Article

Adrenoleukodystrophy: Incidence, new mutation rate, and results of extended family screening

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Abstract

Utilizing the plasma very long chain fatty acid assay, supplemented by mutation analysis and immunofluorescence assay, we determined the number of X-linked adrenoleukodystrophy (X-ALD) hemizygotes from the United States identified each year in the two laboratories that perform most of the assays in this country: the Kennedy Krieger Institute between 1981 and 1998 and the Mayo Clinic Rochester from 1996 to 1998. The minimum frequency of hemizygotes identified in the United States is estimated to be 1:42,000 and that of hemizygotes plus heterozygotes 1:16,800. Our studies involved 616 pedigrees with a total of 12,787 identified at-risk members. Diagnostic assays were performed in 4,169 at-risk persons (33%) and included members of the extended family. Only 5% of male probands and 1.7% of X-ALD hemizygotes were found to have new mutations. The extended family testing led to the identification of 594 hemizygotes and 1,270 heterozygotes. Two hundred fifty of the newly identified hemizygotes were asymptomatic and represent the group in which therapy has the greatest chance of success. Identification of heterozygotes provides the opportunity for disease prevention through genetic counseling. Diagnostic tests should be offered to all at-risk relatives of X-ALD patients and should include members of the extended family. Ann Neurol 2001;49:512–517

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... X-linked adrenoleukodystrophy (X-ALD), is the most common peroxisomal disorder, with an estimated incidence of ~1 in 17,000 births (male and female) and 1 in 21,000 males in the United States (Bezman et al., 2001). X-ALD is caused by mutations in the ABCD1 gene, located on the X chromosome ( Mosser et al., 1993). ...
... In the first year of screening in Minnesota, the birth prevalence of X-ALD in males was found to be 1 in 3,878. This birth prevalence is more than five times the incidence in males observed by Bezman et al. (2001) in which the incidence was calculated based on VLCFA results from two of the main laboratories that completed testing at the time, Kennedy Krieger Institute and Mayo Medical Laboratories ( Bezman et al., 2001). The birth prevalence found in Minnesota was also more than four times that observed in males detected by NBS in New York State, which was 1 in 16,074 (Caggana, 2018). ...
... In the first year of screening in Minnesota, the birth prevalence of X-ALD in males was found to be 1 in 3,878. This birth prevalence is more than five times the incidence in males observed by Bezman et al. (2001) in which the incidence was calculated based on VLCFA results from two of the main laboratories that completed testing at the time, Kennedy Krieger Institute and Mayo Medical Laboratories ( Bezman et al., 2001). The birth prevalence found in Minnesota was also more than four times that observed in males detected by NBS in New York State, which was 1 in 16,074 (Caggana, 2018). ...
... First appreciated through its more severe phenotypes in the 1910s and 1920s, X-linked adrenoleukodystrophy (X-ALD; MIM: 300100) is the most common peroxisomal disorder, affecting about 1 in 15,000 births [1,2]. It is caused by pathogenic variants in the ABCD1 gene, which encodes an ATP-binding cassette membrane protein that transports very-longchain saturated fatty acids (≥C22:0; VLCFAs) into the peroxisome for β-oxidation [3,4]. ...
... Previously, extended family screening suggested an X-ALD incidence of 1 in 17,000 births [1]. Incidence rates following implementation of NBS for the condition are higher, ranging from 1 in 4845 births in Minnesota to 1 in 16,200 in Illinois [2,[40][41][42][43][44]. Results from Pennsylvania fell within that range and recapitulated a higher incidence rate than previously appreciated. ...
... The higher incidence may also reflect identification of individuals with de novo variants and those without known family histories but who carry pathogenic variants. It was previously reported that 1.7% of X-ALD hemizygotes harbor de novo variants in ABCD1 [1]. Although we did not identify any de novo ABCD1 variants in hemizygote males, there were 2/23 (9%) identified among heterozygous females. ...
Article
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X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder. It results from pathogenic variants in ABCD1, which encodes the peroxisomal very-long-chain fatty acid transporter, causing a spectrum of neurodegenerative phenotypes. The childhood cerebral form of the disease is particularly devastating. Early diagnosis and intervention improve outcomes. Because newborn screening facilitates identification of at-risk individuals during their asymptomatic period, X-ALD was added to the Pennsylvania newborn screening program in 2017. We analyzed outcomes from the first four years of X-ALD newborn screening, which employed a two-tier approach and reflexive ABCD1 sequencing. There were 51 positive screens with elevated C26:0-lysophosphatidylcholine on second-tier screening. ABCD1 sequencing identified 21 hemizygous males and 24 heterozygous females, and clinical follow up identified four patients with peroxisomal biogenesis disorders. There were two false-positive cases and one false-negative case. Three unscreened individuals, two of whom were symptomatic, were diagnosed following their young siblings’ newborn screening results. Combined with experiences from six other states, this suggests a U.S. incidence of roughly 1 in 10,500, higher than had been previously reported. Many of these infants lack a known family history of X-ALD. Together, these data highlight both the achievements and challenges of newborn screening for X-ALD.
... X-linked adrenoleukodystrophy (X-ALD) is a genetic neurodegenerative disorder resulting from mutations in the ABCD1 gene. It has an estimated incidence in the United States population of 1 in 14,700 births [1]. The disorder is associated with impaired peroxisomal oxidation of very-long-chain fatty acids (VLCFA) and VLCFA elevations as measured in plasma. ...
... Overall, 91 of 276,000 infants (0.03%) had a positive or borderline result requiring some type of further testing. 1 Values for C26:0-LPC are expressed as µmol/L. 2 Value for n includes four males, seven female heterozygotes, and one female homozygous for ABCD1 mutation due to isodisomy X. ...
... Outcome of newborn screening for X-ALD in Illinois from 18 June 2019 to 31 May 2021.1 Values for C26:0-LPC are expressed as µmol/L. ...
Article
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X-linked adrenoleukodystrophy (X-ALD) is a genetic neurodegenerative disorder with an approximate incidence of 1 in 14,700 births. Both males and females are affected. Approximately one-third of affected males develop childhood cerebral adrenoleukodystrophy, which progresses rapidly to severe disability and death. In these cases, early surveillance and treatment can be lifesaving, but only if initiated before the onset of neurologic symptoms. Therefore, X-ALD was added to the Recommended Uniform Screening Panel. We report outcomes of the initial screening of approximately 276,000 newborns in Illinois. The lipid C26:0 lysophosphatidylcholine (C26:0-LPC) was measured in dried blood spots (DBS) using liquid chromatography with tandem mass spectrometry. Results ≥ 0.28 µmol/L were considered screen positive. Of 18 screen positive results detected, 12 cases were confirmed. Results were reported as borderline if initial and repeat analyses were ≥0.18 and <0.28 µmol/L. Of the 73 borderline screen results, 57 were normal after analysis of a second sample. Five X-ALD cases were identified from borderline screens. Newborn screening of X-ALD was successfully implemented in Illinois, and results were comparable to reports from other states. Early identification of infants with this potentially life-threatening disorder will significantly improve outcomes for these children.
... adrenoleukodystrophy (X-ALD; OMIM #300100) has an incidence of 1:15 000 and is therefore the most common monogenetic neuroinflammatory disorder that mainly affects the central and peripheral nervous system as well as the adrenal cortex and testis. [1][2][3] The disease is caused by mutations in the ABCD1 gene encoding the adrenoleukodystrophy protein (ALDP), a peroxisomal ATP binding cassette transporter at the organelle membrane, resulting in the accumulation of very long-chain fatty acids (VLCFA) in organs and plasma. Human phenotypes range from asymptomatic carriers to severe childhood cerebral X-ALD (CCALD). ...
... and ns P ≥ .05. Serum of individual patients, who were included in more than one disease group were labeled with numbers (1)(2)(3) locally in the tissue and have a short half-life. Thus, the measurement of the AA itself is usually not possible. ...
Article
Full-text available
X‐linked adrenoleukodystrophy (X‐ALD) is the most common leukodystrophy. Despite intensive research in recent years, it remains unclear, what drives the different clinical disease courses. Due to this missing pathophysiological link, therapy for the childhood cerebral disease course of X‐ALD (CCALD) remains symptomatic; the allogenic hematopoietic stem cell transplantation or hematopoietic stem‐cell gene therapy is an option for early disease stages. The inclusion of dried blood spot (DBS) C26:0‐lysophosphatidylcholine to newborn screening in an increasing number of countries is leading to an increasing number of X‐ALD patients diagnosed at risk for CCALD. Current follow‐up in asymptomatic boys with X‐ALD requires repetitive cerebral MRIs under sedation. A reliable and easily accessible biomarker that predicts CCALD would therefore be of great value. Here we report the application of targeted metabolomics by AbsoluteIDQ® p180‐Kit from Biocrates to search for suitable biomarkers in X‐ALD. LysoPC a C20:3 and lysoPC a C20:4 were identified as metabolites that indicate neuroinflammation after induction of experimental autoimmune encephalitis in the serum of Abcd1tm1Kds mice. Analysis of serum from X‐ALD patients also revealed different concentrations of these lipids at different disease stages. Further studies in a larger cohort of X‐ALD patient sera are needed to proof the diagnostic value of these lipids for use as early biomarkers for neuroinflammation in CCALD patients.
... X-linked adrenoleukodystrophy (ALD) is the most common inherited peroxisomal disorder, which is caused by variants in the X chromosome ATP binding cassette subfamily D member 1 (ABCD1) gene [1,2]. Mostly manifested among males, the disorder can lead to increased concentrations of very long-chain fatty acids (VLCFA) in plasma, as well as in adrenal and nervous tissues, affecting the adrenal cortex and the central nervous system with a wide range of clinical phenotypes that include adrenal insufficiency, adrenomyeloneuropathy (AMN), and its most severe form, childhood cerebral ALD [3][4][5]. ...
... The reduction could be extended to over 60% if a more aggressive informative threshold was used. Without any reduction in diagnosed ALD cases with VUS, the prevalence of ALD in California screening population was about 1 in 10,000, higher than that reported in the earlier literature (1 in 21,000) and in New York (1 in 16,074) [2,28], although significantly lower than that reported by Minnesota [21]. With a more aggressive interpretation algorithm when using the CLIR POX tool, the reduction in ALD cases would lead to a prevalence that was similar to the prevalence reported by the New York newborn screening program. ...
Article
Full-text available
Since the start of X-linked adrenoleukodystrophy (ALD) newborn screening in California, more than half of the diagnosed cases were found to have an ATP binding cassette subfamily D member 1 (ABCD1) gene variant of uncertain significance (VUS). To determine retrospectively the likelihood that these were true positive cases, we used a web-based post-analytical tool in Collaborative Laboratory Integrated Reports (CLIR). Confirmatory plasma very long-chain fatty-acids (VLCFA) profiles for ALD screen positive infant boys were run through the CLIR ALD tool. We compared the distribution by ABCD1 variant classification (pathogenic, likely pathogenic, VUS, and no variant) with the CLIR tool score interpretation (non-informative, possibly ALD, likely ALD, and very likely ALD) and the current case diagnosis. The study showed that CLIR tool positive interpretations were consistent with 100% of the pathogenic and likely pathogenic variants on the ABCD1 gene if a more conservative guideline was used. The tool interpretations were also consistent with screened cases that were determined to not have disease (our no-disorder group). The CLIR tool identified 19 diagnosed ALD cases with VUS to be potential false positives, representing a 40% reduction among all diagnosed ALD cases with VUS. The reduction could be extended to 65% if a more aggressive threshold was used. Identifying such preventable false positives could alleviate the follow-up burden for patients, their families, and California Special Care Centers.
... These defects may alter the ability to extract necessary energy from nutrients, leading to metabolic disorders and/or the accumulation of toxic intermediate metabolites. X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by mutations in the ABCD1 gene and affects approximately 1 in 42,000 men [76,77]. In addition, 1 out of 28,000 women carry heterozygous mutations in ABCD1 [77]. ...
... X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by mutations in the ABCD1 gene and affects approximately 1 in 42,000 men [76,77]. In addition, 1 out of 28,000 women carry heterozygous mutations in ABCD1 [77]. Newborn screening for X-ALD is based on recording an elevated level of a very-long-chain fatty acid derivative of lysophosphatidylcholine (C26: 0-LPC) in DBS samples. ...
Article
Full-text available
Over the past few years, dried blood spot (DBS) technology has become a convenient tool in both qualitative and quantitative biological analysis. DBS technology consists of a membrane carrier (MC) on the surface of which a biomaterial sample becomes absorbed. Modern analytical, immunological or genomic methods can be employed for analysis after drying the sample. DBS has been described as the most appropriate method for biomaterial sampling due to specific associated inherent advantages, including the small volumes of biomaterials required, the absence of a need for special conditions for samples’ storage and transportation, improved stability of analytes and reduced risk of infection resulting from contaminated samples. This review illustrates information on the current state of DBS technology, which can be useful and helpful for biomedical researchers. The prospects of using this technology to assess the metabolomic profile, assessment, diagnosis of communicable diseases are demonstrated.
... Incidence is estimated 1 in 20,000 males, and 1 in 17,000 births (combined male and female). 1 There are multiple phenotypes of ALD depending on age at presentation and gender of the carrier. In male children, ALD can present with isolated Addison's disease with or without slow progressive cognitive deterioration or cerebral ALD (cerALD). ...
... In total, 40% of boys diagnosed with ALD develop cerALD in their first two decades of life, and other 20% develop cerALD in adulthood. 1 Surprisingly, genotype does not predict the likelihood of severe cerALD phenotype. Significant intrafamilial phenotype variability has been observed as different clinical phenotypes can occur even among monozygotic twins. ...
Article
X-linked adrenoleukodystrophy (ALD) is a leukodystrophy characterized not only by progressive loss of myelin in the central nervous system due to dysmyelination, but also by acute, subacute, or chronic inflammatory demyelination. This results in the phenotypic variability of cerebral ALD (cerALD), which is independent of the genotype. In this manuscript, we report a fulminant presentation with fluctuating encephalopathy and visual loss in a patient with childhood onset cerALD. Brain MRI showed symmetric confluent occipito-temporal demyelination with severe disruption of the blood–brain barrier and prechiasmal optic neuropathy. The patient's cerebral spinal fluid (CSF) demonstrated an elevated IgG index, myelin basic proteins, and oligoclonal bands. Within 48 hours of receiving immunomodulating therapy, the patient's symptoms of psychomotor slowing, visual impairment, and areflexia partially resolved. High plasma C26:0 levels and high ratios of C24/22 and C26/22 were diagnostic of ALD. It has been shown that environmental factors play an important role in the inflammatory demyelination responsible for the severe phenotypes of cerALD.
... The most severe presentations of ALD occur in males, but 80% of females with ALD manifest milder myelopathy symptoms by the age of 60 years [13]. Prior to the introduction of newborn screening, the incidence of ALD in the United States was described to be 1:21,000 males and 1:16,800 females [14]. A retrospective study of the US Children's Hospital Association's Pediatric Health Information System database noted higher frequencies of ABCD1 pathogenic variants in those of Latino and African descent, despite higher diagnostic rates in those of non-Hispanic Caucasian descent, suggesting a potential racial bias in diagnosis prior to newborn screening [15]. ...
... A retrospective study of the US Children's Hospital Association's Pediatric Health Information System database noted higher frequencies of ABCD1 pathogenic variants in those of Latino and African descent, despite higher diagnostic rates in those of non-Hispanic Caucasian descent, suggesting a potential racial bias in diagnosis prior to newborn screening [15]. While de novo variants do occur (estimates~5%), the sex discrepancy, as well as the racial disparities in diagnosis, have been hypothesized to be at least in part due to unrecognized adrenal insufficiency [14,[16][17][18]. The published prevalence of ALD based on newborn screening has varied but is consistent with improved identification of those with ALD. ...
Article
Full-text available
Adrenoleukodystrophy (ALD) is a peroxisomal disorder affecting the nervous system, adrenal cortical function, and testicular function. Newborn screening for ALD has the potential to identify patients at high risk for life-threatening adrenal crisis and cerebral ALD. The current understanding of the natural history of endocrine dysfunction is limited. Surveillance guidelines for males with ALD were developed to address the unpredictable nature of evolving adrenal insufficiency. Early recognition and management of adrenal insufficiency can prevent adrenal crisis. While testicular dysfunction in ALD is described, the natural history and complications of low testosterone, as well as the management, are not well described.
... PAI is often the first documented clinical finding in boys with X-linked adrenoleukodystrophy (X-ALD). X-ALD is a rare (1/14 700-20 000 live male births) genetic disorder in which deficiency of a peroxisomal membrane protein (ALDP) leads to accumulation of very long chain fatty acid (VLCFA; ≥C22) in the plasma, white matter, spinal cord, and adrenal cortex [3][4][5]. It presents more severely in males and is often categorized into 3 main clinical phenotypes. ...
... MRI demonstrated cerebral involvement. The patient's brother was also found to have elevated ACTH (>1250 pg/mL, ref < 47) and a low normal cortisol level (6.8 µg/dL, ref [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] consistent with primary adrenal insufficiency. ...
Article
Full-text available
Primary adrenal insufficiency (PAI) is often the first clinical sign of X-linked adrenoleukodystrophy (X-ALD), a rare genetic disorder that can present with various clinical phenotypes. A subset of boys with X-ALD develop cerebral ALD (cALD), characterized by progressive central demyelination, neurocognitive decline, and ultimately death. Timely intervention with hematopoietic cell transplant (HCT) can be a life-saving therapy by stopping progression of cerebral disease. We report the case of an eleven-year-old boy with Type 1 Diabetes Mellitus (T1DM) who presented with PAI, growth delay, and symptoms of attention deficit hyperactivity disorder (ADHD). Given his history of T1DM his PAI was presumed to be autoimmune and he was started on hydrocortisone and fludrocortisone. Eleven months later a brain MRI revealed white matter hyperintensity consistent with advanced cALD. The degree of disease progression at the time of diagnosis rendered the patient ineligible for transplant and he has continued to experience progressive neurologic decline. Initial symptoms of cALD are often subtle but should not be overlooked, as early identification of X-ALD is critical to allow early intervention with lifesaving HCT. PAI typically presents prior to the onset of neurologic symptoms. All boys who present with PAI should undergo workup for X-ALD with plasma very long chain fatty acid (VLCFA) testing, even in the setting of underlying autoimmune disease.
... ALD is an X-linked peroxisomal disorder caused by mutations in the ABCD1 gene leading to accumulation of VLCFAs primarily in the CNS and adrenal tissue. ALD has a complex clinical presentation that is progressive in nature and cannot be predicted by genotype [63,64]. Nearly all males with ALD will develop adrenal insufficiency, although the timing is variable [65,66]. ...
... Adrenal insufficiency (recognized or clinically silent) often precedes neurologic symptoms [8]. Cerebral disease is the most severe manifestation of ALD, occurring in approximately 40% of individuals during childhood or adolescence [63,67]. Early neurologic findings of cALD include behavior changes or attention issues and, if untreated, lead to rapid neurologic decline and death [8]. ...
Article
Full-text available
The leukodystrophies are a heterogeneous group of inherited diseases characterized by progressive demyelination of the central nervous system leading to devastating neurologic symptoms and premature death. Hematopoietic stem cell transplantation (HSCT) has been successfully used to treat certain leukodystrophies, including adrenoleukodystrophy, globoid leukodystrophy (Krabbe disease), and metachromatic leukodystrophy, over the past 30 years. To date, these complex patients have primarily been transplanted at a limited number of pediatric centers. As the number of cases identified through pregnancy and newborn screening is increasing, additional centers will be required to treat these children. Hunter's Hope created the Leukodystrophy Care Network in part to create and standardize high-quality clinical practice guidelines to guide the care of affected patients. In this report the clinical guidelines for the care of pediatric patients with leukodystrophies undergoing treatment with HSCT are presented. The initial transplant evaluation, determination of patient eligibility, donor selection, conditioning, supportive care, and post-transplant follow-up are discussed. Throughout these guidelines the need for early detection and treatment and the role of the partnership between families and multidisciplinary providers are emphasized.
... Adrenoleukodystrophy is a neurodegenerative disorder being reported in all ethnic groups and populations. Its prevalence is estimated between 1:20,000 and 1:50,000 which is almost the same between different ethnic groups [15]. Genetic analysis is important in the case of prenatal diagnosis of X-ALD, because the VLCFA level of cultured chorionic villus cells may be normal in the affected fetus, so genetic analysis should be considered prior to the detection of VLCFA level [16]. ...
Article
Background X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disorder, is caused by mutations in the ABCD1 gene located on Xq28. X-ALD is characterized by a spectrum of different manifestations varying in patients and families. Methods Four pedigrees with X-ALD consisting of patients and healthy members were selected for investigation of ABCD1 gene mutations. The mutation analysis was performed by polymerase chain reaction (PCR) followed by direct sequencing of all exons. The identified mutations were investigated using bioinformatics tools to predict their effects on the protein product and also to compare the mutated sequence with close species. Results One previously known missense mutation (c.1978 C > T) and three novel mutations (c.1797dupT, c.879delC, c.1218 C > G) were identified in the ABCD1 gene, each in one family. Predicting the effects of the mutations on protein structure and function indicated the probable damaging effect for them with significant alterations in the protein structure. We found three novel mutations in the ABCD1 gene with damaging effects on its protein product and responsible for X-ALD.
... X-ALD is caused by mutations in the ABCD1 gene located at Xq28. The incidence of X-ALD has been reported to be 1:21,000 in males and 1:14,000 in females [1] . Primary adrenal insufficiency (Addison´s disease) is reported to develop in up to 86% of males with X-ALD. ...
Article
Cardiac tamponade is a life-threatening medical emergency and can arise in many clinical situations. We present the case of a 59-year-old man with adrenoleukodystrophy and Addison’s disease who was admitted to the emergency department with severe abdominal pain that turned out to be cardiac tamponade of unknown aetiology. An association between cardiac tamponade and Addison’s disease has been reported in the literature, so this aetiology should be considered in the differential diagnosis for patients presenting with unexplained cardiac tamponade.
... The incidence of X-ALD has been reported to be 1:21,000 in males and 1:14,000 in females. 25 And most patients are misdiagnosed as other diseases such as multiple sclerosis and hereditary spastic paraparesis, especially for heterozygous female carriers. The clinical phenotypes of X-ALD vary greatly among males than female patients, and can be classified into the following categories: childhood cerebral ALD, adolescent cerebral ALD, adolescent cerebral ALD, AMN, Addison-only, preclinical type and asymptomatic ALD. 26 According to the affected sites and imaging features, AMN can be further classified: firstly, Cerebral AMN: The patient presents spinal symptoms accompanied by leukodystrophy and cognitive dysfunction. ...
Article
Full-text available
Adrenomyeloneuropathy (AMN) is a kind of varied disease caused by ABCD1 gene mutation and characterized by very-long-chain fatty acids (VLCFA) accumulation. It is diagnosed by clinical features, high VLCFAs levels and ABCD1 gene mutation. AMN is rarely reported in Chinese population. In this study, we report the genetic and clinical features of a Chinese pure AMN patient. Meanwhile, we conducted a literature review of AMN cases to summarize the characteristics of AMN. We report a rare Chinese pure AMN case with slowly progressive weakness of the lower extremities, caused by a novel c.1202G > A mutation in ABCD1 gene. The literature review indicates that spastic paraplegia is the mainly clinical manifestation in patients with AMN. VLCFAs and ABCD1 gene test should be performed in patients with spastic paraplegia of the lower limbs to diagnose AMN.
... X-linked adrenoleukodystrophy (ALD, OMIM:300100) is a rare genetic disease with an overall frequency of 1:17,000 [1]. The clinical manifestation of ALD is expressed as inflammatory cerebral demyelination, progressive myelopathy, and endocrine dysfunction such as an adrenal insufficiency or gonadal dysfunction [2]. ...
Preprint
X-linked adrenoleukodystrophy (ALD) caused by the ABCD1 mutation, is the most common inherited peroxisomal disease. It is characterized by three phenotypes: inflammatory cerebral demyelination, progressive myelopathy, and adrenal insufficiency, but there is no genotype-phenotype correlation. Hematopoietic stem cell transplantation can only be used in a few patients in the early phase of cerebral inflammation; therefore, most affected patients have no curative option. Previously, we reported the generation of an ALD patient-derived iPSC model and its differentiation to oligodendrocytes. In this study, we have performed the first genome editing of ALD patient-derived iPSCs using homology-directed repair (HDR). The mutation site, c.1534G>A [GenBank: NM_000033.4 ], was corrected by introducing ssODN and the CRISPR/Cas9 system. The cell line exhibited normal ALD protein expression following genome editing. We differentiated the intermediate oligodendrocytes from mutation-corrected iPSCs and the metabolic derangement of ALD tended to correct but was not statistically significant. Mutation-corrected iPSCs from ALD patient can be used in research into the pathophysiology of and therapeutics for ALD.
... Based on the experience of New York State's, Minnesota's, and North Carolina's NBS for ALD, the birth prevalence of ALD in Minnesota is strikingly high, with 1 in 3878 male infants affected, which is more than 5 times the estimated incidence of 1 in 21 000 males based on VLCFA testing from Kennedy Krieger Institute and Mayo Medical Laboratories, 4 times the birth prevalence of 1 in 16 074 detected by NBS in New York State, and double the prevalence of 1 in 8814 males in North Carolina (10,12,(41)(42)(43). One potential explanation for the differences in birth prevalence of ALD in the 3 states is the cutoff level of C26:0-LPC used to define an abnormal value. ...
Article
Adrenoleukodystrophy (ALD) is a rare X-linked disorder of peroxisomal oxidation due to mutations in ABCD1. It is a progressive condition with a variable clinical spectrum that includes primary adrenal insufficiency, myelopathy, and cerebral ALD. Adrenal insufficiency affects over 80% of ALD patients. Cerebral ALD affects one-third of boys under the age of 12 years and progresses to total disability and death without treatment. Hematopoietic stem cell transplantation (HSCT) remains the only disease-modifying therapy if completed in the early stages of cerebral ALD, but does not affect the course of adrenal insufficiency. It has significant associated morbidity and mortality. A recent gene therapy clinical trial for ALD reported short-term MRI and neurological outcomes comparable to historical patients treated with HSCT without the associated adverse side effects. In addition, over a dozen states have started newborn screening (NBS) for ALD, and the number of states is expected to double in 2020. Genetic testing of NBS-positive neonates has identified novel variants of unknown significance, providing further opportunity for genetic characterization but also uncertainty in the monitoring and therapy of subclinical and/or mild adrenal insufficiency or cerebral involvement. As more individuals with ALD are identified at birth, it remains uncertain if availability of matched donors, transplant (and potentially, gene therapy) centers, and specialists may affect the timely treatment of these individuals. As these promising gene therapy trials and newborn screening transform the clinical management and outcomes of ALD, there will be an increasing need for the endocrine management of pre-symptomatic and subclinical adrenal insufficiency.
... Accumulation of VLCFAs causes demyelination in the central nervous system (CNS) and adrenal insufficiency in the adrenal cortex [2]. X-ALD occurs in approximately 1 in 20,000 births for hemizygotes and 1 in 16,800 for heterozygotes [3]. As clinical signs and symptoms overlap considerably with more common demyelinating, cerebrovascular, or metabolic disorders, diagnosis and disposition into an appropriate pipeline of care is a challenge without clearly defined guidelines. ...
Article
Full-text available
X-linked adrenoleukodystrophy (X-ALD) is a metabolic disorder characterized by endocrine and neurological degeneration. A rare and variegated entity in adults, diagnosis is often a significant challenge and can lead to extensive testing, including invasive procedures if clinical suspicion is not high. We present the case of a 46-year-old-male with neurological dysfunction that is uncommon in X-ALD with preserved adrenocortical function. Initially misdiagnosed with multiple sclerosis, the patient faced a significant neurological and cognitive decline in a short follow-up time frame, ultimately losing meaningful independent function. Emphasis is placed on criteria for appropriate discernment based on imaging studies and previous literature data. We also highlight the value of shared decision making to maximize the quality of life in such advanced stage neurodegenerative disorders.
... The group of single enzyme deficiency results in the loss of a single peroxisomal function and includes more than 10 disorders, out of which the most common ones are: X-linked adrenoleukodystrophy (X-ALD; OMIM #300100) and D-bifunctional protein deficiency (DBP; OMIM #261515), with the frequency of 1:17.000 and 1:100.000 respectively [12,13]. The defect of peroxisomal functions consequently leads to changes in the levels of relevant metabolites detected in body fluids. ...
Article
Full-text available
Peroxisomal disorders (PD) are a heterogeneous group of rare diseases caused by a defect in peroxisome biogenesis or a disruption of a peroxisomal function at a single enzyme or at transporter level. The main biochemical markers for PD are very long-chain fatty acids (VLCFA). The aim of the study was to investigate the correlation of basic diagnostic parameter, i.e. VLCFA, with disease severity, determined through the survival time. We performed a retrospective study in patients with PD (n = 31; aged 1 week—21 years). Evaluation of VLCFA results from patients were as follows: 15 patients with classical Zellweger syndrome (ZS), 3 patients with mild outcome of ZS, 9 individuals with D-Bifunctional Protein Deficiency (DBP), and no specified results in the case of 4 patients. Patients with classical ZS had higher VLCFA levels, compared to individuals with mild form of ZS and also to patients with DBP; for C26:0/C22:0: 0.65±0.18; 0.11±0.09; 0.30±0.13 (P < 0.001) and for C26:0: 5.20±1.78; 0.76±0.46; 2.61±0.97[mg/mL] (P < 0.001) respectively. The only variable parameter, i.e. the one that determines the survival time of patients, was C26:0 (Chi² = 19,311, P < 0.0001). Correlation coefficient between survival time and C26:0 level was statistically significant (r = -0.762), and the results showed that high levels of C26:0 were associated with short survival time. Conclusion VLCFA levels correlate with the severity of the clinical course of ZS, DBP and mild ZSD. The best predictive value for estimating the projected disease severity and survival time is a concentration of C26:0.
... With an estimated birth prevalence of 1 in 17,000, X-linked adrenoleukodystrophy (ALD, OMIN 300100) is the most common inherited peroxisomal disorder [1,2]. ALD is caused by variants in the ATP binding cassette subfamily D member 1 (ABCD1) gene, located on the X chromosome, which can lead to increased concentrations of very longchain fatty acids (VLCFAs) in plasma, as well as in adrenal and nervous tissues [3,4]. ...
Article
Full-text available
X-linked adrenoleukodystrophy (ALD) is a recent addition to the Recommended Uniform Screening Panel, prompting many states to begin screening newborns for the disorder. We provide California’s experience with ALD newborn screening, highlighting the clinical and epidemiological outcomes observed as well as program implementation challenges. In this retrospective cohort study, we examine ALD newborn screening results and clinical outcomes for 1,854,631 newborns whose specimens were received by the California Genetic Disease Screening Program from 16 February 2016 through 15 February 2020. In the first four years of ALD newborn screening in California, 355 newborns screened positive for ALD, including 147 (41%) with an ABCD1 variant of uncertain significance (VUS) and 95 males diagnosed with ALD. After modifying cutoffs, we observed an ALD birth prevalence of 1 in 14,397 males. Long-term follow-up identified 14 males with signs of adrenal involvement. This study adds to a growing body of literature reporting on outcomes of newborn screening for ALD and offering a glimpse of what other large newborn screening programs can expect when adding ALD to their screening panel.
... Adrenal insufficiency is the deficiency of hormones produced by the adrenal gland cortex. It has a prevalence of 5 out of 10,000 individuals in the general population [1]. The most common cause is autoimmune disease, accounting for 70% to 90%. ...
... X-linked adrenoleukodystrophy (X-ALD; Online Mendelian Inheritance in Man no. 300100) is the most common type of inherited peroxisomal disorder and monogenic leukodystrophy that occurs in ~1 in 17,000 live male births with no apparent difference in the prevalence among different ethnicities (1). The clinical manifestation is highly variable, including progressive demyelination of the central and peripheral nervous systems, adrenal insufficiency, and accumulation of very long chain fatty acids (VLCFAs) in body fluid and tissues (2). ...
Article
X-linked adrenoleukodystrophy (X-ALD) is the most frequent type of inherited demyelinating peroxisomal disease caused by mutations in the ATP binding cassette subfamily D member 1 (ABCD1) gene. The rate of early recognition and genetic diagnosis of X-ALD remains low due to its variable clinical manifestations. The present study summarized the clinical features Chinese X-ALD patients and performed a follow-up study to further precisely characterize this disease. A total of 10 patients diagnosed with X-ALD between 1994 and 2016 at Shandong Provincial Hospital Affiliated to Shandong University (Jinan, China) were included in the present study. Through reviewing their medical records and performing telephone follow-ups, the clinical features, biochemical laboratory data, brain images, treatments and long-term outcomes were retrospectively summarized. Mutation analysis of the ABCD1 gene was performed in certain patients. Most of the patients (8/10) had the childhood cerebral form of X-ALD. One patient presented with the olivo-ponto-cerebellar form, the rarest form of X-ALD. In all patients, brain magnetic resonance images revealed abnormalities with typical T2-weighted hyperintensity. Analysis of very long chain fatty acid revealed high plasma levels of hexacosanoic acid in all patients. Increased adrenocorticotropic hormone, decreased cortisol and neurophysiological manifestations were also observed. Three different mutations of the ABCD1 gene were identified in the 3 patients subjected to genotyping. During the follow-ups, most patients took neurotrophic drugs and received hydrocortisone replacement when required. One patient received a hematopoietic stem cell transplantation, but died 1 year following the transplantation. Chronic myelopathy and peripheral neuropathy progressed with time, gradually leading to a vegetative state or paralysis within several years of clinical symptom onset. In conclusion, male patients with adrenocortical insufficiency should be further investigated for X-ALD. Early detection is critical to prevent the progression of X-ALD with mutation analysis of ABCD1 the most accurate method to confirm diagnosis.
... Expanding worldwide availability of newborn screening for X-ALD will significantly aid in early diagnosis, monitoring and initiation of appropriate treatment. 15 The incidence of X-ALD has been reported to be approximately 1 in 20000 worldwide, [16][17][18] but data from newborn screening may be changing that estimate. In the United States, the incidence of X-ALD as determined by newborn screening differs from the worldwide incidence and varies substantially by state, for example: 1:15000 in New York versus 1:4845 in Minnesota. ...
Preprint
X-linked adrenoleukodystrophy (X-ALD) is an inherited, neurodegenerative rare disease that can result in devastating symptoms of blindness, gait disturbances, and spastic quadriparesis due to progressive demyelination. Typically, the disease progresses rapidly, causing death within the first decade of life. With limited treatments available, efforts to determine an effective therapy that can alter disease progression or mitigate symptoms have been undertaken for many years, particularly through drug repurposing. Repurposing has generally been guided through clinical experience and small trials. At this time, none of the drug candidates have been approved for use, which may be due, in part, to the lack of pharmacokinetic/pharmacodynamic (PK/PD) information on the repurposed medications in the target patient population. Greater consideration for the disease pathophysiology, drug pharmacology, and potential drug-target interactions, specifically at the site of action, would improve drug repurposing and facilitate development. Although there is a good understanding of X-ALD pathophysiology, the absence of information on drug targets, pharmacokinetics, and pharmacodynamics hinders the repurposing of drugs for this condition. Incorporating advanced translational and clinical pharmacological approaches in preclinical studies and early stages clinical trials will improve the success of repurposed drugs for X-ALD as well as other rare diseases.
... X-linked adrenoleukodystrophy (ALD) is both the most common inborn error of metabolism of peroxisomal beta-oxidation and the most frequent monogenetically inherited demyelinating disorder [1]. In the United States, the estimated overall minimum frequency is about 1:21,000 for hemizygote men and 1:14,000 for heterozygote women [2]. Now that newborn screening has been implemented in some parts of the world, the true prevalence could be even higher [3]. ...
Chapter
X-linked adrenoleukodystrophy (ALD) is the most common inborn error of peroxisomal beta-oxidation, caused by pathogenic variants in the ABCD1 gene, affecting the functioning of a protein responsible for the transportation of very long-chain fatty acids (VLCFA) into the peroxisome. This defect results in the accumulation of VLCFA in different tissues, specially the central nervous system, suprarenal glands, and testis. There is no genotype-phenotype correlation, and affected families have a noticeable intrafamilial variability. Several different clinical presentations have been described for men with ALD, including a pre-symptomatic state, cerebral demyelinating ALD, adrenomyeloneuropathy (AMN), Addison’s disease, and a spinocerebellar subtype. The lifetime risk of Addison’s disease in ABCD1 carriers is about 80%. Virtually all men and up to 80% of heterozygous women develop AMN. Women present with milder and usually later-onset myelopathy than men. Neuroimaging carries diagnostic and prognostic implications. The diagnosis is based on the biochemical analysis of VLCFA plasma levels (although less sensitive in women), and/or genetic testing. A newborn ALD screening is now available. There is no cure, but early hematopoietic stem cell transplantation can arrest brain demyelination in appropriate candidates. Preventing Addisonian crisis is a mainstay in patient management, through corticosteroid replacement. Symptomatic treatment for AMN is primarily based on relieving spasticity and pain.
... Notably, there is no established genotype and phenotype correlation in X-ALD [2,3]. While a range of clinical manifestations are observed in both sexes, approximately 30% of males who possess a pathogenic ABCD1 variant become afflicted with severe cerebral adrenoleukodystrophy (CALD) characterized by the demyelination of nerve cells within the brain [3][4][5][6][7][8]. Symptoms include dementia, seizures, loss of muscle control, hearing loss, and learning disabilities, but it ultimately leads to death within a few years. ...
Article
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X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder caused by pathogenic variants in the ATP-binding cassette subfamily D member 1 gene (ABCD1) that encodes the adrenoleukodystrophy protein (ALDP). Defects in ALDP result in elevated cerotic acid, and lead to C26:0-lysophosphatidylcholine (C26:0-LPC) accumulation, which is the primary biomarker used in newborn screening (NBS) for X-ALD. C26:0-LPC levels were measured in dried blood spot (DBS) NBS specimens using a flow injection analysis (FIA) coupled with electrospray ionization (ESI) tandem mass spectrometry (MS/MS) performed in negative ion mode. The method was validated by assessing and confirming linearity, accuracy, and precision. We have also established C26:0-LPC cutoff values that identify newborns at risk for X-ALD. The mean concentration of C26:0-LPC in 5881 de-identified residual routine NBS specimens was 0.07 ± 0.02 µM (mean + 1 standard deviation (SD)). All tested true X-ALD positive and negative samples were correctly identified based on C26:0-LPC cutoff concentrations for borderline between 0.15 µM and 0.22 µM (mean + 4 SD) and presumptive screening positive at ≥0.23 µM (mean + 8 SD). The presented FIA method shortens analysis run-time to 1.7 min, while maintaining the previously established advantage of utilizing negative mode MS to eliminate isobaric interferences that could lead to screening false positives.
... se consideriamo i maschi eterozigoti e diviene di 1:17.000 se consideriamo sia i maschi che le femmine eterozigoti [1]. Il gene candidato che sintetizza la proteina di membrana perossisomale (ALDP) mappa a livello del braccio lungo del cromosoma X (Xq28). ...
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Sommario L’adrenoleucodistrofia/adrenomieloneuropatia (ALD/AMN) è una patologia invalidante che, ad oggi, non ha una terapia definitiva, anche se il trapianto di midollo e la terapia genica hanno mostrato in pazienti selezionati la possibilità di rallentare e/o arrestare l’evoluzione clinica. Nella seguente rassegna si delineano le varie opzioni e gli approcci terapeutici tentati fino ad oggi con l’intento di normalizzare il difetto metabolico e di ridurre l’infiammazione del sistema nervoso centrale. Si passa in rassegna una serie di esperienze che dal 1980 ad oggi hanno contribuito a un’evoluzione terapeutica che ha permesso di rallentare e, in alcuni casi, di arrestare l’evoluzione clinica di una malattia devastante da un punto di vista neurologico.
... ABCD1 encodes for a gene product that affects the transportation of very long-chain fatty acids (VLCFAs) to peroxisomes. The loss of ABCD1 function implicates VLCFAs accumulation, and can lead to neurologic and adrenal dysfunction [1]. Cerebral X-ALD (cALD) is a severe form that generally affects young boys, is associated with cerebral inflammation and demyelination, and is generally progressive and lethal. ...
Article
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Cerebral adrenoleukodystrophy (ALD) is a rare neuroinflammatory disorder characterized by progressive demyelination. Mutations within the ABCD1 gene result in very long-chain fatty acid (VLCFA) accumulation within the peroxisome, particularly in the brain. While this VLCFA accumulation is known to be the driving cause of the disease, oxidative stress can be a contributing factor. For patients with early cerebral disease, allogeneic hematopoietic stem cell transplantation (HSCT) is the standard of care, and this can be supported by antioxidants. To evaluate the involvement of fatty acid oxidation in the disease, F2-isoprostanes (F2-IsoPs), F2-dihomo-isoprostanes (F2-dihomo-IsoPs) and F4-neuroprostanes (F4-NeuroPs)—which are oxygenated metabolites of arachidonic (ARA), adrenic (AdA) and docosahexaenoic (DHA) acids, respectively—in plasma samples from ALD subjects (n = 20)—with various phenotypes of the disease-were measured. Three ALD groups were classified according to patients with: (1) confirmed diagnosis of ALD but without cerebral disease; (2) cerebral disease in early period post-HSCT (
... Adrenoleukodystrophy (ALD) is a rare X-linked metabolic disorder resulting from ABCD1 gene mutations with an estimated incidence of 1/20 000 to 1/30 000 males. 1,2 Mutations lead to deficiency of the peroxisomal membrane ALD protein important in transporting very long chain fatty acids to the peroxisome for degradation, causing their accumulation in tissues and plasma. 3,4 The most severe, cerebral form (CALD) develops in35% of males #10 years of age with ALD. 3 If not treated in a timely manner, inflammatory cerebral demyelination in CALD leads to loss of neurological and cognitive function and death, typically in early childhood. ...
Article
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in early cerebral adrenoleukodystrophy (CALD) can stabilize neurologic function and improve survival but has associated risks including transplant related mortality (TRM), graft failure, and graft-versus-host disease (GVHD). An observational study of 59 patients with median age at allo-HSCT of 8 years addressed impact of donor source, donor match, conditioning regimen, and cerebral disease stage on first allo-HSCT outcomes. Efficacy analyses included 53 patients stratified by disease category: advanced disease (AD; n=16) with Loes score >9 or neurological function score (NFS) >1 and two early disease (ED) cohorts (ED1 [Loes ≤4 and NFS ≤1; n=24] and ED2 [Loes >4-9 and NFS ≤1; n=13]). Survival free of major functional disabilities and without second allo-HSCT at 4 years was significantly higher in the ED (66%) versus AD (41%) cohort (p=0.015) and comparable between ED1 and ED2 cohorts (p=0.991). The stabilization of neurologic function post-transplant was greater in the ED versus AD cohort, with a median change from baseline at 24 months post-allo-HSCT in NFS and Loes score, respectively, of 0 and 0.5 in ED1 (n=13), 0.5 and 0 in ED2 (n=6), and 2.5 and 3.0 (n=4) in AD cohort. TRM was lower in the ED (7%) compared with AD (22%) cohort, however the difference was not significant (p=0.094). Transplant-related safety outcomes were also impacted by transplant-related characteristics: graft failure incidence was significantly higher with unrelated umbilical cord grafts versus matched related donors (MRD) (p=0.039), and acute GVHD and graft failure incidences varied by conditioning regimen. The study is registered to https://clinicaltrials.gov as NCT02204904.
... This ultimately leads to degeneration of the white matter (Table 1). The estimated incidence of X-ALD is about 1 in 14,700 live births (Bezman et al., 2001;Moser et al., 2016). ...
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Microglia are highly dynamic cells crucial for developing and maintaining lifelong brain function and health through their many interactions with essentially all cellular components of the central nervous system. The frequent connection of microglia to leukodystrophies, genetic disorders of the white matter, has highlighted their involvement in the maintenance of white matter integrity. However, the mechanisms that underlie their putative roles in these processes remain largely uncharacterized. Microglia have also been gaining attention as possible therapeutic targets for many neurological conditions, increasing the demand to understand their broad spectrum of functions and the impact of their dysregulation. In this Review, we compare the pathological features of two groups of genetic leukodystrophies: those in which microglial dysfunction holds a central role, termed 'microgliopathies', and those in which lysosomal or peroxisomal defects are considered to be the primary driver. The latter are suspected to have notable microglia involvement, as some affected individuals benefit from microglia-replenishing therapy. Based on overlapping pathology, we discuss multiple ways through which aberrant microglia could lead to white matter defects and brain dysfunction. We propose that the study of leukodystrophies, and their extensively multicellular pathology, will benefit from complementing analyses of human patient material with the examination of cellular dynamics in vivo using animal models, such as zebrafish. Together, this will yield important insight into the cell biological mechanisms of microglial impact in the central nervous system, particularly in the development and maintenance of myelin, that will facilitate the development of new, and refinement of existing, therapeutic options for a range of brain diseases.
Chapter
The blood–brain barrier (BBB) is the interface between the surrounding blood circulation and the nervous tissue in the brain, maintaining brain homeostasis by regulating the transport of substances between the cardiovascular system and the central nervous system (CNS). The BBB is composed of brain microvascular endothelial cells (BMECs), which are linked together by tight junctions (TJ), forming a physical paracellular barrier. A series of specialized transporters and efflux pumps regulates the transcellular transport of various substances, protecting the brain from foreign substances and maintaining the homeostasis of the brain. In addition, BMECs are structurally and functionally supported by other components in the neurovascular unit (NVU), such as pericytes, astrocytes, and basement membranes, and the interactions among components in the NVU contribute to the maintenance and development of BBB. Since the impaired BBB function has been observed in several neurological diseases, it is important to build a reliable in vitro BBB model for the research of disease mechanisms and CNS drug development. Induced pluripotent stem cells (iPSCs) raise concerns as an ideal cell source for in vitro BBB modeling given their human origin, scalability, and potential to generate syngeneic cellular components of the NVU. In this chapter, the schemes in differentiating iPSCs into BMECs, the key step in BBB modeling, are discussed. Additionally, several applications of iPSCs-BBB model will also be introduced.
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Objective Vitamin D status has been linked to risk of inflammatory brain lesions. We sought to assess the safety and pharmacokinetics of oral vitamin D dosing regimens in boys with X-linked adrenoleukodystrophy (ALD). Methods In this open-label, multi-center, phase I study, we enrolled 21 ALD males without brain lesions, aged 1.5 to 25 years to oral vitamin D supplementation for 12 months. Our primary outcome was attainment of plasma 25-hydroxyvitamin D levels in target range (40-80ng/ml) at 6 and 12 months. Secondary outcomes included safety and glutathione levels in brain and blood. Participants were initially assigned to a fixed dosing regimen starting at 2,000 IU daily, regardless of weight. Following a mid-study safety assessment, we modified the dosing regimen so all subsequent participants were assigned to a weight-stratified dosing regimen starting as low as 1,000 IU daily. Results Between October 2016 and June 2019, we recruited 21 participants (n=12 fixed dose; n=9 weight-stratified) with a median age and weight of 6.7 years and 20 kilograms. Most participants achieved target plasma vitamin D levels at 6 and 12 months regardless of dosing regimen. In the fixed dose regimen, 6 of 12 participants had asymptomatic elevation in urine calcium:creatinine or plasma 25-hydroxyvitamin D; no laboratory deviations occurred with the weight-stratified regimen. Glutathione levels increased between baseline and 12 months in the brain but not in the blood. Conclusions Our weight-stratified vitamin D dosing regimen was well-tolerated and achieved target 25-hydroxyvitamin D levels in most participants. Brain glutathione levels increased over the 12-month trial period. Clinicaltrials.gov identifier NCT02595489 Classification of Evidence This study provides Class II evidence that a weight-stratified dosing regimen of vitamin D supplementation is safe, well-tolerated, and effective at achieving moderately high vitamin D levels in boys with ALD. Sources of funding NIH/NINDS K23NS087151
Article
X-linked adrenoleukodystrophy (XALD) is a genetic neurologic disorder with multiple phenotypic presentations and limited therapeutic options. The childhood cerebral phenotype (CCALD), a fatal demyelinating disorder affecting about 35% of patients, and the adult-onset adrenomyeloneuropathy (AMN), a peripheral neuropathy affecting 40%–45% of patients, are both caused by mutations in the ABCD1 gene. Both phenotypes are characterized biochemically by elevated tissue and plasma levels of saturated very long-chain fatty acids (VLCFA), and an increase in plasma cerotic acid (C26:0), along with the clinical presentation, is diagnostic. Administration of oils containing monounsaturated fatty acids, for example, Lorenzo's oil, lowers patient VLCFA levels and reduced the frequency of development of CCALD in presymptomatic boys. However, this therapy is not currently available. Hematopoietic stem cell transplant and gene therapy remain viable therapies for boys with early progressive cerebral disease. We asked whether any existing approved drugs can lower VLCFA and thus open new therapeutic possibilities for XALD. Using SV40-transformed and telomerase-immortalized skin fibroblasts from an XALD patient, we conducted an unbiased screen of a library of approved drugs and natural products for their ability to decrease VLCFA, using measurement of C26:0 in lysophosphatidyl choline (C26-LPC) by tandem mass spectrometry as the readout. While several candidate drugs were initially identified, further testing in primary fibroblast cell lines from multiple CCALD and AMN patients narrowed the list to one drug, the anti-hypertensive drug irbesartan. In addition to lowering C26-LPC, levels of C26:0 and C28:0 in total fibroblast lipids were reduced. The effect of irbesartan was dose dependent between 2 and 10 μM. When male XALD mice received orally administered irbesartan at a dose of 10 mg/kg/day, there was no reduction in plasma C26-LPC. However, irbesartan failed to lower mouse fibroblast C26-LPC consistently. The results of these studies indicate a potential therapeutic benefit of irbesartan in XALD that should be validated by further study.
Article
Objective: This study summarized the clinical characteristics of X-linked adrenoleukodystrophy (X-ALD) patients in this family, and two different manifestations of the same variants in a Chinese family were reported in this article. That conducted a follow-up study to further clarify the characteristics of this disease. Basic methods: Clinical data and test results were analyzed, and the exon region of ALD-related gene ABCD1 was sequenced by Sanger sequencing. Main results: Gene analysis showed that there were three ABCD1 variants in the proband, c.1047C>A, c.1415-1416delAG and c.1548G>A. The elder brother of the proband had the same three variants as the proband, but showed different clinical symptoms. The mother was the carrier of three variants. Multisite variants were uncovered in this family, which caused two different manifestations of adult-onset childhood cerebral ALD and adrenomyeloneuropathy. Principal conclusion: These findings further increase our knowledge about ABCD1 mutations and the associated phenotypes, which is beneficial for the genetic counseling of patients with X-ALD.
Article
Adrenoleukodystrophy (ALD) is a rare X-linked disease caused by a mutation of the peroxisomal ABCD1 gene. This review summarizes our current understanding of the pathogenic cell- and tissue-specific role of lipid species in the context of experimental therapeutic strategies and provides an overview of critical historical developments, therapeutic trials, and the advent of newborn screening in the United States. In ALD, very long chain fatty acid (VLCFA) chain-length-dependent dysregulation of endoplasmic reticulum stress and mitochondrial radical generating systems inducing cell death pathways has been shown, providing the rationale for therapeutic moiety-specific VLCFA reduction and antioxidant strategies. The continuing increase in newborn screening programs and promising results from ongoing and recent therapeutic investigations provide hope for ALD.
Purpose of review: Adrenoleukodystrophy (ALD) is a peroxisomal disorder with varying clinical presentations, including adrenal insufficiency, neurologic disease, and testicular dysfunction. The present review is intended to describe the current knowledge of the pathophysiology of ALD and provide an update regarding newborn screening, diagnosis, monitoring, and treatment. Recent findings: New York State initiated newborn screening for ALD on December 30, 2013. Successful ALD newborn screening has led to its addition on other state newborn screens and recommendations for universal screening. Initial incidence reports, based on newborn screening, suggest ALD may be more common than previously described. The Pediatric Endocrine Society has published guidance for monitoring newborn males with ALD and case reports suggest biochemical adrenal insufficiency can be present during early infancy. Allogeneic hematopoietic stem cell transplant and gene therapy have been effective at halting the progression of cerebral ALD. Summary: Early diagnosis and monitoring for progression of ALD can prevent adrenal crisis and treat the cerebral form of the disease. Initial guidelines for surveillance are likely to evolve as newborn screening not only aids in early detection and therapeutic interventions for ALD, but also expands our knowledge of the natural history of ALD.
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L’insuffisance surrénale primaire dans la population pédiatrique (0-18 ans) est le plus souvent attribuée à une hyperplasie congénitale des surrénales, qui survient dans environ une naissance sur 15 000, suivie de la maladie d’Addison, caractérisée par une étiologie auto-immune. Cependant, d’autres étiologies sont méconnues telle l’hypoplasie congénitale, des progrès moléculaires ont augmenté le nombre de diagnostics possibles. L’hypoplasie congénitale des surrénales est une maladie génétique rare, hétérogène sur le plan clinique, de révélation parfois précoce et létale en absence de traitement adapté, une survie prolongée en l’absence de traitement conduisant à un diagnostic tardif de la maladie est aussi possible, certaines de ces hypoplasies congénitales sont liées à des mutations observées dans le gène DAX1 sur l’X qui code pour un membre de la superfamille des récepteurs nucléaires aux hormones. Nous rapportons ici l’observation d’un enfant de 12 ans, qui a présenté une insuffisance surrénalienne périphérique, avec absence d’individualisation des surrénales sur tomodensitométrie; chez qui l’hypoplasie congénitale des surrénales a été suspecté.
Article
X-linked adrenoleukodystrophy (ALD) caused by the ABCD1 mutation, is the most common inherited peroxisomal disease. Previously, we generated an ALD patient-derived SCHi001-A iPSC model. In this study, we have performed the first genome editing of ALD patient-derived SCHi001-A iPSCs using homology-directed repair (HDR). The mutation site, c.1534G>A [GenBank: NM_000033.4], was corrected by introducing ssODN and the CRISPR/Cas9 system. The cell line exhibited normal iPSC plulipotency marker expression following genome editing. Mutation-corrected iPSCs from SCHi001-A iPSC line can be used in research into the pathophysiology of and therapeutics for ALD.
Article
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Adrenoleukodystrophy (ALD) is a rare X-linked disease caused by a mutation of the peroxisomal ABCD1 gene. This review summarizes our current understanding of the pathogenic cell- and tissue-specific role of lipid species in the context of experimental therapeutic strategies and provides an overview of critical historical developments, therapeutic trials, and the advent of newborn screening in the United States. In ALD, very long chain fatty acid (VLCFA) chain-length-dependent dysregulation of endoplasmic reticulum stress and mitochondrial radical generating systems inducing cell death pathways has been shown, providing the rationale for therapeutic moiety-specific VLCFA reduction and antioxidant strategies. The continuing increase in newborn screening programs and promising results from ongoing and recent therapeutic investigations provide hope for ALD.
Chapter
Peroxisomal disorders (PD) are genetic disorders caused by peroxisome dysfunction and are classified into two groups: genetic defects in peroxisome-localized proteins and genetic defects in peroxisomal biogenesis. The dawn of PD research came with the detailed analysis of the Zellweger syndrome, the prototype of PD. Even recently, new PD are still being identified by whole-exome sequencing analysis, which means that the concept of PD has been expanding. Furthermore, the role of peroxisome in cancer and age-related diseases has also been studied. In contrast, PD pathophysiology and treatment are not clarified yet completely and even in adrenoleukodystrophy, which is the most common PD, the prognosis of phenotype and disease in pre-symptomatic patients is a difficult task.
Article
Purpose The growing size of public variant repositories prompted us to test the accuracy of pathogenicity prediction of DNA variants using population data alone. Methods Under the a priori assumption that the ratio of the prevalence of variants in healthy population vs that in affected populations form 2 distinct distributions (pathogenic and benign), we used a Bayesian method to assign probability to a variant belonging to either distribution. Results The approach, termed Bayesian prevalence ratio (BayPR), accurately parsed 300 of 313 expertly curated CFTR variants: 284 of 296 pathogenic/likely pathogenic variants in 1 distribution and 16 of 17 benign/likely benign variants in another. BayPR produced an area under the receiver operating characteristic curve of 0.99 for 103 functionally confirmed missense CFTR variants, which is equal to or exceeds 10 commonly used algorithms (area under the receiver operating characteristic curve range = 0.54-0.99). Application of BayPR to expertly curated variants in 8 genes associated with 7 Mendelian conditions led to the assignment of a disease-causing probability of ≥80% to 1350 of 1374 (98.3%) pathogenic/likely pathogenic variants and of ≤20% to 22 of 23 (95.7%) benign/likely benign variants. Conclusion Irrespective of the variant type or functional effect, the BayPR approach provides probabilities of pathogenicity for DNA variants responsible for Mendelian disorders using only the variant counts in affected and unaffected population samples.
Article
Background Current outcomes used to evaluate adrenomyeloneuropathy are limited by rater bias, not sensitive to preclinical changes and require years to decades to detect disease progression. Quantitative outcomes are needed that detect meaningful change in a short time period over a broad range of disability. Objective To track sensorimotor outcomes in adults with adrenomyeloneuropathy and evaluate differences in progression between men and women. Methods This prospective observational cohort study analyzes data collected annually in the Phase III study of adults with adrenomyeloneuropathy. Outcomes include postural sway in four static standing conditions, great-toe vibration, hip strength, walking velocity, timed up-and-go, and six-minute walk distance. Linear mixed model analysis was used to detect change in the outcomes in 2 years, correcting for age, sex, disability, symptom duration and treatment across the cohort. Modeling was repeated for each sex to evaluate differences. Power computations were done by sex and for the full dataset. Results 61 men and 87 women participated. Average age, 46±12yrs; Expanded Disability Status Scale, 3 (1-6.5); symptom duration, 10.8±9.4yrs. The cohort showed significant worsening in all standing conditions (p<0.001), sensation (p=0.0223) and strength (p=0.001); but more stability in walking with only velocity (p<0.0337) significantly declining. For each sex, postural sway declines significantly in all conditions (p<0.01)) except for eyes closed feet together for women. Strength declines significantly by sex for hip flexion (p<0.03). Sex-specific significant decline is seen in walking (velocity p=0.0276; distance p=0.0072) for men only. Conclusions Quantitative measures of postural sway, sensation strength and walking are effective measures of adrenomyeloneuropathy progression in 2 years. This article is protected by copyright. All rights reserved.
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Background: Adrenoleukodystrophy (ALD) is a rare sex-linked recessive disorder that disrupts adrenal gland function and the white matter of the nervous system. According to recent epidemiological statistics, up to this moment, the disease is the most recorded peroxisomal disorder. ABCD1 is a gene related to ALD, with more than 850 unique mutations have been reported. Early diagnosis of the disease would help to consult families with ALD to plan for interventions to prevent passing along the pathogenic mutations to their children. Material and methods: A heterozygous ABCD1 gene mutation related to ALD found in a Vietnamese woman was used to design primers for the polymerase chain reaction (PCR) to amplify the segment spanning the mutation. Then, combining sequencing methods for the PCR products, especially Sanger sequencing and next-generation sequencing (NGS), a protocol was developed to detect mutations on the ABCD1 gene to apply for the DNA samples of in-vitro fertilization (IVF) embryos biopsied at the blastocyst stage to screen for pathogenic alleles. Results: The established protocol for PGD of ALD detected mutant alleles in 5/8 embryos (62.5%), while the remaining 3 embryos (37.5%) did not carry any mutation. One of the 3 embryos was transferred, and a healthy female baby was born after a full-term pregnancy. Conclusion: The developed protocol was helpful for the preimplantation genetic diagnosis process to help families with the monogenic disease of ALD but wish to have healthy children.
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Background Myelopathy is the core clinical manifestation of adrenoleukodystrophy (ALD), which is the most common peroxisomal disorder. Development of therapies requires sensitive and clinically relevant outcome measures. Together with spastic paraparesis, balance disturbance is the main cause of disability from myelopathy in ALD. In this cross-sectional study, we evaluated whether postural body sway – a measure of balance – could serve as a surrogate outcome in clinical trials.Methods Forty-eight male ALD patients and 49 age-matched healthy male controls were included in this study. We compared sway amplitude and sway path of ALD patients to controls. We then correlated the body sway parameters showing the largest between-group differences with clinical measures of severity of myelopathy. To correct for age, we performed multiple linear regression analysis with age and severity of myelopathy as independent variables.ResultsAll body sway parameters were significantly higher in patients than in controls, with medium to large effect sizes (r = 0.43–0.66, p < 0.001). In the subgroup of asymptomatic patients, body sway amplitude was also higher, but the difference with controls was smaller than for symptomatic patients (effect size r = 0.38–0.46). We found moderate to strong correlations between body sway amplitude and clinical severity of myelopathy (r = 0.40–0.79, p < 0.005). After correction for age, severity of myelopathy was a significant predictor of body sway amplitude in all regression models.Conclusions These results indicate that postural body sway may serve as a surrogate outcome for myelopathy in ALD. Such outcomes are important to evaluate new therapies in clinical trials. Further longitudinal studies are needed and ongoing in this cohort.
Article
X-linked adrenoleukodystrophy (X-ALD) is caused by a mutation in the ABCD1 gene which encodes for a peroxisomal very long-chain fatty acid (VLCFA) transporter. Clinically, X-ALD can present a wide range of phenotypes, from slowly progressive myelopathy to rapid demyelination of brain white matter (cerebral X-ALD—CALD). Adrenocortical insufficiency (AI) occurs mainly in the pediatric age group, and it can be the first manifestation of the disease. Female carriers may also develop manifestations of myelopathy, but later in life. We present two cases of patients who show the heterogeneous clinical manifestations of X-ALD. Case 1 was a man with AI diagnosed at 6 years old and with the first manifestations of myelopathy at 44 years old, which led to the diagnosis of X-ALD. At 47 years, he developed rapidly progressive CALD. Case 2 was a woman with progressive spastic gait disturbance that started at 49 years old. The diagnosis of X-ALD was confirmed at 54 years old after the discovery of a family history of the disease. Mild progression of the neurologic manifestations was noted, but with no signs of AI nor CALD. She is currently 60 years old and under surveillance. We review the current knowledge on X-ALD as concerns its genetic and pathophysiological mechanisms, clinical presentations, diagnosis, treatment, and follow-up. This condition is a real diagnostic challenge. The early detection of AI and CALD, potentially life-threatening complications in men, is very difficult. The surveillance of these complications in female patients still raises controversy.
Article
Background and purpose X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder affecting particularly the nervous tissue and adrenal cortex. Adrenomyeloneuropathy (AMN) is the most frequent phenotype, although adrenal insufficiency is usually the first manifestation in male patients. We set out to describe the clinical and biochemical features, together with the clinical course of X-ALD patients, focusing particularly on endocrine dysfunction. Patients and methods A retrospective study of 10 male X-ALD patients followed up at the Endocrinology Department. Epidemiologic data, phenotype evolution, endocrine and neurological findings and family history were analysed. Results All the patients presented with adrenal insufficiency, 4 of them during adulthood, with a mean age of 19.6 ± 17.1 years (6–64 years). Six patients had mineralocorticoid deficiency. At diagnosis, 8 patients had Addison-only phenotype and 2 AMN phenotype. In the course of follow-up (24.9 ± 16.1 years), 4 patients developed AMN about 25.0 ± 7.4 years after the initial diagnosis and 2 patients presented the cerebral adult form 11 and 17 years after the initial diagnosis. Testosterone levels were within the normal range in all patients. There were 7 families, and age of onset and clinical course were similar in 3 of them. Conclusions The presentation of X-ALD varied widely, 40% of the patients presented with adrenal insufficiency in adulthood, 60% had mineralocorticoid deficiency, and the onset and progression of neurological manifestations showed no pattern. Nevertheless, some similarities in the clinical course were found in some families. Our findings reinforce the need for screening for X-ALD at any age when approaching adrenal insufficiency and the importance of a multidisciplinary approach between endocrinologists and neurologists.
Article
X‐linked adrenoleukodystrophy (X‐ALD) is an inherited, neurodegenerative rare disease that can result in devastating symptoms of blindness, gait disturbances, and spastic quadriparesis due to progressive demyelination. Typically, the disease progresses rapidly, causing death within the first decade of life. With limited treatments available, efforts to determine an effective therapy that can alter disease progression or mitigate symptoms have been undertaken for many years, particularly through drug repurposing. Repurposing has generally been guided through clinical experience and small trials. At this time, none of the drug candidates have been approved for use, which may be due, in part, to the lack of pharmacokinetic/pharmacodynamic (PK/PD) information on the repurposed medications in the target patient population. Greater consideration for the disease pathophysiology, drug pharmacology, and potential drug‐target interactions, specifically at the site of action, would improve drug repurposing and facilitate drug development. Incorporating advanced translational and clinical pharmacological approaches in preclinical studies and early stages clinical trials will improve the success of repurposed drugs for X‐ALD as well as other rare diseases.
Article
Several genetic disorders have variable degree of central nervous system white matter abnormalities. We retrieved and reviewed 422 genetic conditions with prominent and consistent involvement of white matter from the literature. We herein describe the current definitions, classification systems, clinical spectrum, neuroimaging findings, genomics, and molecular mechanisms of these conditions. Though diagnosis for most of these disorders relies mainly on genomic tests, specifically exome sequencing, we collate several clinical and neuroimaging findings still relevant in diagnosis of clinically recognizable disorders. We also review the current understanding of pathophysiology and therapeutics of these disorders.
Article
Full-text available
X-linked adrenoleukodystrophy (ALD) is a neurodegenerative disorder with variable phenotypic expression that is characterized by elevated plasma and tissue levels of very long-chain fatty acids. However, the product of the gene defective in ALD (ALDP) is a membrane transporter of the ATP-binding cassette family of proteins and is not related to enzymes known to activate or oxidize fatty acids. We generated an antibody that specifically recognizes the C-terminal 18 amino acids of ALDP and can detect ALDP by indirect immunofluorescence. To better understand the mechanism by which mutations in ALDP lead to disease, we used this antibody to examine the subcellular distribution and relative abundance of ALDP in skin fibroblasts from normal individuals and ALD patients. Punctate immunoreactive material typical of fibroblast peroxisomes was observed in cells from seven normal controls and eight non-ALD patients. Of 35 ALD patients tested, 17 had the childhood-onset cerebral form of the disease, 13 had the milder adult phenotype adrenomyeloneuropathy, 3 had adrenal insufficiency only, and 2 were affected fetuses. More than two-thirds (69%) of all patients studied showed no punctate immunoreactive material. There was no correlation between the immunofluorescence pattern and clinical phenotype. We determined the mutation in the ALD gene in 15 of these patients. Patients with either a deletion or frameshift mutation lacked ALDP immunoreactivity, as expected. Four of 11 patients with missense mutations were also immunonegative, indicating that these mutations affected the stability or localization of ALDP. In the seven immunopositive patients with missense mutations, correlation of the location and nature of the amino acid substitution may provide new insights into the function of this peroxisomal membrane protein. Furthermore, the study of female relatives of immunonegative ALD probands may aid in the assessment of heterozygote status.
Article
Full-text available
We studied 19 women, heterozygous for adrenoleukodystrophy (ALD) in whom the carrier status was demonstrated by abnormally high plasma levels of very-long-chain fatty acids. Clinical examination revealed slight neurological signs in two patients. Clear-cut neurological deficits in three, and it was fully normal in the remaining 14. All subjects underwent motor evoked potential (MEP) and somatosensory evoked potential (SEP) studies. Seventeen out of 19 subjects underwent brain MRI which demonstrated various degrees of abnormality in one asymptomatic and five symptomatic subjects; SEPs and MEPs revealed CNS involvement in 12 and 8 out of the 19 subjects, respectively. Symptomatic patients showed severe neurophysiological abnormalities, whereas milder but unequivocal EP abnormalities were found in seven of the 14 patients with normal clinical examination. Our data thus suggest CNS involvement in the majority of the ALD carriers, evident also in preclinical stages and progressively severe. The possibility of assessing different degrees of neurological involvement could be relevant for therapeutical purposes. Moreover, neurophysiological studies could provide the only objective marker of functional nervous system involvement, e.g. in order to monitor the efficacy of treatment, and in clinically and radiologically silent cases.
Article
A rapid method with potential to screen for many of the peroxisomal disorders using 5μl of plasma or a 3‐mm blood spot (3.6μl blood impregnated on filter paper) is described. Fatty acids are liberated from plasma or blood spots and converted to dimethylaminoethyl esters. Trideuterated fatty acids, added as internal standards, are used to quantify eicosanoic (C20:0), docosanoic (C22:0), tetracosanoic (C24:0) and hexacosanoic (C26:0) acids by electrospray tandem mass spectrometry. The C26:0/C22:0 and C24:0/C22:0 ratios are significantly greater in the plasma of patients with peroxisomal disorders compared to controls. The C20:0/C22:0 ratio is elevated in the plasma of peroxisomal patients who accumulate phytanic acid. Blood spots collected from four peroxisomal patients between 2 and 10 days after birth and stored for up to 17 years, were shown to give between 33% and 233% higher C26:0/C22:0 ratios compared to age‐matched controls.
Article
The assay of plasma very long chain fatty acids (VLCFAs), developed in our laboratory in 1981, has become the most widely used procedure for the diagnosis of X-linked adrenoleukodystrophy (X-ALD) and other peroxisomal disorders. We present here our 17 years' experience with this assay. Three VLCFA parameters, the level of hexacosanoic acid (C26:0), the ratio of C26:0 to tetracosanoic acid (C24:0), and of C26:0 to docosanoic acid (C22:0), were measured in 1,097 males (hemizygotes) with X-ALD, 1,282 women heterozygous for this disorder, including 379 obligate heterozygotes, 797 patients with other peroxisomal disorders, and 29,600 control subjects. All X-ALD hemizygotes who had not previously received Lorenzo's oil or a diet with a high erucic acid content had increased VLCFA levels, but the application of a discriminant function based on all three measurements is required to avoid the serious consequences of a false-negative result. VLCFA levels are increased at day of birth, thus providing the potential for neonatal mass screening, are identical in the childhood and adult forms, and do not change with age. Eighty-five percent of obligate heterozygotes had abnormally high VLCFA levels, but a normal result does not exclude carrier status. VLCFA levels were increased in all patients homozygous for Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum's disease, and in patients with deficiencies of peroxisomal acyl-coenzyme A oxidase, bifunctional enzyme, and 3-oxoacyl-coenzyme A thiolase. In these patients the degree of VLCFA excess correlated with clinical severity. Ann Neurol 1999;45:100–110
Article
A sensitive and selective stable isotope dilution electron capture negative ion chemical ionization mass fragmentography method applying pentafluorobenzyl derivatives was developed for the accurate quantitation of very long chain fatty acids. This technique allowed detection of 1-5 pg of each compound and was applied to plasma (100 microliters), amniotic fluid (1 ml) and urine (1 ml). Normal concentrations were established and the concentrations in samples of selected patients with classified peroxisomal disorders were determined. In plasma samples of all patients the C26:0/C22:0 ratios were elevated (range 0.03-0.43), compared to the control ratios (range 0.003-0.021). The ratio C26:0/C22:0 was elevated in four of five amniotic fluid samples from fetuses with peroxisomal disorders (range 0.18-0.54) when compared with controls (range 0.05-0.25). An elevation of the ratio C26:1/C22:0 was observed in all five amniotic fluid samples (range 0.22-0.60 vs. 0-0.08 in controls). Urinary C26:0 concentrations were lower than in plasma and amniotic fluid and diagnostic ratios were not elevated in patients with peroxisomal disorders.
Article
One hundred and thirty-six individuals with a family history of X-linked adrenoleukodystrophy (ALD) or adrenomyeloneuropathy (AMN) were given a questionnaire surveying their sociodemographic characteristics, knowledge of X-linked inheritance, and attitudes toward prenatal, presymptomatic, and carrier testing. Of the respondents, 68% indicated that they would use prenatal testing. Of these, 57.1% would terminate a pregnancy of a male fetus hemizygous for the ALD gene and 13.5% would reportedly choose to terminate a heterozygote female fetus. Presymptomatic testing would be used by 88.7% of respondents to test at-risk sons and carrier testing would reportedly be used by 95.4% of respondents to test their at-risk daughters. Respondents correctly answered an average of 61% of the questions testing understanding of X-linked inheritance. This indicates a strong interest in prenatal, presymptomatic, and carrier testing and a need for genetic counselors to provide information about these available tests and X-linked inheritance.
Article
Within the past decade, bone marrow transplantation has been applied to over 200 patients worldwide with the intention of treating storage diseases. Bone marrow transplantation has provided a method for treatment of adrenoleukodystrophy, metachromatic leukodystrophy, globoid cell leukodystrophy and Hurler syndrome. After engraftment, significant improvement in the clinical course of each of these diseases occurs. Survival data of engrafted patients are superior to those of non-transplanted. Engraftment and the resulting enzymatic reconstitution are concordant. Outcomes based on neuropsychological tests indicate continued maintenance and in some cases increase in cognitive function. Magnetic resonance imaging as well as spectroscopic examinations of the brain provide further evidence that positive changes occur in the central nervous system following long-term engraftment. A better quality of life follows engraftment. Greater gains from use of bone marrow transplantation for these particular storage diseases will occur in the future. Earlier diagnosis will allow bone marrow transplantation in the presymptomatic stage at a younger age, providing an enhancement of positive effects noted from such treatment. At the same time, advances in bone marrow technology will serve to reduce the risk factors involved with the bone marrow transplantation process itself. These two factors taken together will be more than additive in providing benefits from use of bone marrow transplantation.
Article
Adrenoleukodystrophy is a severe genetic demye-llnating disease associated with an impairment of β-oxidation of very long chain fatty acids (VLCFA) In peroxisomes. Earlier studies had suggested that a deficiency in VLCFA CoA synthetase was the primary defect. A candidate adrenoleukodystrophy gene has recently been cloned and was found unexpectedly to encode a putative ATP-binding cassette transporter. We have raised monoclonal antibodies against this protein, that detect a 75kDa band. This protein was absent in several patients with adrenoleukodystrophy. Immunofluorescence and Immunoelectron microscopy showed that the adrenoleukodystrophy protein (ALDP) is associated with the peroxisomal membrane. Distinct Immunofluorescence patterns were observed in cell lines from patients with Zellweger syndrome (a peroxisomal biogenesis disorder) belonging to different complementation groups.
Article
X-linked adrenoleukodystrophy (ALD), a neurodegenerative disorder associated with impaired beta-oxidation of very-long-chain fatty acids (VLCFA), is due to mutations in a gene encoding a peroxisomal ATP-binding cassette (ABC) transporter (ALD protein [ALDP]). We analyzed the open reading frame of the ALD gene in 44 French ALD kindred by using SSCP or denaturing gradient-gel electrophoresis and studied the effect of mutations on ALDP by immunocytofluorescence and western blotting of fibroblasts and/or white blood cells. Mutations were detected in 37 of 44 kindreds and were distributed over the whole protein-coding region, with the exception of the C terminus encoded in exon 10. Except for two mutations (delAG1801 and P560L) observed four times each, nearly every ALD family has a different mutation. Twenty-four of 37 mutations were missense mutations leading to amino acid changes located in or close to putative transmembrane segments (TMS 2, 3, 4, and 5), in the EAA-like motif and in the nucleotide fold of the ATP-binding domain of ALDP. Of 38 ALD patients tested, 27 (71%) lacked ALDP immunoreactivity in their fibroblasts and/or white blood cells. More than half of missense mutations studied (11 of 21) resulted in a complete lack of ALDP immunoreactivity, and six missense mutations resulted in decreased ALDP expression. The fibroblasts and/or white blood cells of 15 of 15 heterozygous carrier from ALD kindred with no ALDP showed a mixture of positive- and negative-ALDP immunoreactivity due to X-inactivation. Since 5%-15% of heterozygous women have normal VLCFA levels, the immunodetection of ALDP in white blood cells can be applicable in a majority of ALD kindred, to identify heterozygous women, particularly when the ALD gene mutation has not yet been identified.
Article
The occasion of the presentation of the eighth Gordon Holmes Lecture left me feeling both honoured and awed, as a result of my review of the Selected Papers of Gordon Holmes (Phillips CG: Selected Papers of Gordon Holmes, compiled and edited for the Guarantors of Brain. Oxford University Press, 1979), kindly presented to me by the sponsors of the meeting. This volume lists 174 publications produced over a 55-year period, and contains reprints of contributions to neuroanatomy, neuropathology, and to disorders that affected the adrenal cortex, the spinal cord, the cerebellum and the cerebral cortex. Yet I also feel a sense of sadness; the invitation to present the lecture came from the late Anita Harding who, such a short time before her illness, gave me personal guidance and encouragement. In this lecture I endeavour to follow the example of Gordon Holmes, namely the stepwise analysis of a clinical problem, first by observation of the patient, followed by the application of techniques that can clarify it, leading to new knowledge not only about the specific disorder, but also about the nervous system and human biology in general and, it is to be hoped, to more effective therapy.
Article
The assay of plasma very long chain fatty acids (VLCFAs), developed in our laboratory in 1981, has become the most widely used procedure for the diagnosis of X-linked adrenoleukodystrophy (X-ALD) and other peroxisomal disorders. We present here our 17 years' experience with this assay. Three VLCFA parameters, the level of hexacosanoic acid (C26:0), the ratio of C26:0 to tetracosanoic acid (C24:0), and of C26:0 to docosanoic acid (C22:0), were measured in 1,097 males (hemizygotes) with X-ALD, 1,282 women heterozygous for this disorder, including 379 obligate heterozygotes, 797 patients with other peroxisomal disorders, and 29,600 control subjects. All X-ALD hemizygotes who had not previously received Lorenzo's oil or a diet with a high erucic acid content had increased VLCFA levels, but the application of a discriminant function based on all three measurements is required to avoid the serious consequences of a false-negative result. VLCFA levels are increased at day of birth, thus providing the potential for neonatal mass screening, are identical in the childhood and adult forms, and do not change with age. Eighty-five percent of obligate heterozygotes had abnormally high VLCFA levels, but a normal result does not exclude carrier status. VLCFA levels were increased in all patients homozygous for Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum's disease, and in patients with deficiencies of peroxisomal acyl-coenzyme A oxidase, bifunctional enzyme, and 3-oxoacyl-coenzyme A thiolase. In these patients the degree of VLCFA excess correlated with clinical severity.
Article
X-linked adrenoleukodystrophy is a serious and often fatal disorder, affecting the white matter of the nervous system, the adrenal cortex, and the testis. The gene mutated in X-ALD encodes a peroxisomal membrane protein, ALDP. The presence of very long chain fatty acids in plasma is highly diagnostic for affected males and carrier females, but exclusion of carrier status biochemically is unreliable. Molecular analysis of the X-ALD gene has the potential to either identify or rule out carrier status accurately, but is complicated by the existence of autosomal paralogs. We have developed and validated a robust DNA diagnostic test for this disorder involving nonnested genomic amplification of the X-ALD gene, followed by fluorescent dye-primer sequencing and analysis. This protocol provides a highly reliable means of determining carrier status in women at risk for transmitting X-ALD and is applicable to a clinical diagnostic laboratory.
Article
Adrenoleukodystrophy (ALD) is caused by mutations in an ATP-binding-cassette transporter located in the peroxisomal membrane, which result in a fatal demyelinating disease in boys and a milder phenotype in men and some heterozygous women. There is no molecular signature to indicate a particular clinical course. The underlying molecular mechanisms of this disease have yet to be targeted clinically. Is the increase in very-long-chain fatty acids (VLCFA) the disease trigger? Why is there no phenotype in ALD null mice that show this increase? Do VLCFA destabilize human myelin, once formed, and lead to the inflammation seen in this genetic disease? Bone-marrow transplantation might save a child by providing normal brain macrophages and allowing myelin regeneration early in disease. The processes that underlie ALD challenge neuroscientists to elucidate peroxisomal transporter functions in the nervous system and to pursue the gene-transfer strategies leading to remyelination until a preventive therapy emerges.
Article
Since 1991, 28 states have enacted laws that prohibit insurers' use of genetic information in pricing, issuing, or structuring health insurance. This article evaluates whether these laws reduce the extent of genetic discrimination by health insurers. From the data collected at multiple sites, we find that there are almost no well-documented cases of health insurers either asking for or using presymptomatic genetic test results in their underwriting decisions, either (a) before or after these laws have been enacted or (b) in states with or without these laws. By using both in-person interviews with insurers and a direct market test, we found that a person with a serious genetic condition who is presymptomatic faces little or no difficulty in obtaining health insurance. Furthermore, there are few indications that the degree of difficulty varies according to whether a state regulates the use of genetic information. Nevertheless, these laws have made it less likely that insurers will use genetic information in the future. Although insurers and agents are only vaguely aware of these laws, the laws have shaped industry norms and attitudes about the legitimacy of using this information.
Article
A rapid method with potential to screen for many of the peroxisomal disorders using 5 microl of plasma or a 3-mm blood spot (3.6 microl blood impregnated on filter paper) is described. Fatty acids are liberated from plasma or blood spots and converted to dimethylaminoethyl esters. Trideuterated fatty acids, added as internal standards, are used to quantify eicosanoic (C20:0), docosanoic (C22:0), tetracosanoic (C24:0) and hexacosanoic (C26:0) acids by electrospray tandem mass spectrometry. The C26:0/C22:0 and C24:0/C22:0 ratios are significantly greater in the plasma of patients with peroxisomal disorders compared to controls. The C20:0/C22:0 ratio is elevated in the plasma of peroxisomal patients who accumulate phytanic acid. Blood spots collected from four peroxisomal patients between 2 and 10 days after birth and stored for up to 17 years, were shown to give between 33% and 233% higher C26:0/C22:0 ratios compared to age-matched controls.
Article
The childhood-onset cerebral form of X-linked adrenoleukodystrophy, a demyelinating disorder of the central nervous system, leads to a vegetative state and death within 3-5 years once clinical symptoms are detectable. The hypothesis to be tested was whether bone-marrow transplantation can over an extended period of time halt the inexorable progressive demyelination and neurological deterioration. 12 patients with childhood onset of cerebral X-linked adrenoleukodystrophy have been followed for 5-10 years after bone-marrow transplantation. Magnetic resonance imaging (MRI), neurological, neuropsychological, electrophysiological, and plasma very-long-chain fatty acid (VLCFA) measurements were used to evaluate the effect of this treatment. MRI showed complete reversal of abnormalities in two patients and improvement in one. One patient showed no change from baseline to last follow-up. All eight patients who showed an initial period of continued demyelination stabilised and remained unchanged thereafter. Motor function remained normal or improved after bone-marrow transplantation in ten patients. Verbal intelligence remained within the normal range for 11 patients. Performance (non-verbal) abilities were improved or were stable in seven patients. Decline in performance abilities followed by stability occurred in five patients. Plasma VLCFA concentrations decreased by 55% and remained slightly above the upper limits of normal. 5-10-year follow-up of 12 patients with childhood-onset cerebral X-linked adrenoleukodystrophy shows the long-term beneficial effect of bone marrow transplantation when the procedure is done at an early stage of the disease.
Article
The phenotypic expression of X-linked adrenoleukodystrophy (X-ALD) ranges from the rapidly progressive childhood cerebral form to the milder adrenomyeloneuropathy (AMN) in adults. It is not possible to predict phenotype by mutation analysis or biochemical assays. This study reports on 372 patients ranging in age from less than 3 years to adulthood, who have been followed at the Kennedy Krieger Institute. With the aim of determining whether a method could be developed to predict clinical course by analysis of data available at time of first contact, the patients were subdivided into 18 subgroups on the basis of age and the extent of brain magnetic resonance (MRI) abnormality utilizing the MRI scoring system devised by Loes et al. Scores to grade degree of neurologic and neuropsychologic impairment were also developed. There was strong correlation between MRI and the neurology and neuropsychology scores at baseline. Information based exclusively on age and MRI score at time of first contact was highly predictive of future clinical course and should aid the evaluation of the effects of bone marrow transplantation and the selection of patients for this procedure, as well as the evaluation of other therapies that may be developed in the future.
Article
Our objective was to study the phenotype evolution of X-linked adrenoleukodystrophy (X-ALD) and the relation between axonal degeneration and cerebral demyelination. Although different X-ALD phenotypes are recognized, little is known about their evolution. Neuropathological and electrophysiological studies have shown that X-ALD is a disease with mixed features of axonal degeneration, leading to myeloneuropathy, and a severe inflammatory reaction in the cerebral white matter, resulting in demyelination. Retrospectively, 129 men with X-ALD were studied who were 1) at least 20 years presently or at the time of death, and 2) regularly monitored. Phenotype assignments were made at diagnosis and at present, or at death, using medical history and findings of neurological examination. Handicap was studied with the modified Rankin scale, and cerebral abnormalities with the X-ALD MRI severity (Loes) score. The mean follow-up interval was 10.1 +/- 5.0 years. Among 32 patients neurologically asymptomatic at diagnosis, 16 (50%) developed neurological deficits. Among 68 adrenomyeloneuropathy (AMN) patients initially without clinical brain involvement, 13 (19%) additionally developed cerebral demyelination. In a subset of 60 AMN patients, a moderate handicap evolved over a period of 16.2 +/- 8.9 years. Among 13 AMN patients with additional definite or probable cerebral involvement at diagnosis, eight died and one remained in a vegetative state. Most of the 16 patients with the cerebral phenotypes deteriorated. There is a high risk for adult neurologically asymptomatic patients to develop neurological deficits and for AMN patients to develop cerebral demyelination. Axonal degeneration and cerebral demyelination emerge in X-ALD independently of each other. This may have implications for the phenotype classification, the search for modifying factors, and the development and evaluation of new therapies.
Article
An analysis of data on sex-linked recessive muscular dystrophy of the Duchenne type suggests that the mutation rate is greater in males than females. It cannot be much less.
The metabolic and molecular basis of inherited disease
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Professional disclosure of familial genetic information: the American Society of Human Genetics Social Issues Subcommittee on Familial Disclosure
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ASHG statement. Professional disclosure of familial genetic information: the American Society of Human Genetics Social Issues Subcommittee on Familial Disclosure. Am J Hum Genet 1998;62:474 – 483.