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ABSTRACT: Betaine critically contributes to the control of hepatocellular hydration and provides protection of the liver from different kinds of stress. To investigate how the hepatocellular hydration state affects gene expression of enzymes involved in the metabolism of betaine and related organic osmolytes we used qRT-PCR gene expression studies in rat hepatoma cells as well as metabolic and gene expression profiling in primary hepatocytes of both wild-type and 5,10-methylenetetrahydrofolate reductase (MTHFR) deficient mice. Anisotonic incubation caused co-ordinated adaptive changes in the expression of various genes involved in betaine metabolism, in particular of betaine homocysteine methyltransferase (BHMT), dimethylglycine dehydrogenase (DMGDH), and sarcosine dehydrogenase (SARDH). The expression of betaine-degrading enzymes was downregulated by cell shrinking and strongly induced by an increase in cell volume under hypotonic conditions. Metabolite concentrations in the culture system changed accordingly. Expression changes were mediated through tyrosine kinases, cyclic nucleotide-dependent protein kinases and JNK-dependent signalling. Assessment of hepatic gene expression using a customised microarray chip showed that hepatic betaine depletion in Mthfr-/- mice was associated with alterations that were comparable to those induced by cell swelling in hepatocytes. In conclusion, the adaptation of hepatocytes to changes in cell volume involves the co-ordinated regulation of betaine synthesis and degradation and concomitant changes in intracellular osmolyte concentrations. The existence of such a well-orchestrated response underlines the importance of cell volume homeostasis for liver function and of methylamine osmolytes such as betaine as hepatic osmolytes.
AJP Gastrointestinal and Liver Physiology 02/2013; · 3.43 Impact Factor
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Cerebrovascular Diseases 02/2013; 35(2):184-185. · 2.72 Impact Factor
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ABSTRACT: Leigh syndrome is a neurometabolic disorder commonly associated with disturbed oxidative phosphorylation, which leads to bilateral symmetric necrotizing lesions in the central nervous system. Neurological symptoms may be accompanied by cutaneous abnormalities. Here, we present images of distinct hypertrichosis in an otherwise asymptomatic one-year-old patient with pathogenic SURF1 gene mutations. We conclude that, if Leigh syndrome is suspected, the presence of characteristic hypertrichosis should prompt SURF1 mutation analysis.
Journal of Inherited Metabolic Disease 02/2013; · 3.58 Impact Factor
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ABSTRACT: Abstract We report on a 16-year-old body builder who suffered from an acute ischemic stroke. In the urine, cannabis metabolites as well as metabolites of the oral androgenic-anabolic steroid methandrostenolone were detected, both known to be associated with stroke events. This report highlights the role of cannabis and steroid abuse that induce strokes in the absence of arteriopathy, cardioembolism or thrombophilia. Owing to new upcoming socio-behavioral aspects of late childhood and early adolescent life, this formally rare abuse of cannabis and/or anabolic steroids as well as their associations with strokes becomes more current than ever.
Journal of pediatric endocrinology & metabolism: JPEM 01/2013; 26(1-2):161-5. · 0.88 Impact Factor
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ABSTRACT: A 14-year-old adolescent boy experienced a nonsevere infection of the upper respiratory tract. After 10 days, he developed headache, intermittent vomiting, and fever. A sudden prominent swelling of the forehead occurred, and his general condition deteriorated. Cranial computed tomography showed a subdural empyema and subperiosteal abscess owing to osteomyelitis of the frontal bone. Surgical drainage of the subdural empyema and the subperiosteal abscess was performed, and appropriate long-term antibiotic therapy was initiated. The swelling of the forehead caused by a subperiosteal abscess with osteomyelitis of the frontal bone after frontal sinusitis or trauma is known as Pott's puffy tumor. This case demonstrates that swelling of the forehead in the presence of upper respiratory tract infection should lead to prompt evaluation for complications.
Journal of Pediatric Surgery 10/2012; 47(10):1919-21. · 1.45 Impact Factor
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ABSTRACT: Brown-Vialetto-Van Laere syndrome (Online Mendelian Inheritance in Man number 211530) is a neurodegenerative disorder characterized by pontobulbar palsy affecting cranial nerves (mainly VII-XII). Sensorineural deafness is often the leading sign, followed by other neurologic signs. Inheritance is often autosomal recessive, with mutations in the C20orf54 gene (Online Mendelian Inheritance in Man number 613350). Three previous patients with mutations in the C20orf54 gene and clinical signs of Brown-Vialetto-Van Laere or Fazio-Londe syndrome revealed a metabolic profile suggesting a multiple acyl-coenzyme A dehydrogenase defect. They benefited from riboflavin. We describe a 3-year-old girl with early-onset Brown-Vialetto-Van Laere syndrome and a novel mutation in the C20orf54 gene (c.989G>T). On T(2)-weighted imaging, increased signal intensity of the vestibular nuclei bilaterally, the pedunculus cerebellaris superior and the central tegmental tract were observed during acute clinical deterioration. Her metabolic profile was normal. Trials with steroids, immunoglobulins, and riboflavin produced no effect. The patient recovered slowly during subsequent months, with residual deficits. Brown-Vialetto-Van Laere syndrome should be considered in patients with sensorineural hearing loss and pontobulbar palsy. Patients should be screened for riboflavin deficiency and a therapy with riboflavin may provide effective treatment in some affected patients.
Pediatric Neurology 06/2012; 46(6):407-9. · 1.52 Impact Factor
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ABSTRACT: We report on a 3.8-year-old girl who was born preterm. Due to a posthemorrhagic hydrocephalus she had a ventriculoperitoneal shunt. Magnetic resonance imaging (MRI) showed mild atrophy of the left cerebellum. She was found unresponsive in a febrile state. After the application of midazolam she regained consciousness. There were no epileptic discharges on electroencephalogram. MRI with diffusion-weighted sequences showed areas of hyperintensity in the right cerebrum. After the patient deteriorated again, MRI showed signs of increased intracranial pressure and high signal intensity throughout the right cerebral and left cerebellar hemispheres, suggesting crossed cerebellar diaschisis (CCD) most likely resulting from a nonconvulsive status epilepticus (SE). A follow-up MRI showed progressive brain atrophy. CCD after SE might be caused by cortical excitatory input through the cortico-pontine-cerebellar pathway. Alternatively, the cerebral edema in SE may decrease neuronal cell activity in the contralateral cerebellar hemisphere. The unilateral cerebellar atrophy before the onset of CCD might be attributed to impaired neuronal connections after peripartal cerebral injury. This case presents a young child with a combination of two CCDs, at first due to perinatal brain injury, and at second to SE. MRI with diffusion-weighted sequences can detect CCD at an early stage.
Neuropediatrics 04/2012; 43(2):55-8. · 0.94 Impact Factor
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ABSTRACT: ECG-gated non-enhanced balanced steady-state free precession (bSSFP) MR angiography requires neither breath-holding nor administration of contrast material.
To investigate the image quality of free-breathing ECG-gated non-enhanced bSSFP MR angiography of renal arteries in children.
Fourteen boys and seven girls (mean age, 9.7 years; range, 7 weeks-17 years) with no history of renovascular disease were included. MRI was performed at 1.5 T. Subjective image quality of axial and coronal maximum-intensity-projection reconstructions of four segments (I, aorta and renal artery ostium; II, main renal artery; III, segmental branches; IV, intrarenal vessels) was evaluated using a 4-point scale (4 = excellent, 3 = good, 2 = acceptable, 1 = non-diagnostic).
Image quality was excellent for segments I (mean ± SD, 3.9 ± 0.3) and II (4.0 ± 0.1), good for segment III (3.4 ± 0.9) and acceptable for segment IV (2.3 ± 1.1 ). Mean image quality did not differ between sedated and non-sedated children.
bSSFP MR angiography enables visualisation of renal arteries in children.
Pediatric Radiology 03/2012; 42(7):785-90. · 1.67 Impact Factor
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ABSTRACT: Caenorhabditis elegans open reading frame T21C9.1 encodes an uncharacterized protein, which is here named MICS-1 (mitochondrial scaffolding protein-1). It is predicted to be the homolog of human outer mitochondrial membrane protein 25 (OMP25 or synaptojanin-2-binding protein), which is a PDZ domain containing protein with a putative role in cellular stress response pathways. Here, we provide evidence that MICS-1 is an interacting partner of mitochondrial protein ATAD-3 (homologue of human ATAD3), which is essential for C. elegans development. We demonstrate that mics-1(RNAi) animals or mics-1 mutants display enhanced longevity with an increased mean lifespan of up to 54% compared to control animals. Of note, also atad-3(RNAi) promoted longevity, although to a lesser extend (29% compared to controls). In addition, thermal stress of mics-1 mutants induced low reactive oxygen species (ROS) production, whereas atad-3(RNAi) animals were highly sensitive to this assay, displaying drastically increased ROS levels. Further studies revealed that MICS-1 and ATAD-3 associated longevity was partially dependent on the presence of DAF-16. However, for both conditions, we also found a DAF-16 independent extension of lifespan. Finally, we observed an additional lifespan extension in mics-1 mutants when subjected to atad-3(RNAi) whereas heat induced ROS production was even aggravated under this condition. This suggests (partially) independent effects of MICS-1 and ATAD-3 on lifespan and ROS production in vivo.
Experimental gerontology 03/2012; 47(3):270-5. · 3.34 Impact Factor
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ABSTRACT: The biogenesis of mitochondrial NADH:ubiquinone oxidoreductase (complex I) requires several assembly chaperones. These so-called complex I assembly factors have emerged as a new class of human disease genes. Here, we identified putative assembly factor homologues in Caenorhabditis elegans. We demonstrate that two candidates (C50B8.3/NUAF-1, homologue of NDUFAF1 and R07H5.3/NUAF-3, homologue of NDUFAF3) clearly affect complex I function. Assembly factor deficient worms were shorter, showed a diminished brood size and displayed reduced fat content. Our results suggest that mitochondrial complex I biogenesis is evolutionarily conserved. Moreover, Caenorhabditis elegans appears to be a promising model organism to study assembly factor related human diseases.
Mitochondrion 02/2012; 12(3):399-405. · 3.62 Impact Factor
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ABSTRACT: Hemodynamically significant patent ductus arteriosus (hsPDA) is the most common functional cardiovascular disease in preterm infants. The necessity to treat hsPDA can neither be derived solely from clinical nor from echocardiographic criteria.
The aim of this study was to establish non-invasive parameters which can differentiate hsPDA from non-hsPDA.
Urinary protein levels of NT-proBNP, NGAL, and H-FABP were measured and correlated with the necessity of therapy for PDA. In 37 neonates (<1,500 g), urinary protein concentrations were tested on days 0, 2, and 7 by ELISA methodology. Of 37 infants, 12 required therapeutic interventions according to current treatment standards. Results: Infants receiving an intervention for PDA showed significantly higher levels of pro-BNP, NGAL, and H-FABP at all time points except for NT-proBNP on day 0. Infants requiring a second or third course of ibuprofen had significantly higher levels of H-FABP and NGAL. In all samples, the concentration of the three proteins correlated positively with each other.
The present study shows that measurement of urinary proteins is a powerful and non-invasive method to quantify the effect of PDA on systemic perfusion in preterm infants. Furthermore, NGAL and H-FABP may be used to indicate the necessity of pharmacological or surgical treatment of PDA.
Neonatology 01/2012; 101(4):260-6. · 2.66 Impact Factor
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ABSTRACT: Worldwide, only nine cases of revealing slipped capital femoral epiphysis (SCFE) associated with primary hyperparathyroidism (PHP) have been reported.
This study included adolescent subjects with the described association, the clinical course, and exhibiting the leading pathogeneses.
Here, we reviewed all known cases and developed an effective approach to the management of SCFE and PHP.
In cases of emergency, SCFE fixation is primarily done regardless of any preexistent hypercalcemia due to PHP and followed by parathyroidectomy as soon as possible. In cases of mild and moderate hypercalcemia, whether SCFE fixation is followed by parathyroidectomy and vice versa or resolved during a single operating session depends on manifest side effects due to hyercalcemia. Patients with severe hypercalcema should undergo urgent parathyroidectomy, followed by immediate orthopedic surgery, even as a simultaneous procedure. This is to avoid onset of hypercalcemic side effects or worsening of preexisting side manifestations resulting from hypercalcemia.
Our report demonstrates that SCFE presenting with hypercalcemia, with signs of low bone density, or in atypical age deserves further workup for secondary causes. In addition, the newly developed systematic approach toward achieving an effective, efficient management should help to improve the patients' long-term outcome.
Journal of pediatric endocrinology & metabolism: JPEM 01/2012; 25(5-6):407-12. · 0.88 Impact Factor
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ABSTRACT: Hereditary sensory and autonomic neuropathies have different phenotypes. We report 2 cousins with differing clinical courses of a hereditary sensory and autonomic neuropathy. The progressive disease in case 1 is dominated by loss of sensation, autonomic crises, and pain. Case 2 shows loss of sensation, mental retardation, and deafness, clinically similar to patients with hereditary sensory and autonomic neuropathy type II. Detailed molecular studies in case 1 for all known genes that are associated with hereditary sensory and autonomic neuropathies were negative. However, the occurrence of the 2 cases within 1 kindred makes a common genetic background likely. We, therefore, propose a Turkish variant of familial dysautonomia in these 2 patients.
Journal of child neurology 12/2011; 27(2):191-6. · 1.59 Impact Factor
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ABSTRACT: The implementation of NTBC into treatment of hypertyrosinemia type I (HT I) greatly improved survival by prevention of acute liver failure and hepatocellular carcinoma. However, there are first reports of cognitive impairment in patients with elevated plasma tyrosine concentrations.
We here assess the neurocognitive development using standardized psychometric test batteries with respect to cognition, motor abilities and speech in nine early-treated patients with HT I under long-term NTBC treatment.
High plasma tyrosine concentrations were frequently documented resulting in elevated 12-month median plasma tyrosine concentrations in seven out of nine patients. Plasma NTBC concentrations were generally in the lower therapeutic range. Five out of seven patients (71%) above 3 years of age had a total IQ score below the average. In addition, five out of seven patients above 3 years showed an inhomogenous test profile with significant differences between the different testing scales. Motor abilities were subnormal in four out of seven patients(57%). Cerebral MRI revealed no abnormalities. Logopedic evaluation in children at school age documented dysfunction or retardation in language development in all but one of the tested patients (80%), however, all but one patients had a migration background.
A high number of patients performed below normal in the assessment of development, motor function and speech. We propose intellectual impairment as long-term complication in HT type I with elevated plasma tyrosine under NTBC treatment as observed in other hypertyrosinemias. These findings remain to be reproduced in greater patient numbers.
Journal of Inherited Metabolic Disease 11/2011; 35(2):263-8. · 3.58 Impact Factor
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ABSTRACT: Mucopolysaccharidosis type II (Hunter disease) is a lysosomal storage disease attributable to X-linked deficiency of the enzyme α-L-iduronate-sulfatase. Because of this deficiency, glycosaminoglycanes accumulate in various tissues and body fluids. We describe three patients representing the broad spectrum of Hunter disease and their response to enzyme replacement therapy. Patient 1 did not manifest central nervous system involvement, patient 2 manifested moderate neurologic disease, and patient 3 had already manifested a severe neurologic course during early infancy. In all patients, improvements in visceral organ size, physical capacity, and gastrointestinal functioning were reported. Moreover, all three patients demonstrated a gain in height, improved functioning of the upper limb, and a reduced need for antibiotics to treat upper airway infections. The response to enzyme replacement therapy occurred independent of type of genetic mutation (missense or frame shift), and we observed only mild infusion-related reactions. We conclude that all patients with mucopolysaccharidosis type II (those with and without clinical central nervous system involvement) may benefit from enzyme replacement therapy.
Pediatric Neurology 09/2011; 45(3):181-4. · 1.52 Impact Factor
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ABSTRACT: Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is caused by a defect in glucose transport across the blood-brain barrier. The main symptoms are epilepsy, developmental delay, movement disorders, and deceleration of head circumference. A ketogenic diet has been shown to be effective in controlling epilepsy in GLUT1-DS. We report a female child (3 y 4 mo) who presented with delayed psychomotor development and frequent episodes of staggering, impaired vigilance, and vomiting that resolved promptly after food intake. Electroencephalography was normal. The cerebrospinal fluid-blood glucose ratio was 0.42 (normal ≥ 0.45). GLUT1-DS was confirmed by molecular genetic testing, which showed a novel de novo heterozygous mutation in the SLC2A1 gene (c.497_499delTCG, p.VAL166del). Before starting a ketogenic diet, the child's cognitive development was tested using the Snijders-Oomen Non-Verbal Intelligence Test, which revealed a heterogeneous intelligence profile with deficits in her visuomotor skills and spatial awareness. Her motor development was delayed. Three months after introducing a ketogenic diet, she showed marked improvement in speech and motor development, as tested by the Movement Assessment Battery for Children (manual dexterity 16th centile, ball skills 1st centile, static and dynamic balance 5th centile). This case demonstrates that GLUT1-DS should be investigated in individuals with unexplained developmental delay. Epilepsy is not a mandatory symptom. The ketogenic diet is also beneficial for non-epileptic symptoms in GLUT1-DS.
Developmental Medicine & Child Neurology 08/2011; 53(12):1154-6. · 2.92 Impact Factor
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Sebastian Kummer,
Abdurrahman Sagir,
Simone Pandey,
Markus Feldkötter,
Sandra Habbig,
Friederike Körber,
Dietrich Ney,
Bernd Hoppe,
Dieter Häussinger, Ertan Mayatepek,
Jun Oh
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ABSTRACT: Cystic renal diseases are characterized by intrarenal cysts of different size and number. Further important diagnostic criteria include, e.g., liver fibrosis. The latter represents a significant cause of morbidity and mortality in autosomal-recessive polycystic kidney disease (ARPKD), whereas patients with autosomal-dominant polycystic kidney disease (ADPKD) can develop hepatic cysts without fibrosis. We report the use of transient elastography [FibroScan®, (FS)] for early and noninvasive detection of increased liver stiffness as marker of liver fibrosis. Compared with matched healthy controls, ADPKD patients (n = 7) showed no significant difference in liver stiffness (5.3 kPa vs. 4.5 kPa; ns). ARPKD patients (n = 7) had significantly increased median liver stiffness compared with controls (12.0 kPa vs. 4.5 kPa, p = 0.002) and ADPKD patients (12.0 kPa vs. 5.3 kPa, p = 0.002). Conventional ultrasound revealed evidence of liver fibrosis in only four of seven ARPKD patients (57%) compared with 100% detection by FS. Additional laboratory examinations showed no pathologic liver parameters. In conclusion, our data found FS to be a valuable, sensitive, and noninvasive new tool for early evaluation of liver fibrosis in cystic kidney diseases. This could facilitate diagnosis, monitoring, and management of liver involvement in ARPKD or any other cystic kidney disease.
Pediatric Nephrology 02/2011; 26(5):725-31. · 2.52 Impact Factor
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ABSTRACT: Cerebellar hemorrhage is an underrecognized complication in the preterm neonate. It is multifactorial including combined maternal, intrapartum, and early postnatal factors. We present the case of 2 preterm brothers, 24 + 1 and 24 + 3 weeks of gestation, who both died because of cerebellar hemorrhage. We sought familial pathogenic factors predisposing to cerebellar hemorrhage. Cerebral imaging performed by ultrasonography through the anterior fontanel was normal and showed no signs of bleeding or brain edema. Postmortem neuropathologic findings confirmed cerebellar hemorrhagic lesions in both infants. Cerebellar vessels showed no signs of morphologic disorders or malformations. There might be a hint to a familial disposition. Neonatal cranial ultrasound protocols should include brainstem and posterior fossa examination with specific scans through the mastoid fontanel.
Journal of child neurology 02/2011; 26(6):767-9. · 1.59 Impact Factor
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ABSTRACT: Psychomotor impairment has been described in hypertyrosinemia types II and III (HT III). Only recently cognitive deficits have also been reported in hypertyrosinemia type I (HT I). The pathogenic mechanisms responsible are unknown. Since implementation of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC, Nitisinone (Swedish Orphan International)) in the treatment of HT I, plasma tyrosine elevation is a common finding as known from the other hypertyrosinemias.
With elevated tyrosine as suspected pathogenic factor in the development of cognitive deficits, we here investigated tyrosine in the cerebrospinal fluid (CSF) and serotonergic and dopaminergic neurotransmitter levels in three patients with HT I during long-term treatment with Nitisinone. In addition, Nitisinone concentrations in plasma and CSF were measured. We also assessed psychomotor and cognitive development by standardized test systems and brain morphology by magnetic resonance imaging.
All patients presented with high tyrosine concentrations in CSF correlating with increased plasma tyrosine levels and a reduced CSF serotonin turnover. MRI revealed no structural abnormalities in the brain. All patients presented with either impaired cognitive development or behavioural abnormalities.
We here outline the need to further study the exact pathogenic mechanisms responsible for the neurotransmitter changes observed in HT type I in order to possibly prevent cognitive dysfunction. Nitisinone has significantly improved outcome and quality of life in HT type I; however, it is also accompanied by elevated plasma and CSF tyrosine. Further studies are essential to identify the necessary dietary tyrosine restriction and the optimal Nitisinone dose.
Molecular Genetics and Metabolism 02/2011; 102(2):122-5. · 3.19 Impact Factor
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ABSTRACT: Rare forms of congenital hyperinsulinism (CHI) are caused by mutations in GLUD1 (encoding glutamate dehydrogenase), GCK (encoding glucokinase), HADH (encoding for L-3-hydroxyacyl-CoA dehydrogenase), SLC16A1 (encoding the monocarboxylat transporter 1), HNF4A (encoding hepatocyte nuclear factor 4α) or UCP2 (encoding mitochondrial uncoupling protein 2). The clinical presentation is very heterogeneous in regards to age of onset, severity, and manner of symptoms, as well as the response to medical treatment. Special individual characteristics have to be accounted in diagnosis and treatment. Diazoxide is the first-line drug for the rare forms of CHI for long-term treatment but is not entirely effective in some of these rarer defects (GCK, MCT1). The use of diazoxide is often limited by side effects and the use of octreotide as second-line drug has to be considered. A near-total pancreatectomy is only reserved for patients with diffuse disease and resistance to medical treatment as a last resort. Patients with CHI should be managed by centers with a highly experienced team in diagnostic work-up and treatment of this disease.
Seminars in Pediatric Surgery 02/2011; 20(1):38-44. · 2.93 Impact Factor
