotype at the time of MRI using movement disorder (MD) and morbidity scores. Evaluation of brain MRI abnormalities followed a systematic and region-specific scoring approach. Brain MRI findings and scores were correlated with MD and morbidity scores, disease onset, and presence of seizures. Results Fifteen (57.7%) cases had insidious onset, eight (30.8%) manifested acute onset, whereas three (11.5%) were asymptomatic. Ten (38.5%) cases had seizures, five of which had no acute encephalopathic crisis. Putamen and caudate abnormalities (found in all acute onset, 93.3 and 73.3% of insidious onset, and one of three asymptomatic cases) were significantly related to MD (p ¼ 0.007 and 0.013) and morbidity (p ¼ 0.005 and 0.003) scores. Globus pallidus abnormalities (50% of acute onset, 46.7% of insidious onset, and one of three of asymptomatic cases) were significantly associated with morbidity score (p ¼ 0.023). Other MRI brain abnormalities as well as gray and white matter score showed no significant association with neurological phenotype. Younger age at onset, acute onset, and seizures were significantly associated with worse neurological manifestations. Conclusion Patients with GA1 manifest characteristic and region-specific brain MRI abnormalities, but only striatal affection appears to correlate with neurological phenotype Keywords ► glutaric acidemia type 1 ► movement disorder ► magnetic resonance imaging ► seizures ► striatal injury

Pharmacologic Modulation of Brain Metabolism by Valproic Acid can Induce a Neuroprotective Environment

Article

Nov 2020

Objective: Traumatic brain injury (TBI) is a leading cause of trauma-related morbidity and mortality. Valproic acid (VPA) has been shown to attenuate brain lesion size and swelling within the first few hours following TBI. As injured neurons are sensitive to metabolic changes, we hypothesized that VPA treatment would alter the metabolic profile in the perilesional brain tissues to create a neuroprotective environment. Methods: We subjected swine to combined TBI (12-mm cortical impact) and hemorrhagic shock (40% blood volume loss, and 2-hours of hypotension) and randomized them to two groups (n=5/group): (i) normal saline (NS; 3×hemorrhage volume); (ii) NS + VPA (NS; 3×hemorrhage volume, VPA; 150mg/kg). After six hours, brains were harvested and 100mg of the perilesional tissue was used for metabolite extraction. Samples were analyzed using Reversed-Phase Liquid Chromatography-Mass Spectrometry (RPLC-MS) in positive and negative ion modes and data analyzed using Metaboanalyst software. Results: In untargeted RPLC-MS analysis, we detected 3750 and 1955 metabolites in positive and negative ion modes, respectively. There were no significantly different metabolites in positive ion mode; however, 167 metabolite features were significantly different (p-values < 0.05) in the negative ion mode, which included VPA derivates. Pathway analysis showed that several pathways were affected in the treatment group, including the biosynthesis of unsaturated fatty acids (p = 0.001). Targeted amino acid analysis on Glycolysis/TCA cycle revealed that VPA treatment significantly decreased the levels of the excitotoxic amino acid serine (p=0.001). Conclusion: VPA can be detected in perilesional tissues in its metabolized form. It also induces metabolic changes in the brains within the first few hours following TBI to create a neuroprotective environment. Level of evidence: not applicable (pre-clinical study).

Disruption of mitochondrial functions and oxidative stress contribute to neurologic dysfunction in organic acidurias

Article

Oct 2020

Organic acidurias (OADs) are inherited disorders of amino acid metabolism biochemically characterized by accumulation of short-chain carboxylic acids in tissues and biological fluids of the affected patients and clinically by predominant neurological manifestations. Some of these disorders are amenable to treatment, which significantly decreases mortality and morbidity, but it is still ineffective to prevent long-term neurologic and systemic complications. Although pathogenesis of OADs is still poorly established, recent human and animal data, such as lactic acidosis, mitochondrial morphological alterations, decreased activities of respiratory chain complexes and altered parameters of oxidative stress, found in tissues from patients and from genetic mice models with these diseases indicate that disruption of critical mitochondrial functions and oxidative stress play an important role in their pathophysiology. Furthermore, organic acids that accumulate in the most prevalent OADs were shown to compromise bioenergetics, by decreasing ATP synthesis, mitochondrial membrane potential, reducing equivalent content and calcium retention capacity, besides inducing mitochondrial swelling, reactive oxygen and nitrogen species generation and apoptosis. It is therefore presumed that secondary mitochondrial dysfunction and oxidative stress caused by major metabolites accumulating in OADs contribute to tissue damage in these pathologies.

Glutaric aciduria type 1: a review of phenotypic and genetic characteristics

Article

Jun 2019

Ali Zada

Glutaric aciduria type I (GA1) is an inherited metabolic disorder in which excessive levels of the amino acids lysine, hydroxylysine, and tryptophan accumulate in the body as a result of defective glutaryl-CoA dehydrogenase (GCDH) enzyme activity. Excessive metabolites are toxic that can cause damage to the brain, particularly due to the occurrence of basal ganglia and intellectual disability. Missense, splicing, and other deletion mutations in GCDH gene lead to the deficiency of the enzyme activity and are known to cause GA1. The severity of GA1 along with its neurological manifestations and clinical outcome is dependent upon the age at onset and therefore, early definitive diagnosis of GA1 becomes essential. GA1 occurs in approximately 1 of every 30,000-40,000 individuals worldwide that may reach up to 1 in 300 newborn babies in the Amish and Canadian communities. Owing to very high consanguinity rates in Saudi Arabia, it is presumed to be much more common in the Kingdom and is one of the initial disorders that were included in the country's neonatal screening program. In the current study, we have reviewed clinical manifestations, diagnosis, updated management, and mutation spectrum in GA1 with an example of one of our patients with GA1, and highlighted the importance of multipara-metric strategy in the early diagnosis and management of the disease. [JBCGenetics 2019; 2(1.000): 40-53]

Pathogenesis of brain damage in glutaric acidemia type I: Lessons from the genetic mice model

Article

May 2019

Glutaric acidemia type I (GA I) is an inherited neurometabolic disease caused by deficient activity of the mitochondrial enzyme glutaryl-CoA dehydrogenase (GCDH), resulting in predominant accumulation of glutaric and 3-hydroxyglutaric acids derived from lysine (Lys), hydroxylysine, and tryptophan catabolism. GA I patients usually present progressive cortical leukodystrophy and frequently develop acute striatal degeneration during encephalopathic crises during the first three years of life. The pathophysiology of the neurodegeneration observed in GA I is still partly known, although the development of the genetic mice model of GA I (Gcdh-/-) has contributed to clarify potential underlying mechanisms involved in brain damage in this disease. In this review we will summarize the knowledge acquired from studies using this animal model indicating that disruption of redox homeostasis, glutamatergic neurotransmission and bioenergetics, as well as vascular alterations, blood-brain barrier breakage and altered myelination underlie the cortical and striatum abnormalities and white matter changes observed in GA I patients. Elucidation of these pathomechanisms potentially offers new standpoints for the development of novel therapeutic strategies for this disease.

Newborn screening: A disease-changing intervention for glutaric aciduria type 1

Article

Apr 2018

Objective: Untreated individuals with glutaric aciduria type 1 (GA1) commonly present with a complex, predominantly dystonic movement disorder (MD) following acute or insidious onset striatal damage. Implementation of GA1 into newborn screening (NBS) programmes has improved the short‐term outcome. It remains unclear, however, whether NBS changes the long‐term outcome and which variables are predictive. Methods: This prospective, observational, multi‐centre study includes 87 patients identified by NBS, four patients missed by NBS and three women with GA1 identified by positive NBS results of their unaffected children. Results: The study population comprises 98.3% of individuals with GA1 identified by NBS in Germany between 1999‐2016. Overall, cumulative sensitivity of NBS is 95.6%, but is lower (84%) for patients with low excretor phenotype. Neurologic outcome of patients missed by NBS is as poor as in the pre‐NBS era, while the clinical phenotype of diagnosed patients depends on the quality of therapeutic interventions rather than non‐interventional variables: Presymptomatic start of treatment according to current guideline recommendations clearly improves the neurologic outcome (MD: 7% of patients), while delayed emergency treatment results in acute onset MD (100%), and deviations from maintenance treatment increase the risk of insidious onset MD (50%). Independent of the neurologic phenotype, kidney function tends to decline with age, a non‐neurologic manifestation not predicted by any variable included in this study. Interpretation: NBS is a beneficial, disease‐changing intervention for GA1. However, improved neurologic outcome critically depends on adherence to recommended therapy while kidney dysfunction does not appear to be impacted by recommended therapy. This article is protected by copyright. All rights reserved.

Arachnoid Cysts in Glutaric Aciduria Type I (GA-I)

Chapter

Jan 2018

Impairment of astrocytic glutaminolysis in glutaric aciduria type I

Article

Nov 2017

Glutaric aciduria type I is a rare, autosomal recessive, inherited defect of glutaryl-CoA dehydrogenase. Deficiency of this protein in L-lysine degradation leads to the characteristic accumulation of nontoxic glutarylcarnitine and neurotoxic glutaric acid (GA), glutaryl-CoA, and 3-hydroxyglutaric acid. Untreated patients develop bilateral lesions of basal ganglia resulting in a complex movement disorder with predominant dystonia in infancy and early childhood. The current pathomechanistic concept strongly focuses on imbalanced neuronal energy metabolism due to accumulating metabolites, whereas little is known about the pathomechanistic role of astrocytes, which are thought to be in constant metabolic crosstalk with neurons. We found that glutaric acid (GA) causes astrocytic cell death under starvation cell culture conditions, i.e. low glucose, without glutamine and fetal calf serum. Glutamine completely abolished GA-induced toxicity, suggesting involvement of glutaminolysis. Increasing dependence on glutaminolysis by chemical induction of hypoxia signaling-potentiated GA-induced toxicity. We further show that GA disturbs glutamine degradation by specifically inhibiting glutamate dehydrogenase. Summarizing our study shows that pathologically relevant concentrations of GA block an important step in the metabolic crosstalk between neurons and astrocytes, ultimately leading to astrocytic cell death.

Experiences during newborn screening for glutaric aciduria type 1: Diagnosis, treatment, genotype, phenotype, and outcomes

Article

Full-text available

Mar 2017

Background: Glutaric aciduria type 1 (GA-1) is an organic acidemia with potentially severe neurological sequelae. In Taiwan, newborn screening (NBS) for GA-1 began in 2001, but large-scale reporting is lacking. This study describes Taiwan's largest newborn screening population to date. Methods: Between 2001 and 2015, 1,490,636 newborns were screened for GA-1. Confirmatory examinations included the carnitine loading test. Confirmed patients were treated with a low lysine diet, carnitine, and high-energy intake during illness. Clinical, laboratory, and neuroimaging data were analyzed. Results: Fourteen newborns were diagnosed with GA-1 (incidence: 1/106,474). C5DC concentration was clearly increased after carnitine loading in the affected newborns, but not in false-positive newborns (p = 0.004), indicating that this test is useful as an adjuvant diagnostic method. Eleven patients followed in our hospital were enrolled, namely nine NBS patients and two patients diagnosed clinically. IVS10-2A>C was the most common mutation. Two novel mutations (T36fs and N291K) were identified. Pendular nystagmus was found in two pediatric GA-1 patients. The corresponding pathology was optic atrophy in one patient, but remained undetermined in the other patient. The frequency of encephalopathic crisis decreased substantially following NBS. Among patients diagnosed by NBS, cognitive functioning was better among patients with good compliance than patients with poor compliance (p = 0.03). Abnormalities were detected by brain MRI including diffusion-weighted imaging and apparent diffusion coefficient maps; these affected various brain regions at different stages of the disease. Basal ganglion injuries occurred after an encephalopathic crisis. White matter disease was prevalent among older patients, either with or without an encephalopathic crisis. Conclusion: Early diagnosis by newborn screening followed by full compliance with treatment guidelines is important to a good outcome.

Cerebral Organic Acid Disorders and Other Disorders of Lysine Catabolism

Chapter

Jan 2016

Species-, organ- and organelle-specific differences in the enzymes involved in the catabolism of lysine, hydroxylysine and tryptophan are not yet completely unravelled, and this synopsis is therefore partially hypothetical as far as human metabolism is concerned. Lysine, hydroxylysine and tryptophan are thought to be degraded within the mitochondrion, initially via separate pathways, which converge into a common pathway at the point of 2-aminoadipic-6-semialdehyde (hydroxylysine catabolism and pipecolic acid pathway of lysine catabolism) and at the point of 2-oxoadipic acid (tryptophan catabolism; ◘ Fig. 22.1).

Modulatory Effects of Dietary Amino Acids on Neurodegenerative Diseases

Chapter

Full-text available

Sep 2016

Proteins are playing a vital role in maintaining the cellular integrity and function, as well as for brain cells. Protein intake and supplementation of individual amino acids can affect the brain functioning and mental health, and many of the neurotransmitters in the brain are made from amino acids. The amino acid supplementation has been found to reduce symptoms, as they are converted into neurotransmitters which in turn extenuate the mental disorders. The biosynthesis of amino acids in the brain is regulated by the concentration of amino acids in plasma. The brain diseases such as depression, bipolar disorder, schizophrenia, obsessive-compulsive disorder (OCD), and Alzheimer’s (AD), Parkinson’s (PD), and Huntington’s diseases (HD) are the most common mental disorders that are currently widespread in numerous countries. The intricate biochemical and molecular machinery contributing to the neurological disorders is still unknown, and in this chapter, we revealed the involvement of dietary amino acids on neurological diseases.

Experimental evidence that overexpression of NR2B glutamate receptor subunit is associated with brain vacuolation in adult glutaryl-CoA dehydrogenase deficient mice: A potential role for glutamatergic-induced excitotoxicity in GA I neuropathology

Article

Oct 2015

Glutaric aciduria type I (GA I) is biochemically characterized by accumulation of glutaric and 3-hydroxyglutaric acids in body fluids and tissues, particularly in the brain. Affected patients show progressive cortical leukoencephalopathy and chronic degeneration of the basal ganglia whose pathogenesis is still unclear. In the present work we investigated parameters of bioenergetics and redox homeostasis in various cerebral structures (cerebral cortex, striatum and hippocampus) and heart of adult wild type (Gcdh(+/+)) and glutaryl-CoA dehydrogenase deficient knockout (Gcdh(-/-)) mice fed a baseline chow. Oxidative stress parameters were also measured after acute lysine overload. Finally, mRNA expression of NMDA subunits and GLT1 transporter was determined in cerebral cortex and striatum of these animals fed a baseline or high lysine (4.7%) chow. No significant alterations of bioenergetics or redox status were observed in these mice. In contrast, mRNA expression of the NR2B glutamate receptor subunit and of the GLT1 glutamate transporter was higher in cerebral cortex of Gcdh(-/-) mice. Furthermore, NR2B expression was markedly elevated in striatum of Gcdh(-/-) animals receiving chronic Lys overload. These data indicate higher susceptibility of Gcdh(-/-) mice to excitotoxic damage, implying that this pathomechanism may contribute to the cortical and striatum alterations observed in GA I patients.

Glutaric aciduria type 1: neuroimaging features with clinical correlation

Article

Jun 2015
PEDIATR RADIOL

Glutaric aciduria type 1 is a rare neurometabolic disease with high morbidity. To describe the MR imaging abnormalities in glutaric aciduria type 1 and to identify any association between the clinical and imaging features. MRI scans of 29 children (mean age: 16.9 months) with confirmed diagnosis of glutaric aciduria type 1 were retrospectively reviewed. Gray matter and white matter scores were calculated based on a previously published pattern-recognition approach of assessing leukoencephalopathies. Hippocampal formation and opercular topography were assessed in relation to the known embryological basis. MRI scores were correlated with morbidity score. The most consistent MRI abnormality was widened operculum with dilatation of the subarachnoid spaces surrounding underdeveloped frontotemporal lobes. Incomplete hippocampal inversion was also seen. The globus pallidus was the most frequently involved gray matter structure (86%). In addition to the central tegmental tract, white matter abnormalities preferentially involved the central and periventricular regions. The morbidity score correlated with the gray matter abnormality score (P = 0.004). Patients with dystonia had higher gray matter and morbidity scores. Morbidity is significantly correlated with abnormality of gray matter, rather than white matter, whether secondary to acute encephalopathic crisis or insidious onset disease.

Hypoxia and related conditions

Article

Full-text available

Jan 2002

Chronic mitochondrial energy impairment produces selective striatal degeneration and abnormal choreiform movements in primates

Article

Full-text available

Aug 1995

Although the gene defect responsible for Huntington disease (HD) has recently been identified, the pathogenesis of the disease remains obscure. One potential mechanism is that the gene defect may lead to an impairment of energy metabolism followed by slow excitotoxic neuronal injury. In the present study we examined whether chronic administration of 3-nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, can replicate the neuropathologic and clinical features of HD in nonhuman primates. After 3-6 weeks of 3-NP administration, apomorphine treatment induced a significant increase in motor activity as compared with saline-treated controls. Animals showed both choreiform movements, as well as foot and limb dystonia, which are characteristic of HD. More prolonged 3-NP treatment in two additional primates resulted in spontaneous dystonia and dyskinesia accompanied by lesions in the caudate and putamen seen by magnetic resonance imaging. Histologic evaluation showed that there was a depletion of calbindin neurons, astrogliosis, sparing of NADPH-diaphorase neurons, and growth-related proliferative changes in dendrites of spiny neurons similar to changes in HD. The striosomal organization of the striatum and the nucleus accumbens were spared. These findings show that chronic administration of 3-NP to nonhuman primates can replicate many of the characteristic motor and histologic features of HD, further strengthening the possibility that a subtle impairment of energy metabolism may play a role in its pathogenesis.

Relationships among cerebral perfusion pressure, autoregulation, and transcranial Doppler waveform: A modeling study

Article

Full-text available

Aug 1998
J NEUROSURG

The aim of this study was to analyze how the main values extrapolated from the transcranial Doppler (TCD) waveform (systolic, mean, and diastolic velocity; velocity peak-to-peak amplitude; and pulsatility index [PI]) are affected by changes in intracranial pressure (ICP), systemic arterial pressure (SAP), autoregulation, and intracranial compliance. The analysis was performed using a mathematical model of the intracranial dynamics. This model includes a passive middle cerebral artery, the biomechanics of large and small pial arteries subjected to autoregulatory mechanisms, a collapsing venous cerebrovascular bed, the cerebrospinal fluid circulation, and the ICP-volume relationship. The results indicate that there are approximately three distinct zones characterized by different relationships between cerebral perfusion pressure (CPP) and velocity parameters in patients with preserved autoregulation. In the central autoregulatory zone (CPP > 70 mm Hg) the mean velocity does not change with decreasing CPP, whereas the PI and velocity peak-to-peak amplitude increase moderately. In a second zone (CPP between 4045 and 70 mm Hg), in which vasodilation of small pial arteries becomes maximal, the mean velocity starts to decrease, whereas the PI and velocity amplitude continue to increase. In the third zone, in which autoregulation is completely exhausted (CPP < 40 mm Hg), arterioles behave passively, mean velocity and velocity amplitude decline abruptly, and the PI exhibits a disproportionate rise. Moreover, this rise is quite independent of whether CPP is reduced by increasing ICP or reducing mean SAP. In contrast, in patients with defective autoregulation, the mean velocity and velocity amplitude decrease linearly with decreasing CPP, but the PI still increases in a way similar to that observed in patients with preserved autoregulation. The information contained in the TCD waveform is affected by many factors, including ICP, SAP, autoregulation. and intracranial compliance. Model results indicate that only a comparative analysis of the concomitant changes in ultrasonographic quantities during multimodality monitoring may permit the assessment of several aspects of intracranial dynamics (cerebral blood flow changes, vascular pulsatility, ICP changes, intracranial compliance, CPP, and autoregulation).

Cerebrospinal fluid - Physiology, analysis and interpretation of protein patterns for diagnosis of neurological diseases

Article

Full-text available

Jul 1998

Hansotto Reiber

The state of the art in routine CSF analysis is reviewed with particular reference to multiple sclerosis regarding: (1) The physiology and pathophysiology of blood-CSF barrier function and dysfunction with the CSF flow rate as main modulator of blood- and brain-derived protein concentrations in CSF; (2) The neuroimmunological aspects regarding (a) patterns of disease-related immunoglobulin class response (IgG, IgA, IgM) in actual Reiber graphs with reference to specific parameters and optional tests, and (b) the oligoclonal, polyspecific antibody synthesis in brain; (3) Particular marker proteins in CSF and blood for differential diagnosis of neurological diseases; (4) Mathematical base for evaluations of CSF data with an example of a multiple sclerosis patient for calculation of intrathecal immunoglobulin and antibody synthesis as well as Antibody Index.

Reevaluation of the Standardized Uptake Value for FDG: Variations with Body Weight and Methods for Correction1

Article

Full-text available

Nov 1999

To reevaluate the relationships between standardized uptake values (SUVs) and body weight by using positron emission tomography (PET) with 2-[fluorine 18]fluoro-2-deoxy-D-glucose (FDG). FDG PET scanning was performed in 138 female patients with known or suspected primary breast cancers. SUVs in blood and tumor (n = 79) were calculated by using body weight (SUVbw), ideal body weight (SUVibw), lean body mass (SUVlbm), and body surface area (SUVbsa) on images obtained 50-60 minutes after the injection of FDG. There was a strong positive correlation between the blood SUVbw and body weight (r = 0.705, P < .001). The blood SUVibw reduced the weight dependence but showed a negative correlation with body weight (r = -0.296, P < .001). Both the blood SUVibm and SUVbsa eliminated the weight dependence and showed no correlation with body weight (r = -0.010, P = .904 and r = 0.106, P = .215, respectively). Although there was a wide variance in the tumor SUVbw, it showed a weak but significant positive correlation with body weight (r = 0.207, P = .033). Plots of the tumor SUVlbm and SUVbsa versus body weight showed relatively flat slopes. SUVlbm and SUVbsa are weight-independent indices for FDG uptake, and SUVlbm appears to be more appropriate for quantifying FDG uptake to avoid overestimation of glucose utilization in obese patients.

Simultaneous measurement of regional cerebral blood flow by perfusion CT and stable Xenon CT : A validation study

Article

Full-text available

Jun 2001

Knowledge of cerebral blood flow (CBF) alterations in cases of acute stroke could be valuable in the early management of these cases. Among imaging techniques affording evaluation of cerebral perfusion, perfusion CT studies involve sequential acquisition of cerebral CT sections obtained in an axial mode during the IV administration of iodinated contrast material. They are thus very easy to perform in emergency settings. Perfusion CT values of CBF have proved to be accurate in animals, and perfusion CT affords plausible values in humans. The purpose of this study was to validate perfusion CT studies of CBF by comparison with the results provided by stable xenon CT, which have been reported to be accurate, and to evaluate acquisition and processing modalities of CT data, notably the possible deconvolution methods and the selection of the reference artery. Twelve stable xenon CT and perfusion CT cerebral examinations were performed within an interval of a few minutes in patients with various cerebrovascular diseases. CBF maps were obtained from perfusion CT data by deconvolution using singular value decomposition and least mean square methods. The CBF were compared with the stable xenon CT results in multiple regions of interest through linear regression analysis and bilateral t tests for matched variables. Linear regression analysis showed good correlation between perfusion CT and stable xenon CT CBF values (singular value decomposition method: R(2) = 0.79, slope = 0.87; least mean square method: R(2) = 0.67, slope = 0.83). Bilateral t tests for matched variables did not identify a significant difference between the two imaging methods (P >.1). Both deconvolution methods were equivalent (P >.1). The choice of the reference artery is a major concern and has a strong influence on the final perfusion CT CBF map. Perfusion CT studies of CBF achieved with adequate acquisition parameters and processing lead to accurate and reliable results.

Simultaneous correction of ghost and geometric distortion artifacts in EPI using a multiecho reference scan

Article

Full-text available

Jul 2001

A computationally efficient technique is described for the simultaneous removal of ghosting and geometrical distortion artifacts in echo-planar imaging (EPI) utilizing a multiecho, gradient-echo reference scan. Nyquist ghosts occur in EPI reconstructions because odd and even lines of k-space are acquired with opposite polarity, and experimental imperfections such as gradient eddy currents, imperfect pulse sequence timing, B0 field inhomogeneity, susceptibility, and chemical shift result in the even and odd lines of k-space being offset by different amounts relative to the true center of the acquisition window. Geometrical distortion occurs due to the limited bandwidth of the EPI images in the phase-encode direction. This distortion can be problematic when attempting to overlay an activation map from a functional magnetic resonance imaging experiment generated from EPI data on a high-resolution anatomical image. The method described here corrects for geometrical distortion related to B0 inhomogeneity, gradient eddy currents, radio-frequency pulse frequency offset, and chemical shift effect. The algorithm for removing ghost artifacts utilizes phase information in two dimensions and is, thus, more robust than conventional one-dimensional methods. An additional reference scan is required which takes approximately 2 min for a matrix size of 64 X 64 and a repetition time of 2 s. Results from a water phantom and a human brain at 3 T demonstrate the effectiveness of the method for removing ghosts and geometric distortion artifacts.

Cerebral Venous Steal: Blood Flow Diversion with Increased Tissue Pressure

Article

Full-text available

Nov 2002

Flow in areas with increased tissue pressure is described by a Starling resistor and is determined by the inflow pressure (P(i)), the external pressure (P(e)), and the outflow or venous pressure (P(v)). Flow is in Zone 1 at P(e) > P(i) > P(v), Zone 2 at P(i) > P(e) > P(v), and Zone 3 at P(i) > P(v) > P(e). A focal tissue pressure increase after stroke or trauma may lead to a transition from Zone 1 or 2 in the center to Zone 3 in the periphery. We hypothesize that the coexistence of different zones may lead to steal-like blood flow diversion in the perifocal area. We used a lumped-parameter model of two parallel Starling resistors with a common inflow. The first resistor, with higher P(e), represented the area with increased tissue pressure. The second resistor, with P(e)' = 0, represented the surrounding area. We evaluated the effects of venous pressure on the flow distribution between the two Starling resistors. The model demonstrated blood flow diversion toward the second Starling resistor with low external pressure. High inflow resistance facilitates this "steal." Flow diversion is caused by effective outflow pressure differences for the Starling resistors (P(e) for the first and P(v) for the second). The venous pressure increase equilibrates the effective backpressure and decreases flow diversion. When the venous pressure equals the external tissue pressure, blood flow diversion (cerebral venous steal) is abolished. Although increased venous pressure causes global flow reduction, it may restore flow to more than 50% of baseline values in areas of increased tissue pressure. Cerebral venous steal is a potential cause of secondary brain injury in areas of increased tissue pressure. It can be eliminated with increased venous pressure. Increased venous pressure may recruit the collapsed vascular network and correct perifocal perfusion maldistribution. This resembles how positive end expiratory pressure recruits collapsed airways and decreases the ventilation/perfusion mismatch.

Temporal profile of experimental ischemic edema after threshold amount of insult to induce infarction - Ultrastructure, gravimetry and Evans' blue extravasation

Article

Full-text available

Feb 2003
Acta Neurochir

When a threshold amount of temporary ischemic insult to induce focal infarction was given to the unilateral cerebral hemisphere of gerbils, a small focal infarct surrounded by a wide penumbra developed in the rostral portion of the cerebral cortex. During the first 5 hours following recirculation, whole astrocytic cell bodies and processes in the ischemic hemisphere were swollen, with an increase in the number of glycogen granules and in number and size of mitochondria. This swelling was an active reaction of astrocytes for neuronal protection, scavenging potassium, glutamate, and other neuronal metabolic products, and for generating fuels for neurons (cyto-reactive edema). This reactive astrocytic swelling continued in the penumbra, but some dead neurons were found disseminated among the surviving neurons. Whereas, at 12 approximately 48 hours, focal infarction developed in which all cell membranes lost their Gibbs-Donnan's equilibrium due to energetic failure of their membranous Na+/K+ ATPase. This is the cytotoxic edema (cyto-necrotic edema). In the infarct focus, when pericapillary astrocytic end-feet were damaged, the capillary BBB was broken; and thus vasogenic edema was superimposed on the cytotoxic edema.

Brain Perfusion in Children: Evolution With Age Assessed by Quantitative Perfusion Computed Tomography

Article

Full-text available

Jul 2004
Pediatrics

The objective of this study was to assess the age-related variations of brain perfusion through quantitative cerebral perfusion computed tomography (CT) results in children without brain abnormality. Brain perfusion CT examinations were performed in 77 children, aged 7 days to 18 years. These patients were admitted at our institution for both noncontrast and contrast-enhanced cerebral CT. Only children whose conventional cerebral CT and clinical/radiologic follow-up, including additional investigations, were normal were taken into account for this study (53 of 77). The average regional rCBF amounts to 40 (mL/100 g per minute) for the first 6 months of life, peaks at approximately 130 (mL/100 g per minute) at approximately 2 to 4 years of age, and finally stabilizes at approximately 50 (mL/100 g per minute) at approximately 7 to 8 years of age, with a small increase of rCBF values at approximately 12 years of age. The rCBF in the gray matter averages 3 times that in the white matter, except for the first 6 months of life. The global CBF represents 10% to 20% of the global cardiac output for the first 6 months of life, peaks at approximately 55% by 2 to 4 years of age, and finally stabilizes at approximately 15% by 7 to 8 years of age. Specific age-related evolution patterns were identified in the different anatomic areas of the cerebral parenchyma, which could be related to the development of neuroanatomic structures and to the emergence of corresponding cognitive functions. Quantitative perfusion CT characterization of brain perfusion shows specific age variations. Brain perfusion of each cortical area evolves according to a specific time course, in close correlation with the psychomotor development.

Neuropathological, biochemical and molecular findings in a glutaric acidemia type 1 cohort

Article

Full-text available

May 2005
BRAIN

Glutaric acidemia type 1 (GA-1) is an autosomal recessive disorder characterized by a deficiency of glutaryl-CoA dehydrogenase (GCDH) activity. GA-1 is often associated with an acute encephalopathy between 6 and 18 months of age that causes striatal damage resulting in a severe dystonic movement disorder. Ten autopsy cases have been previously described. Our goal is to understand the disorder better so that treatments can be designed. Therefore, we present the neuropathological features of six additional cases (8 months-40 years), all North American aboriginals with the identical homozygous mutation. This cohort displays similar pathological characteristics to those previously described. Four had macroencephaly. All had striatal atrophy with severe loss of medium-sized neurons. We present several novel findings. This natural time course study allows us to conclude that neuron loss occurs shortly after the encephalopathical crisis and does not progress. In addition, we demonstrate mild loss of large striatal neurons, spongiform changes restricted to brainstem white matter and a mild lymphocytic infiltrate in the early stages. Reverse transcriptase-PCR to detect the GCDH mRNA revealed normal and truncated transcripts similar to those in fibroblasts. All brain regions demonstrated markedly elevated concentrations of GA (3770-21 200 nmol/g protein) and 3-OH-GA (280-740 nmol/g protein), with no evidence of striatal specificity or age dependency. The role of organic acids as toxic agents and as osmolytes is discussed. The pathogenesis of selective neuronal loss cannot be explained on the basis of regional genetic and/or metabolic differences. A suitable animal model for GA-1 is needed.

Cerebral Venous and Tissue Gases and Arteriovenous Shunting in the Dog

Article

Sep 1999
ANESTH ANALG

Circulation and Energy Metabolism of the Brain

Article

Jan 1999

Ischemic Thresholds for Gray and White Matter: A Diffusion and Perfusion Magnetic Resonance Study

Article

Jun 2006
STROKE

Background and purpose: Although gray matter (GM) and white matter (WM) have differing neurochemical responses to ischemia in animal models, it is unclear whether this translates into differing thresholds for infarction. We studied this issue in ischemic stroke patients using magnetic resonance (MR) techniques. Methods: MR studies were performed in patients with acute hemispheric ischemic stroke occurring within 24 hours and at 3 months. Cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), and apparent diffusion coefficient (ADC) were calculated. After segmentation based on a probabilistic map of GM and WM, tissue-specific diffusion and perfusion thresholds for infarction were established. Results: Twenty-one patients were studied. Infarction thresholds for CBF were significantly higher in GM (median 34.6 mL/100 g per minute, interquartile range 26.0 to 38.8) than in WM (20.8 mL/100 g per minute; interquartile range 18.0 to 25.9; P<0.0001). Thresholds were also significantly higher in GM than WM for CBV (GM: 1.67 mL/100 g; interquartile range 1.39 to 2.17; WM: 1.19 mL/100 g; interquartile range 0.94 to 1.53; P<0.0001), ADC (GM: 918x10(-6) mm2/s; 868 to 975x10(-6); WM: 805x10(-6); 747 to 870x10(-6); P<0.001), and there was a trend toward a shorter MTT in GM (GM 4.94 s, 4.44 to 5.38; WM 5.15, 4.11 to 5.68; P=0.11). Conclusions: GM has a higher infarction threshold for CBF, CBV, and ADC than WM in patients within 24 hours of ischemic stroke onset. Hence, when assessing patients for potential therapies, tissue-specific rather than whole-brain thresholds may be a more precise measure of predicting the likelihood of infarction.

Glutaric aciduria type I: A common cause of episodic encephalopathy and spastic paralysis in the Amish of Lancaster County, Pennsylvania

Article

Oct 1991

We have diagnosed type I glutaric aciduria (GA-I) in 14 children from 7 Old Order Amish families in Lancaster County, Pennsylvania. An otherwise rare disorder, GA-I appears to be a common cause of acute encephalopathy and cerebral palsy among the Amish. The natural history of the disease, which was previously unrecognized in this population, is remarkably variable and ranges from acute infantile encephalopathy and sudden death to static extrapyramidal cerebral palsy to normal adult. Ten patients first manifested the disease between 3 and 18 months at the time of an acute infectious illness. Four of these children died in early childhood, also during acute illnesses. However, there has been little progression of the neurological disease after age 5 years in the surviving children and intellect usually has been preserved, even in children with severe spastic paralysis. When well, patients have plasma glutaric acid concentrations ranging from 4.8 to 14.2 mumol/liter (nl 0-5.6 mumol/liter) and urinary glutaric acid concentrations from 12.5 to 196 mg/g creatinine (nl 0.5-8.4 mg/g creatinine). We have found that GA-I can be diagnosed in the Amish by measurement of urinary glutaric acid concentrations using isotope-dilution gas chromatography/mass spectrometry, whereas the diagnosis can easily be missed by routine urine organic acid gas chromatography.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuropathology in glutaric acidemia type I

Article

Feb 1988

The neuropathology in three cases of glutaric acidaemia type 1 is presented. All three showed extensive neuronal loss in the caudate nucleus and the putamen, with only small numbers of large neurons surviving. The globus pallidus showed moderate shrinkage and gliosis but no conspicuous decreases in neurons. Severe spongiform change was seen in many regions, involving predominantly white matter. These features are very similar to some cases described previously in familial striatal degeneration in childhood, but are different from other cases. If found in a brain at autopsy, they should lead to studies to diagnose glutaric acidaemia type 1 retrospectively, so that accurate genetic counselling and prenatal diagnosis in future pregnancies can be offered.

Determination of rat cerebral cortical blood volume changes by capillary mean transit time analysis during hypoxia, hypercapnia and hyperventilation

Article

Jul 1988
BRAIN RES

Changes in cerebral blood volume due to augmented or diminished numbers of blood-perfused capillaries can be studied in small animals by optical methods. Capillary mean transit time was determined by detection of the passage of a hemodilution bolus through a region of the parietal cerebral cortical surface, using a reflectance spectrophotometer through a small craniotomy in chloral hydrate-anesthetized rats. Local cerebral blood flow was determined in the same region by the butanol indicator-fractionation method. Blood volume was calculated from the product of blood flow and transit time. Normoxic, normocapnic values for these variables were blood flow = 144 ml/100 g/min; mean transit time = 1.41 s; and blood volume = 3.4 ml/100 g. Mean transit time reached a minimum (1.1 s) with moderate hypoxia or hypercapnia. Combined hypoxia and hypercapnia did not result in any further decrease in mean transit time although blood flow was much higher than either hypoxia or hypercapnia alone. The maximum blood volume recorded during hypercapnic hypoxia (12.1 ml/100 g) was 3.6 times greater than that at normoxic normocapnia, which suggests that under control conditions in the anesthetized rat considerably less than 100% of the cerebral capillaries were actively perfusing the tissue. These studies demonstrate that optical methods can be used to quantitatively measure blood volume. The data suggest that capillary recruitment is a physiologically significant phenomenon in rat cerebral cortex.

Nature and distribution of brain lesions in rats intoxicated with 3-nitropropionic acid: A type of hypoxic (energy deficient) brain damage

Article

Feb 1987

The clinical signs and morphological brain lesions associated with histotoxic hypoxia induced by subcutaneous injection of 3-nitropropionic acid (NPA) in rats are described, and compared to hypoxic brain damage from other causes including ischemia and hypoglycemia. The brains were perfusion-fixed with paraformaldehyde/glutaraldehyde fixative, and examined by light and electron microscopy. Intoxicated rats developed severe neurological disease characterized by somnolence, uncoordinated gait with stereotypical paddling movements, and ventral or lateral recumbency. Recumbent rats had a selective, bilaterally symmetrical pattern of severe morphological injury in the caudate-putamen, hippocampus, and thalamus. Recumbency was a consistent indicator of the development of morphological brain lesions. In contrast to reports describing rat models of ischemia and hypoglycemia, morphological injury was not seen in the cerebral and cerebellar cortices of NPA-intoxicated rats. Ultrastructurally, neuronal alterations ranged from chromatin clumping with increased cytoplasmic lucency to severe cellular shrinkage or swelling with marked mitochondrial swelling (high amplitude swelling). White matter alterations included axonal swelling and adaxonal splitting of myelin lamellae. Vascular changes included perivascular deposits of proteinaceous material presumably from leakage of serum proteins, variable electron lucency of endothelial cell cytoplasm, an apparent increase in pinocytotic vesicles, rare platelet thrombosis of capillaries, and rare intravascular blebs of luminal plasma membrane. As a model of brain damage following energy deficiency, NPA intoxication has the advantages of producing morphological brain injury in a highly predictable anatomical pattern, and at a time paralleling the onset of clinical recumbency.

Failure of neuronal ion exchange, not potentiated excitation, causes excitotoxicity after inhibition of oxidative phosphorylation

Article

Feb 1995
NEUROSCIENCE

Neuronal cell death during impaired energy metabolism is often attributed to increased activity at glutamate receptors, but this increase has not been directly demonstrated. We recorded responses to glutamate and N-methyl-D-aspartate in hippocampal slice CA1 neurons and glia while inhibiting mitochondrial complex II with 3-nitropropionic acid. As the period of inhibition increased, neuronal depolarization following bath application of glutamate (5 mM) or N-methyl-D-aspartate (50 microM) increased dramatically. However, depolarization upon iontophoresis of glutamate and N-methyl-D-aspartate decreased with time. A transient hyperpolarization, reflecting electrogenic sodium pump activity, was present immediately after responses to iontophoretic glutamate agonists. In the presence of the inhibitor, this hyperpolarization decreased and eventually disappeared. Even the repolarization seen upon washing of the iontophoretic or bath application of glutamate or N-methyl-D-aspartate was incomplete. Glial depolarization upon bath application of glutamate increased during inhibition, while glial depolarization upon application of N-methyl-D-aspartate decreased. Application of the N-methyl-D-aspartate antagonists aminophosphonovaleric acid (100 microM) or MK-801 (20 microM) resulted in a delay of further depolarization when applied early during the terminal decay of membrane potential following metabolic inhibition. We conclude that during impaired oxidative phosphorylation the failure of repolarizing mechanisms, not potentiated neuronal depolarization by excitants, is the primary cause of the terminal depolarization. Large glial depolarization increases the demand for neuronal ion exchange which cannot be met in situations of reduced energy metabolism. Our results provide further evidence that acute and chronic blockade of energy metabolism have different effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Basal Ganglia Infarction in Propionic Acidemia

Article

Feb 1995

An 8-year-old girl with propionic acidemia had acute and rapidly fatal symmetric necrosis of the caudate, globus pallidus, and putamen. Clinical presentation was with acute aphasia, generalized hypotonia, and muscle weakness. There was no evidence of metabolic decompensation, and analysis of the organic acids of the urine indicated good metabolic control. Organic acids in the cerebrospinal fluid were unremarkable. These observations indicate that the pathophysiology of "metabolic stroke" is more complicated than previously thought.

Neurological manifestations of organic acid disorders

Article

Feb 1994

Neurological manifestations are very common and can be the leading and/or presenting feature in organic acid disorders, sometimes in the absence of metabolic derangement. Review of the time course and presentation of neurological disease in organic acid disorders reveals characteristic clinical findings of ataxia, myoclonus, extrapyramidal symptoms, metabolic stroke and megalencephaly. A group of organic acid disorders presents exclusively with neurological symptoms. These include glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type I), succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria), mevalonic aciduria, N-acetylaspartic aciduria (Canavan disease) and L-2-hydroxyglutaric aciduria. As a group these "cerebral" organic acid disorders appear to remain often undiagnosed and their true incidence is much less well-known than that of the "classical" organic acid disorders. Unfortunately, stringent guidelines for a clinical preselection of neuropaediatric patients to be investigated for organic acid disorders cannot be provided. Today, screening for neurometabolic disorders should be as comprehensive as possible and include determinations of amino acids, purines and pyrimidines and markers of peroxisomal function in addition to organic acid analysis.

Reproducibility of regional brain metabolic responses to lorazepam

Article

Nov 1996

Changes in regional brain glucose metabolism in response to benzodiazepine agonists have been used as indicators of benzodiazepine-GABA receptor function. The purpose of this study was to assess the reproducibility of these responses. Sixteen healthy right-handed men underwent scanning with PET and [18F]fluorodeoxyglucose (FDG) twice: before placebo and before lorazepam (30 micrograms/kg). The same double FDG procedure was repeated 6-8 wk later on the men to assess test-retest reproducibility. The regional absolute brain metabolic values obtained during the second evaluation were significantly lower than those obtained from the first evaluation regardless of condition (p < or = 0.001). Lorazepam significantly and consistently decreased both whole-brain metabolism and the magnitude. The regional pattern of the changes were comparable for both studies (12.3% +/- 6.9% and 13.7% +/- 7.4%). Lorazepam effects were the largest in the thalamus (22.2% +/- 8.6% and 22.4% +/- 6.9%) and occipital cortex (19% +/- 8.9% and 21.8% +/- 8.9%). Relative metabolic measures were highly reproducible both for pharmacologic and replication condition. This study measured the test-retest reproducibility in regional brain metabolic responses, and although the global and regional metabolic values were significantly lower for the repeated evaluation, the response to lorazepam was highly reproducible.

Neurosurgical Treatment for Hydrocephalus, Subdural Hematomas, and Arachnoid Cysts in Glutaric Aciduria Type 1

Article

Jan 1997

Juan F Martínez-Lage

Cerebral energy metabolism, glucose transport and blood flow: Changes with maturation and adaptation to hypoglycemia

Article

Mar 1997
DIABETES METAB

Astrid Nehlig

Brain maturation is characterized by a peak of cerebral energy metabolism and blood flow occurring between 3 and 8 years of age in humans and around 14-17 days of postnatal life in rats. This high activity coincides with the period of active brain growth. The human brain is dependent on glucose alone during that period, whereas rat brain uses both glucose and ketone bodies to cover its energetic and biosynthetic needs. The maturation of the density of glucose transporter sites-GLUT1 located at the blood-brain barrier and GLUT3 at the neuronal membrane-parallels the development of cerebral glucose utilization. During moderate acute hypoglycaemia, there are no changes in cerebral functional activity; cerebral glucose utilization decreases and blood flow increases only when hypoglycaemia is severe (lower than 2 mumol/ml). During chronic hypoglycaemia, the brain adapts to the low circulating levels of glucose: the number of glucose transporter sites is increased, and cerebral glucose utilization and function are maintained at normal levels while cerebral blood flow is more moderately increased than during acute hypoglycaemia. Neuronal damage consecutive to severe and prolonged hypoglycaemia occurs mainly in the cerebral cortex, hippocampus and caudate-putamen as a result of active release of excitatory amino acids.

Blood Flow in the Cerebral Capillary Network: A Review Emphasizing Observations with Intravital Microscopy

Article

Jul 1997

Anthony G Hudetz

Capillary perfusion in the brain is characterized by an essentially continuous flow of erythrocytes and plasma in almost all capillaries. Rapid fluctuations and spatial heterogeneity or red blood cell (RBC) velocity (0.5-1.8 mm/s) within the capillary network are present. In addition, low-frequency (4-8 cpm) synchronous oscillations in RBC velocity in the capillary network emerge when perfusion to cerebral tissue is challenged. Despite the tortuous, three-dimensional architecture of microvessels, functional intercapillary anastomoses are absent. At rest, red cells travel through the capillary network in 100-300 ms along 150- to 500-micron-long paths. Physiological challenges elicit sizable changes in RBC velocity with a minor role for capillary recruitment, change in capillary diameter, or flow shunting. During acute hypoxia, RBC velocity increases in all capillaries; the corresponding response to hypereapnia is more complex and involves redistribution of capillary flow toward more homogeneous perfusion. The response of capillary flow to decreased perfusion pressure reflects autoregulation of cerebral blood flow but also involves intranetwork redistribution of RBC flow between two populations of capillaries, postulated as thoroughfare channels and exchange capillaries. Flow reserve may be provided by the thoroughfare channels and may help maintain flow velocity and capillary exchange and protect the microcirculation from perfusion failure. Isovolemic hemodilution increases RBC velocity three- to fourfold and increases RBC flux to a moderate degree with a relatively small decrease in capillary hematocrit, under normal and compromised arterial blood supply. In cerebral ischemia, leukocyte adhesion is enhanced and appears reversible when the ischemia is moderate but may be progressive when the injury is severe. The observed flow behavior suggests the presence of a physiological regulatory mechanism of cerebral capillary flow that may involve communication among various microvascular and parenchymal cells and utilize locally acting endothelial and parenchymal mediators such as endothelium-derived relaxing factor or nitric oxide.

Partial Inhibition of Brain Succinate Dehydrogenase by 3-Nitropropionic Acid Is Sufficient to Initiate Striatal Degeneration in Rat

Article

Mar 1998

Chronic inhibition of succinate dehydrogenase (SDH) by systemic injection of the selective inhibitor 3-nitropropionic acid (3NP) has been used as an animal model for Huntington's disease (HD). However, the mechanisms by which 3NP produces lesions in the striatum are not fully characterized. A quantitative histochemical method was developed to study the level of regional SDH inhibition resulting from intraperitoneal injection of 3NP or chronic intoxication using osmotic pumps. The results showed that (a) 3NP was an irreversible SDH inhibitor in vivo, (b) the level of SDH inhibition in the striatum (the brain region most vulnerable to 3NP) was similar to that observed in other brain regions not affected by the toxin, such as the cerebral cortex, and (c) the neurotoxic threshold of SDH inhibition in the brain was 50-60% of control levels. The present study demonstrates that the selective degeneration in the striatum observed after chronic 3NP administration cannot be ascribed to a preferential inhibition of SDH in this particular brain region. This work also suggests that the partial decrease in the activity of the respiratory chain complex II-III reported in HD patients may be sufficient to induce the selective striatal degeneration observed in this disorder.

Regulation of Oxygen Supply in the Cerebral Circulation

Article

Feb 1997
ADV EXP MED BIOL

Anthony G Hudetz

The dynamics and regulation of red blood cell flow in the cerebral microcirculation was studied by intravital fluorescence video-microscopy in a closed cranial window preparation in the rat. The studies revealed that capillary perfusion in the brain is essentially continuous but a stationary difference from capillary to capillary within the same microvascular network exists. The main mechanism of an increase in flow in cerebral capillaries is an increase in linear velocity with no or minor role for classical capillary recruitment. While cyclic opening and closing of capillaries is not evident, low frequency oscillations in capillary flow velocity are present when perfusion or oxygen supply to tissue is challenged. In hypoxic hypoxia and moderate hypercapnia, RBC velocity increases in all capillaries while in severe hypercapnia, redistribution of RBC velocity in the capillary network occurs. Both systemic hypotension and severe hypercapnia are accompanied by an increase in the homogeneity of capillary flow; this change involves the redistribution of RBC flow between thoroughfare channels and exchange capillaries. Thoroughfare channels may thus provide a recruitable flow reserve in the cerebral microcirculation. The capillary flow response to hypoxic and anemic hypoxia depends on the activity neuronal nitric oxide synthase. These findings suggest the presence of a physiological regulatory mechanism of cerebral capillary red blood cell flow and oxygen supply which may involve neuronal nitric oxide as a mediator.

Time Course of ADCw Changes in Ischemic Stroke: Beyond the Human Eye!

Article

Oct 1998

Using newly developed computerized image analysis, we studied the heterogeneity of apparent diffusion coefficient of water (ADCw) values in human ischemic stroke within 10 hours of onset. Echo-planar trace diffusion-weighted images from 9 patients with focal cortical ischemic stroke were obtained within 10 hours of symptom onset. An Iterative Self-Organizing Data Analysis (ISODATA) clustering algorithm was implemented to segment different tissue types with a series of DW images. ADCw maps were calculated from 4 DW images on a pixel-by-pixel basis. The segmented zones within the lesion were characterized as low, pseudonormal, or high, expressed as a ratio of the mean+/-SD of ADCw of contralateral noninvolved tissue. The average ADCW in the ischemic stroke region within 10 hours of onset was significantly depressed compared with homologous contralateral tissue (626.6+/-76.8 versus 842.9+/-60.4x10(-6) mm2/s; P<0.0001). Nevertheless, ISODATA segmentation yielded multiple zones within the stroke region that were characterized as low, pseudonormal, and high. The mean proportion of low:pseudonormal:high was 72%:20%:8%. Despite low average ADCW, computer-assisted segmentation of DW MRI detected heterogeneous zones within ischemic lesions corresponding to low, pseudonormal, and high ADCw not visible to the human eye. This supports acute elevation of ADCw in human ischemic stroke and, accordingly, different temporal rates of tissue evolution toward infarction.

Diffusion-weighted MRI for evaluation of acute stroke

Article

Oct 1998

Gregory W Albers

Diffusion-weighted imaging (DWI) is a new magnetic resonance imaging technique that detects the tiny random movements of water molecules (diffusion) in tissues. This technique allows a map of the average apparent diffusion coefficient (ADC) to be calculated. Shortly after the onset of an ischemic stroke, the ADC of brain tissue is significantly reduced because of cytotoxic edema. Over several days, the rapid initial drop in ADC is followed by a return to "pseudonormal" values at approximately 1 week. Subsequently, elevated ADC values are seen at chronic time points. DWI is remarkably sensitive in detecting and localizing acute ischemic brain lesions and allows differentiation of acute regions of ischemia from chronic infarcts. Recent studies have shown a high correlation between the volume of early DWI lesions and clinical neurologic outcome. In addition, the volume of the early DWI lesion correlates well with final infarct volume as measured by T2-weighted imaging. Therefore, this technique may facilitate optimal selection of patients for new medical therapies for stroke and may provide a highly sensitive technique for evaluating the efficacy of new treatments.

Neuron-specific enolase levels in the cerebrospinal fluid of neurologically healthy children

Article

Feb 1999
BRAIN DEV-JPN

Levels of neuron-specific enolase (NSE) levels in the cerebrospinal fluid (CSF) of children without neurological disease were assessed. CSF samples were obtained from 37 subjects aged between 1 month and 13 years. All subjects had undergone lumbar puncture for diagnostic purposes, and were subsequently shown not to be suffering any form of neurological disease. NSE levels in CSF were determined by an enzyme immunoassay method. NSE level ranged from below the detection limit to 4.8 ng/ml (1.52+/-1.01 ng/ml). The present results may be useful as a basis for defining reference levels of NSE in CSF in post-neonatal children.

Glutaric aciduria and suspected child abuse

Article

Jun 1999
Arch Dis Child

Temporal evolution of 3-nitropropionic acid-induced neurodegeneration in the rat brain by T2-weighted, diffusion-weighted, and perfusion magnetic resonance imaging

Article

Feb 1999
NEUROSCIENCE

An appropriate detecting technique is necessary for the early detection of neurodegenerative diseases. 3-Nitropropionic acid-intoxicated rats serve as the animal model for one neurodegenerative disease, Huntington's disease. Non-invasive diffusion- and T2-weighted magnetic resonance imaging were applied to study temporal evolution and spatial distribution of brain lesions which were produced by intravenous injection of 3-nitropropionic acid in rats. Lesions in the striatum, hippocampus, and corpus callosum but not in the cortex were observed 3 and 4.5 h after 3-nitropropionic acid injection (30 mg/kg) on the diffusion- and T2-weighted images, respectively (n = 6). The results demonstrated that the diffusion-weighted imaging is not only superior to T2-weighted imaging in detecting onset of 3-nitropropionic acid-induced excitotoxic brain damage but also differentiates lesion and non-lesion areas with better spatial resolution than T2-weighted imaging. Additionally, to correlate structural alterations with pathophysiological conditions, dynamic susceptibility contrast magnetic resonance imaging was performed before and 4 h after 3-nitropropionic acid administration (n = 8). The relative cerebral blood volume was significantly elevated in the striatum (P < 0.001) but not in the cortex after 3-nitropropionic acid administration. The changes in regional relative cerebral blood volume were well correlated to the changes in signal intensities in the corresponding areas on the diffusion- and T2-weighted images. The combined structural and functional information in this study may provide new insights and therapeutic strategies in treating neurodegenerative diseases.

Cerebral Venous and Tissue Gases and Arteriovenous Shunting in the Dog

Article

Oct 1999
ANESTH ANALG

Unlabelled: Cerebral venous blood gas values have been used to indicate brain tissue oxygenation. However, it is not clear how cerebral tissue and venous measures may vary under physiologic conditions caused by arteriovenous shunt. The purpose of this study was to measure brain tissue and local cerebral venous oxygen (PO2) and carbon dioxide (P(CO2)) partial pressure during changes in ventilation and to calculate shunt fraction. Eight dogs were anesthetized with isoflurane. After a craniotomy, a Neurotrend probe (Diametrics Inc., St. Paul, MN) that measures P(O2), P(CO2), pH, and temperature was inserted into brain tissue, and a small vein that drained the same tissue was catheterized. Arterial, cerebral venous, and brain tissue P(O2) and Pco2 were measured during random changes in ventilation to produce five different levels of inspired oxygen (room air, 40%, 60%, 80%, 95%) at each of three different end-tidal Pco2 (20 mm Hg, 40 mm Hg, 60 mm Hg). Arteriovenous shunt was calculated from oxygen and C(O2) content in artery, vein, and tissue, representing capillary. Tissue P(CO2) was 8 mm Hg greater than vein Pco2 during hypocapnia and this difference increased to 20 mm Hg during hypercapnia. Vein P(O2) was 8 mm Hg higher than tissue P(O2) during hypocapnia, and this difference increased to 40 mm Hg during hypercapnia. Shunt fraction increased from 10%-20% during hypocapnia to 50%-60% during hypercapnia. These results show that brain vein and tissue P(O2) and P(CO2) differ because of arteriovenous shunting and this difference is increased as end-tidal P(CO2) increases. Implications: We found, in dogs, that the gradient between brain venous and tissue P(O2) and PCO2 is increased with increased arterial P(CO2). The divergence between tissue and venous gases can be described by arterial to venous shunting.

Relationship between residual cerebral blood flow and oxygen metabolism as predictive of ischemic tissue viability: Sequential multitracer positron emission tomography scanning of middle cerebral artery occlusion during the critical first 6 hours after stroke in pigs

Article

Oct 2000
J NEUROSURG

The authors tested the hypothesis that oxygen metabolism is the key factor linking the long-term viability of ischemic brain tissue to the magnitude of residual blood flow during the first 6 hours following a stroke. Eleven anesthetized pigs underwent a series of positron emission tomography studies to measure cerebral blood flow (CBF) and metabolism before and for 7 hours after the animals were subjected to permanent middle cerebral artery (MCA) occlusion. The extent of collateral blood supply was assessed using angiography. Abnormal metabolism of the ischemic tissue progressed as a function of time in inverse proportion to the magnitude of residual CBF, and the volume of the infarct grew in inverse proportion to the residual blood supply. Ten hours after occlusion of the MCA, the infarct topographically matched the tissue with a cerebral metabolic rate of oxygen consumption below 50% of values measured on the contralateral side. This was also the threshold for the decline of the oxygen extraction fraction below normal, which was critical for the prediction of nonviable ischemic tissue. Mildly ischemic tissue (CBF > 30 ml/100 g/min) did not reach the cerebral metabolic rate of oxygen threshold of viability during the first 6 hours after MCA occlusion; moderately ischemic tissue (CBF 12-30 m1/100 g/ min) reached the threshold of viability in 3 hours; and severely ischemic tissue (CBF < 12 ml/100 g/min) remained viable for less than 1 hour. The relationship between the residual CBF and both oxygen metabolism and extraction is critical to the evolution of metabolic deficiency and lesion size after stroke.

Cellular factors controlling neuronal vulnerability in the brain: A lesson from the striatum

Article

Dec 2000

In many acute and chronic neurologic disorders, both deficits in energy metabolism and defects in glutamate-mediated excitatory synaptic transmission have been proposed as important pathogenic factors. Brain cells, however, express variable vulnerability to these insults, as indicated by the fact that certain brain areas and even different cell types in the same area are preferentially spared until the very late stages of various diseases. This can be clearly seen in the striatum, where GABAergic projection cells but not cholinergic interneurons are precociously damaged in the course of both acute metabolic insults (such as hypoxia, hypoglycemia, and ischemia) and chronic neurodegenerative disorders (such as Huntington's disease). A well-mapped pattern of cell loss, in fact, is a common finding in the striatum of patients suffering from these pathologic conditions. Physiologic and molecular studies have been directed in recent years to the identification of the cellular mechanisms underlying the cell-type specific vulnerability of striatal cells. These studied recognized that, in striatal spiny and aspiny cells, specific membrane ion channels, glutamate receptor subtypes and subunits, and intracellular enzymatic activities are involved in the cascade of events responsible for opposite responses and vulnerabilities to oxygen or glucose deprivation and to glutamate receptor-mediated toxicity. Specific molecules able to target these cellular factors might be employed as therapeutic agents during acute and chronic neurologic disorders affecting this brain area.

Evolution of apparent diffusion coefficient, diffusion-weighted, and T2-weighted signal intensity of acute stroke

Article

May 2001

Serial study of such MR parameters as diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC), ADC with fluid-attenuated inversion recovery (ADC(FLAIR)), and T2-weighted imaging may provide information on the pathophysiological mechanisms of acute ischemic stroke. Our goals were to establish the natural evolution of MR signal intensity characteristics of acute ischemic lesions and to assess the potential of using specific MR parameters to estimate lesion age. Five serial echo-planar DWI studies with and without an inversion recovery pulse were performed in 27 patients with acute stroke. The following lesion characteristics were studied: 1) conventional ADC (ADC(CONV)); 2) ADC(FLAIR); 3) DWI signal intensity (SI(DWI)); 4) T2-weighted signal intensity (SI(T2)), and 5) FLAIR signal intensity (SI(FLAIR)). The lesion ADC(CONV) gradually increased from low values during the first week to pseudonormal during the second week to supranormal thereafter. The lesion ADC(FLAIR) showed the same pattern of evolution but with lower absolute values. A low ADC value indicated, with good sensitivity (88%) and specificity (90%), that a lesion was less than 10 days old. All signal intensities remained high throughout follow-up. SI(DWI) showed no significant change during the first week but decreased thereafter. SI(T2) initially increased, decreased slightly during week 2, and again increased after 14 days. SI(FLAIR) showed the same initial increase as the SI(T2) but remained relatively stable thereafter. Our findings further clarify the time course of stroke evolution on MR parameters and indicate that the ADC map may be useful for estimating lesion age. Application of an inversion recovery pulse results in lower, potentially more accurate, absolute ADC values.

Acute and chronic changes of the apparent diffusion coefficient in neurological disorders-biophysical mechanisms and possible underlying histopathology

Article

Jun 2001
J NEUROL SCI

Diffusion-weighted imaging (DWI) of the brain has become a valuable tool for the reliable detection and diagnosis of several neurological disorders. Although DWI is in wide use in daily practice, the underlying biophysical mechanisms that contribute to changes in the apparent diffusion coefficient (ADC) are still under discussion. Alterations in the apparent water diffusion rate reflect pathological changes in the brain tissue state, via changes in the diffusion characteristics of the intra- and extra-cellular water compartments including restricted diffusion, water exchange across permeable boundaries, the concept of the extra-cellular tortuosity and the intra- and extra-cellular volume fraction. A reduction of the ADC has been detected in acute neurological diseases, while disease states associated with dominant acute vasogenic edema formation or chronic tissue destruction usually show elevations of the ADC. Compromise of energy metabolism is likely to contribute to a reduction of the ADC while already minor structural disintegration may contribute to elevations of the ADC.

Viability Thresholds of Ischemic Penumbra of Hyperacute Stroke Defined by Perfusion-Weighted MRI and Apparent Diffusion Coefficient

Article

May 2001
STROKE

The penumbra of ischemic stroke consists of hypoperfused, but not irreversibly damaged, tissue surrounding the ischemic core. The purpose of this study was to determine viability thresholds in the ischemic penumbra, defined as the perfusion/diffusion mismatch in hyperacute stroke, by the use of diffusion- and perfusion-weighted MRI (DWI and PWI, respectively). DWI and PWI were performed in 11 patients </=6 hours after the onset of symptoms of acute ischemic stroke. Regions of interest (ROIs) were placed covering the ischemic core (ROI 1), the penumbra that progressed to infarction on the basis of follow-up scans (ROI 2), and the penumbra that recovered (ROI 3). The ratios of relative cerebral blood flow (rCBF), relative cerebral blood volume (rCBV), mean transit time (MTT), and apparent diffusion coefficient were calculated as lesion ROIs relative to the contralateral mirror ROIS: The post hoc analysis showed that the penumbra progressed to infarction at the following cutoff values: rCBF <0.59 and MTT >1.63. Higher sensitivity and accuracy in predicting outcome of the penumbra were obtained from the rCBF maps compared with the rCBV and MTT maps. The initial rCBV and apparent diffusion coefficient ratios did not differentiate between the part of the penumbra that recovered and the part that progressed to infarction. The mean rCBF ratio was optimal in distinguishing the parts of the penumbra recovering or progressing to infarction. The thresholds found in this study by combined DWI/PWI might aid in the selection of patients suitable for therapeutic intervention within 6 hours. However, these hypothesized thresholds need to be prospectively tested at the voxel level on a larger patient sample before they can be applied clinically.

Severe ADC Decreases Do Not Predict Irreversible Tissue Damage In Humans

Article

Jan 2002
STROKE

A mismatch between diffusion- and perfusion-weighted MRI is thought to define tissue at risk of infarction. This concept is based on the assumption that diffusion slowing of and decreases in the apparent diffusion coefficient (ADC) serve as indicator of tissue proceeding to infarction. We tested this hypothesis. MRI (diffusion weighted, perfusion weighted, MRA, T2 weighted) was performed in 15 patients with acute stroke within 2.9+/-0.8 hours (mean+/-SD) of onset and on days 1 and 7. After intraindividual realignment of the ADC maps, the development of ADC range volumes and ADC values was determined. An increase (354%, group A1) in the total ADC-based lesion volume below a threshold of < 80% occurred in 4 patients on day 1, persisting on day 7 with a pronounced increase of ADC range volumes with low ADC values. An increase in total ADC-based lesion volume (201%, group A2) followed by a secondary drop to day 7 was found in 7 patients. A significant reduction in total ADC-based lesion volume (14%, group B) was found in 4 patients. ADC-based lesion volume increase was associated with persistent vessel occlusion in group A, whereas recanalization in group B resulted in ADC volume decrease. ADC normalization was observed independently from the degree of the initial ADC decrease on days 1 and 7 in group B. In line with results from animal experiments, ADC decreases do not reliably indicate tissue infarction Even severely decreased ADC values may normalize in human stroke, and it seems likely that ADC normalization depends on the duration and severity of ischemia rather than the absolute value.

Standardized uptake value in pediatric patients: An investigation to determine the optimum measurement parameter

Article

Feb 2002

Although the standardized uptake value (SUV) is currently used in fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) imaging, concerns have been raised over its accuracy and clinical relevance. Dependence of the SUV on body weight has been observed in adults and this should be of concern in the pediatric population, since there are significant body changes during childhood. The aim of the present study was to compare SUV measurements based on body weight, body surface area and lean body mass in the pediatric population and to determine a more reliable parameter across all ages. Sixty-eight pediatric FDG-PET studies were evaluated. Age ranged from 2 to 17 years and weight from 11 to 77 kg. Regions of interest were drawn at the liver for physiologic comparison and at FDG-avid malignant lesions. SUV based on body weight (SUV(bw)) varied across different weights, a phenomenon less evident when body surface area (SUV(bsa)) normalization is applied. Lean body mass-based SUV (SUV(lbm)) also showed a positive correlation with weight, which again was less evident when normalized to bsa (SUV(bsa-lbm)). The measured liver SUV(bw) was 1.1+/-0.3, a much lower value than in our adult population (1.9+/-0.3). The liver SUV(bsa) was 7.3+/-1.3. The tumor sites had an SUV(bw) of 4.0+/-2.7 and an SUV(bsa) of 25.9+/-15.4 (65% of the patients had neuroblastoma). The bsa-based SUVs were more constant across the pediatric ages and were less dependent on body weight than the SUV(bw). These results indicate that SUV calculated on the basis of body surface area is a more uniform parameter than SUV based on body weight in pediatric patients and is probably the most appropriate approach for the follow-up of these patients.

Ischaemic brain edema

Article

Apr 2002
J CLIN NEUROSCI

Ischaemic brain oedema appears to involve two distinct processes, the relative contribution and time course of which depend on the duration and severity of ischaemia, and the presence of reperfusion. The first process involves an increase in tissue Na+ and water content accompanying increased pinocytosis and Na+, K+ ATPase activity across the endothelium. This is apparent during the early phase of infarction and before any structural damage is evident. This phenomenon is augmented by reperfusion. A second process results from a more indiscriminate and delayed BBB breakdown that is associated with infarction of both the parenchyma and the vasculature itself. Although, tissue Na+ level still seems to be the major osmotic force for oedema formation at this second stage, the extravasation of serum proteases is an additional potentially deleterious factor. The relative importance of protease action is not yet clear, however, degradation of the extracellular matrix conceivably leads to further BBB disruption and softening of the tissue, setting the stage for the most pronounced forms of brain swelling. A number of factors mediate or modulate ischaemic oedema formation, however, most current information comes from experimental models, and clinical data on this microcosmic level is lacking.

Cerebral dicarboxylate transport and metabolism studied with isotopically labelled fumarate, malate and malonate

Article

Aug 2002

Transport and metabolism of dicarboxylates may be important in the glial-neuronal metabolic interplay. Further, exogenous dicarboxylates have been suggested as cerebral energy substrates. After intrastriatal injection of [(14) C]fumarate or [(14) C]malate, glutamine attained a specific activity 4.1 and 2.6 times higher than that of glutamate, respectively, indicating predominantly glial uptake of these four-carbon dicarboxylates. In contrast, the three-carbon dicarboxylate [(14) C]malonate gave a specific activity in glutamate which was approximately five times higher than that of glutamine, indicating neuronal uptake of malonate. Therefore, neurones and glia take up different types of dicarboxylates, probably by different transport mechanisms. Labelling of alanine from [(14) C]fumarate and [(14) C]malate demonstrated extensive malate decarboxylation, presumably in glia. Intravenous injection of 75 micromol [U-(13) C]fumarate rapidly led to high concentrations of [U-(13) C]fumarate and [U-(13) C]malate in serum, but neither substrate labelled cerebral metabolites as determined by (13) C NMR spectroscopy. Only after conversion of [U-(13) C]fumarate into serum glucose was there (13) C-labelling of cerebral metabolites, and only at <10% of that obtained with 75 micromol [3-(13) C]lactate or [2-(13) C]acetate. These findings suggest a very low transport capacity for four-carbon dicarboxylates across the blood-brain barrier and rule out a role for exogenous fumarate as a cerebral energy substrate.

Type I glutaric aciduria, part 1: Natural history of 77 patients

Article

Aug 2003

Time is that wherein there is opportunity, and opportunity is that wherein there is no great time. … Healing is a matter of time, but it is also a matter of opportunity. —Hippocrates, Epidemics Type I glutaric aciduria (GA1) results from mitochondrial matrix flavoprotein glutaryl-CoA dehydrogenase deficiency and is a cause of acute striatal necrosis in infancy. We present detailed clinical, neuroradiologic, molecular, biochemical, and functional data on 77 patients with GA1 representative of a 14-year clinical experience. Micrencephalic macrocephaly at birth is the earliest sign of GA1 and is associated with stretched bridging veins that can be a cause of subdural hematoma and acute retinal hemorrhage. Acute striatal necrosis during infancy is the principal cause of morbidity and mortality and leads to chronic oromotor, gastroesophageal, skeletal, and respiratory complications of dystonia. Injury to the putamen is heralded by abrupt-onset behavioral arrest. Tissue degeneration is stroke-like in pace, radiologic appearance, and irreversibilty. It is uniformly symmetric, regionally selective, confined to children under 18 months of age, and occurs almost always during an infectious illness. Our knowledge of disease mechanisms, though incomplete, is sufficient to allow a rational approach to management of encephalopathic crises. Screening of asymptomatic newborns with GA1 followed by thoughtful prospective care reduces the incidence of radiologically and clinically evident basal ganglia injury from approximately 90% to 35%. Uninjured children have good developmental outcomes and thrive within Amish and non-Amish communities.

Genetic heritage of Old Order Mennonites of Southeastern Pennsylvania

Article

Aug 2003

Erik G Puffenberger

The Old Order Mennonites of southeastern Pennsylvania are a religious isolate with origins in 16th-century Switzerland. The Swiss Mennonites immigrated to Pennsylvania over a 50-year period in the early 18th century. The history of this population in the United States provides insight into the increased incidence of several genetic diseases, most notably maple syrup urine disease (MSUD), Hirschsprung disease (HSCR), and congenital nephrotic syndrome. A comparison between the Old Order Mennonites and the Old Order Amish demonstrates the unique genetic heritage of each group despite a common religious and geographic history. Unexpectedly, several diseases in both groups demonstrate allelic and/or locus heterogeneity. The population genetics of the 1312T --> A BCKDHA gene mutation, which causes classical MSUD, are presented in detail. The incidence of MSUD in the Old Order Mennonites is estimated to be 1/358 births, yielding a corrected carrier frequency of 7.96% and a mutation allele frequency of 4.15%. Analysis of the population demonstrates that repeated cycles of sampling effects, population bottlenecks, and subsequent genetic drift were important in shaping the current allele frequencies. A linkage disequilibrium analysis of 1312T --> A mutation haplotypes is provided and discussed in the context of the known genealogical history of the population. Finally, data from microsatellite marker genotyping within the Old Order Mennonite population are provided that show a significant but modest decrease in genetic diversity and elevated levels of background linkage disequilibrium.

Pediatric medicine and the genetic disorders of the Amish and Mennonite people of Pennsylvania

Article

Aug 2003

The Clinic for Special Children in Lancaster County, Pennsylvania, is a community-supported, nonprofit pediatric medical practice for Amish and Mennonite children who have genetic disorders. Over a 14-year period, 1988-2002, we have encountered 39 heritable disorders among the Amish and 23 among the Mennonites. We emphasize early recognition and long-term medical care of children with genetic conditions. In the clinic laboratory we perform amino acid analyses by high-performance liquid chromatography (HPLC), organic acid analyses by gas chromatography/mass spectrometry (GC/MS), and molecular diagnoses and carrier tests by polymerase chain reaction (PCR) amplification and sequencing or restriction digestion. Regional hospitals and midwives routinely send whole-blood filter paper neonatal screens for tandem mass spectrometry and other modern analytical methods to detect 14 of the metabolic disorders found in these populations as part of the NeoGen Inc. Supplemental Newborn Screening Program (Pittsburgh, PA). Medical care based on disease pathophysiology reduces morbidity, mortality, and costs for the majority of disorders. Among our patients who are homozygous for the same mutation, differences in disease severity are not unusual. Clinical problems typically arise from the interaction of the underlying genetic disorder with common infections, malnutrition, injuries, and immune dysfunction that act through classical pathophysiological disease mechanisms to influence the natural history of disease.

Glutaryl-CoA Dehydrogenase Deficiency: Region-Specific Analysis of Organic Acids and Acylcarnitines in post mortem Brain Predicts Vulnerability of the Putamen

Article

Jul 2003

The neurometabolic disorder glutaryl-CoA dehydrogenase (GCDH) deficiency is biochemically characterised by an accumulation of the marker metabolites 3-hydroxyglutaric acid, glutaric acid, and glutarylcarnitine. If untreated, the disease is complicated by acute encephalopathic crises, resulting in neurodegeneration of vulnerable brain regions, in particular the putamen. 3-hydroxyglutaric acid is considered the major neurotoxin in this disease. There are only preliminary data concerning glutaric acid concentrations in the brains of affected children and the distribution of 3-hydroxyglutaric acid and glutarylcarnitine has not been described. In the present study, we investigated post mortem the distribution of 3-hydroxyglutaric and glutaric acids as well as glutarylcarnitine in 14 different brain regions, internal organs, and body fluids (urine, plasma, cerebrospinal fluid) in a 14-year-old boy. 3-Hydroxyglutaric acid showed the highest concentration (62 nmol/g protein) in the putamen among all brain areas investigated. The glutarylcarnitine concentration was also highest in the putamen (7.1 nmol/g protein). We suggest that the regional-specific differences in the relative concentrations of 3-hydroxyglutaric acid contribute to the pattern of neuronal damage in this disease. These results provide an explanatory basis for the high vulnerability of the putamen in this disease, adding to the strong corticostriatal glutamatergic input into the putamen and the high excitotoxic susceptibility of neostriatal medium spiny neurons.

Prediction of tissue survival after stroke based on changes in the apparent diffusion of water (cytotoxic edema)

Article

Feb 2003
Acta Neurochir

This study tested the hypothesis that the estimate of the apparent diffusion coefficient (ADC; an index of cytotoxic edema) of water is a reliable pathophysiological index of the viability of ischemic brain tissue. CBF, the partition volume of water (PVW; an index of vasogenic edema), cerebral metabolic rate of oxygen (CMRO2), and of glucose (CMR(glc)) were measured before and after permanent middle cerebral artery occlusion (MCAO) or reperfusion with positron emission tomography (PET) in pigs. Then, the ADC was measured by diffusion-weighted magnetic resonance imaging (DW-MRI) and was compared with physiological variables obtained by PET and with histological findings. Both after permanent MCAO and reperfusion, the ADC was significantly correlated to the CMRO2 and CMR(glc). The sequential decrease of ADC was also correlated to the sequential reduction of CMRO2 in relation to the residual CBF after permanent MCAO. The infarction coincided with a threshold CMRO2 of 50% of the contralateral value and a threshold ADC of 75% of the contralateral value, respectively. The PVW was decreased in relation to the magnitude of residual CBF after MCAO, whereas it was transiently increased in the severely ischemic lesions below 75% of the contralateral ADC value after reperfusion. Thus, the ADC is a reliable pathophysiological index which allows therapy to be tailored to the condition of individual patients in clinical practice.

Time course of NAA T2 and ADC(w) in ischaemic stroke patients: H-1 MRS imaging and diffusion-weighted MRI

Article

Jun 2004
J NEUROL SCI

Proton spectroscopy and quantitative diffusion-weighted imaging (DWI) were used to investigate the pertinence of N-acetyl aspartate (NAA) as a reliable marker of neuronal density in human stroke. The time courses of tissue water apparent diffusion coefficient (ADC(w)) and metabolite T2 were investigated on a plane corresponding to the largest area of cerebral infarction, within and outside the site of infarction in 71 patients with a large cortical middle cerebral artery territory infarction. Significant reductions are seen in NAA T2 deep within the infarction during the period comprised between 5 and 20 days postinfarction; the relaxation times appearing to normalise several months after stroke. After an acute reduction in ADC(w), the pseudonormalisation of ADC(w) occurs at 8-12 days after the ischaemic insult. The minimum in N-acetyl aspartate T2 relaxation times and the pseudonormalisation of ADC(w) appear to coincide. The data suggest that modifications in the behaviour of the observed proton metabolites occur during the period when the vasogenic oedema is formed and cell membrane integrity is lost. For this reason, NAA may not be a reliable marker of neuronal density during this period.

3-Nitropropionic acid-induced neurotoxicity - Assessed by ultra high resolution positron emission tomography with comparison to magnetic resonance spectroscopy

Article

Jul 2004

To explore acute and long-term effects of 3-nitropropionic acid (3-NP)-induced neurotoxicity, longitudinal positron emission tomography (PET) studies of energy metabolism and magnetic resonance spectroscopic (MRS) studies of neurochemicals were conducted in a rat model. The first injection of 3-NP (20 mg/kg i.p.) was followed by MRS study of neurochemicals and PET study of glucose utilization using [(18)F]2-fluorodeoxy-D-glucose ((18)F-FDG). After that, 3-NP administration was done two times a day with a dose of 10 mg/kg i.p. until animals were symptomatic or for a maximum of 5 days combined with daily PET studies. Long-term effects were investigated 4 weeks and 4 months after cessation of 3-NP. These studies showed a significant inter-animal variation in response of 3-NP toxicity. Animals that developed large striatal lesions had decreased glucose utilization in the striatum and cortex 1 day after starting 3-NP injections. Similarly succinate and lactate/macromolecule levels were enhanced; these changes being, however, reversible. Progressive degeneration was observed by decreasing striatal glucose utilization and N-acetylaspartate (NAA) and increasing choline. These observations paralleled with weight loss and deficits in behavior. Animals that did not develop lesions showed reversible enhancement in cortical glucose utilization and no change in striatal glucose utilization or neurochemicals or locomotor activity.

Energy metabolism in mammalian brain during development

Article

Sep 2004
PROG NEUROBIOL

Production of energy for the maintenance of ionic disequilibria necessary for generation and transmission of nerve impulses is one of the primary functions of the brain. This review attempts to link the plethora of information on the maturation of the central nervous system with the ontogeny of ATP metabolism, placing special emphasis on variations that occur during development in different brain regions and across the mammalian species. It correlates morphological events and markers with biochemical changes in activities of enzymes and pathways that participate in the production of ATP. The paper also evaluates alterations in energy levels as a function of age and, based on the tenet that ATP synthesis and utilization cannot be considered in isolation, investigates maturational profiles of the key processes that utilize energy. Finally, an attempt is made to assess the relevance of currently available animal models to improvement of our understanding of the etiopathology of various disease states in the human infant. This is deemed essential for the development and testing of novel strategies for prevention and treatment of several severe neurological deficits.

Multimodal imaging of striatal degeneration in Amish patients with glutaryl-CoA dehydrogenase deficiency

Abstract

No full-text available

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