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215 Sjögren-Larsson syndrome: New biochemical insights
A107
Abstracts In the liver of PEX5-/-mice, a 55% reduction of complex 1 and a 300% increase of complex IV activity was observed. In heart tissue the differences were less pronounced, i.e. a 35% reduction in complex I and an increase of about 20% in complex IV activity. There was no difference in the activities of complex II, II+III, III, V or citrate synthase in either tissue. These results will be complemented with analyses of ATP, lactate and pyruvate to examine whether the observed reduction of complex I activity impairs the production of high energy phosphates. In conclusion, the abnormal structure of mitochondrial cristae observed in Zellweger mice is accompanied by altered activities of the complexes of the electron transfer chain. However, the possible significance in the pathogenesis of peroxisome deficiency disorders is not clear yet. Supported by Biomed BMH4-CT98-3569
381
Biotinidase deficiency make
is an important
diagnosis to
E WASSMER, M A PREECE, G GRAY, S GREEN, W WHITEHOUSE Birmingham Birmingham,
Children’s UK
Hospital,
Steelhouse
Lane,
Case 2: Presented at the age of 14 months with progressive weakness and lethargy. This was followed by two separate acute episodes of weakness, hypotonia and tachypnoea with a lactic acidosis. He had alopecia and a high frequency hearing loss. Urine organic acids showed increased 3-hydroxyisovalerate and 3-methylcrotonly glycine. Case 2: Presented at the age of 6 weeks with failure to thrive and poor visual attention. He was noted to have splenomegaly. At 1 year of age he developed myoclonic jerks. On examination he had marked hypotonia, with normal reflexes and a red scaly rash. Brain MRI showed global cerebral atrophy with unmyelinated white matter. Motor nerve conduction studies indicated mild demyelinating polyneuropathy. Urine organic acids were tested on several occasions and did not show metabolites consistent with biotinidase deficiency. Diagnosis:
confirmed 15 mg/day
In both children biotinidase deficiency was in plasma. They were treated with biotin loand improved gradually.
Conclusion: Although biotinidase deficiency is rare (1:50000) it is an important diagnosis to make as the condition is treatable and early diagnosis may prevent severe neurodisability. The presentation varies as these two patients demonstrate. The children can present with tachypnoea and metabolic acidosis, skin rashes and alopecia, convulsions, ataxia, hypotonia, development delay, deafness and visual loss. Case 2 illustrates that urinary organic acids may be normal in biotinidase deficiency. We need to consider this important diagnosis in everyday practice.
215
SjGgren-Larsson syndrome: New biochemical insights M A A P WILLEMSEN,’ E MAYATEPEK,’ J J ROTTEVEEL,’ ‘Department of Paediatric Neurology, University Hospital Nijmegen, Nijmegen, The Netherlands; 2Department of General Pediatrics, University Children’s Hospital, Heidelberg, Germany
Introduction: The Sjogren-Larsson syndrome (SLS) is an autosomal recessive inherited disorder characterized by ichthyosis, spastic diplegia and mental retardation. The syndrome is caused by the deficiency of microsomal fatty aldehyde dehydrogenase (FALDH) which catalyses the oxidation of medium- and long-chain fatty aldehydes. Leukotriene B4 (LTB,) is a potent pro-inflammatory mediator that plays a role in a variety of disease processes. LTB4 is degraded by microsomal w-oxidation, yielding w-hydroxy-LTB4, w-aldehyde-LTBp and wcarboxy-LTB4 respectively. Given the known deficiency of microsomal FALDH in SLS, we postulated that the latter step in the metabolism of LTB4 might be affected SLS. Materials and methods: We investigated urinary samples of 10 patients with SLS, in whom the diagnosis has been proven by demonstrating FALDH deficiency in cultured skin fibroblasts. Urinary LTBJ, w-hydroxy-LTB4 and cu-carboxy-LTBJ were separated by reversed-phase highperformance liquid chromatography and subsequently quantified by immunoassays and/or gas chromatographymass spectrometry using (180)-labelled leukotrienes as internal standards. Results: LTB4 and o-hydroxy-LTB4 were readily detected in the urine of all patients (mean (SD) urinary concentrations of LTBJ and o-OH-LTB4:30 (17) and 336 (142) nmol/ml creatinine respectively), whereas these compounds were undetectable in the urine from healthy controls. o-Carboxy-LTBJ was not detected in the urine of patients with SLS or in the urine from control subjects. Conclusions and discussion: These findings point to a crucial role for FALDH in the inactivation of LTB4. Defective metabolism of LTBJ is the first biochemical pathway demonstrated to be abnormal in vivo in patients with SLS. Analysis of these metabolites in urine offers a new and non-invasive diagnostic approach for patients with SLS. Moreover, defective LTB4 inactivation might play a part in the pathophysiology of SLS.
223
Leukodystrophy in 40 children: Clinical features, MRVMRS, follow-up Z YAPI A UCQUL, E DENIZ, F ERDOCAN, M ERAKSOY, H tjZCAN
M BARLAS,
Department of Neurology, Istanbul Medical Faculty,
Neurology,
Division of Child Istanbul, Turkey
Over the last 15 years, we have analysed 40 patients in whom leukodystrophy was suspected based on clinical and/or MRI findings in the Child Neurology Division, Department of Neurology in Istanbul Faculty of Medi-
Abstracts In the liver of PEX5-/-mice, a 55% reduction of complex 1 and a 300% increase of complex IV activity was observed. In heart tissue the differences were less pronounced, i.e. a 35% reduction in complex I and an increase of about 20% in complex IV activity. There was no difference in the activities of complex II, II+III, III, V or citrate synthase in either tissue. These results will be complemented with analyses of ATP, lactate and pyruvate to examine whether the observed reduction of complex I activity impairs the production of high energy phosphates. In conclusion, the abnormal structure of mitochondrial cristae observed in Zellweger mice is accompanied by altered activities of the complexes of the electron transfer chain. However, the possible significance in the pathogenesis of peroxisome deficiency disorders is not clear yet. Supported by Biomed BMH4-CT98-3569
381
Biotinidase deficiency make
is an important
diagnosis to
E WASSMER, M A PREECE, G GRAY, S GREEN, W WHITEHOUSE Birmingham Birmingham,
Children’s UK
Hospital,
Steelhouse
Lane,
Case 2: Presented at the age of 14 months with progressive weakness and lethargy. This was followed by two separate acute episodes of weakness, hypotonia and tachypnoea with a lactic acidosis. He had alopecia and a high frequency hearing loss. Urine organic acids showed increased 3-hydroxyisovalerate and 3-methylcrotonly glycine. Case 2: Presented at the age of 6 weeks with failure to thrive and poor visual attention. He was noted to have splenomegaly. At 1 year of age he developed myoclonic jerks. On examination he had marked hypotonia, with normal reflexes and a red scaly rash. Brain MRI showed global cerebral atrophy with unmyelinated white matter. Motor nerve conduction studies indicated mild demyelinating polyneuropathy. Urine organic acids were tested on several occasions and did not show metabolites consistent with biotinidase deficiency. Diagnosis:
confirmed 15 mg/day
In both children biotinidase deficiency was in plasma. They were treated with biotin loand improved gradually.
Conclusion: Although biotinidase deficiency is rare (1:50000) it is an important diagnosis to make as the condition is treatable and early diagnosis may prevent severe neurodisability. The presentation varies as these two patients demonstrate. The children can present with tachypnoea and metabolic acidosis, skin rashes and alopecia, convulsions, ataxia, hypotonia, development delay, deafness and visual loss. Case 2 illustrates that urinary organic acids may be normal in biotinidase deficiency. We need to consider this important diagnosis in everyday practice.
215
SjGgren-Larsson syndrome: New biochemical insights M A A P WILLEMSEN,’ E MAYATEPEK,’ J J ROTTEVEEL,’ ‘Department of Paediatric Neurology, University Hospital Nijmegen, Nijmegen, The Netherlands; 2Department of General Pediatrics, University Children’s Hospital, Heidelberg, Germany
Introduction: The Sjogren-Larsson syndrome (SLS) is an autosomal recessive inherited disorder characterized by ichthyosis, spastic diplegia and mental retardation. The syndrome is caused by the deficiency of microsomal fatty aldehyde dehydrogenase (FALDH) which catalyses the oxidation of medium- and long-chain fatty aldehydes. Leukotriene B4 (LTB,) is a potent pro-inflammatory mediator that plays a role in a variety of disease processes. LTB4 is degraded by microsomal w-oxidation, yielding w-hydroxy-LTB4, w-aldehyde-LTBp and wcarboxy-LTB4 respectively. Given the known deficiency of microsomal FALDH in SLS, we postulated that the latter step in the metabolism of LTB4 might be affected SLS. Materials and methods: We investigated urinary samples of 10 patients with SLS, in whom the diagnosis has been proven by demonstrating FALDH deficiency in cultured skin fibroblasts. Urinary LTBJ, w-hydroxy-LTB4 and cu-carboxy-LTBJ were separated by reversed-phase highperformance liquid chromatography and subsequently quantified by immunoassays and/or gas chromatographymass spectrometry using (180)-labelled leukotrienes as internal standards. Results: LTB4 and o-hydroxy-LTB4 were readily detected in the urine of all patients (mean (SD) urinary concentrations of LTBJ and o-OH-LTB4:30 (17) and 336 (142) nmol/ml creatinine respectively), whereas these compounds were undetectable in the urine from healthy controls. o-Carboxy-LTBJ was not detected in the urine of patients with SLS or in the urine from control subjects. Conclusions and discussion: These findings point to a crucial role for FALDH in the inactivation of LTB4. Defective metabolism of LTBJ is the first biochemical pathway demonstrated to be abnormal in vivo in patients with SLS. Analysis of these metabolites in urine offers a new and non-invasive diagnostic approach for patients with SLS. Moreover, defective LTB4 inactivation might play a part in the pathophysiology of SLS.
223
Leukodystrophy in 40 children: Clinical features, MRVMRS, follow-up Z YAPI A UCQUL, E DENIZ, F ERDOCAN, M ERAKSOY, H tjZCAN
M BARLAS,
Department of Neurology, Istanbul Medical Faculty,
Neurology,
Division of Child Istanbul, Turkey
Over the last 15 years, we have analysed 40 patients in whom leukodystrophy was suspected based on clinical and/or MRI findings in the Child Neurology Division, Department of Neurology in Istanbul Faculty of Medi-