3- Methylcrotonyl-coa Carboxylase Deficiency: Biochemical and Molecular Studies in 36 Patients (original) (raw)
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Pyruvate dehydrogenase complex deficiency: four neurological phenotypes with differing pathogenesis
Developmental Medicine & Child Neurology, 2009
METHOD Twenty-two participants with enzymologically and genetically confirmed PDHc deficiency were analysed for clinical and imaging features over a 15-year period. RESULTS Four groups were identified: (1) those with neonatal encephalopathy with lactic acidosis (one male, four females; diagnosis at birth); (2) those with non-progressive infantile encephalopathy (three males, three females; age at diagnosis 2-9mo); (3) those with Leigh syndrome (eight males; age at diagnosis 1-13mo); and (4) those with relapsing ataxia (three males; 18-30mo). Seventeen mutations involved PDHA1 (a hotspot was identified in exons 6, 7, and 8 in seven males with Leigh syndrome or recurrent ataxia). Mutations in the PDHX gene (five cases) were correlated with non-progressive encephalopathy and long-term survival in four cases. INTERPRETATION Two types of neurological involvement were identified. Abnormal prenatal brain development resulted in severe non-progressive encephalopathy with callosal agenesis, gyration anomalies, microcephaly with intrauterine growth retardation, or dysmorphia in both males and females (12 cases). Acute energy failure in infant life produced basal ganglia lesions with paroxysmal dystonia, neuropathic ataxia due to axonal transport dysfunction, or epilepsy only in males (11 cases). The ketogenic diet improved only paroxysmal dysfunction, providing an additional argument in favour of paroxysmal energy failure.
Inborn errors of metabolism causing epilepsy
Developmental Medicine & Child Neurology, 2013
Seizures may be the first and the major presenting feature of an inborn error of metabolism (IEM), for example in a neonate with pyridoxine-dependent epilepsy. In other IEMs, seizures may be preceded by other major symptoms: by a reduced level of consciousness in a child with an organic acidaemia or urea cycle defect; or by loss of skills, progressive weakness, ataxia, and upper motor signs in a child with a lysosomal storage disorder or peroxisomal leukodystrophy. This review concentrates on those IEMs for which specific treatment is available. The common metabolic causes of seizures vary according to the age at presentation. Features from the history, examination, imaging, and first line biochemical investigations can all provide clues to an inborn error. This review attempts to delineate these and to provide a guide to the specific tests that can be used to make the diagnosis of disorders with specific treatment.
Brain and Development, 2013
Inborn errors of metabolism comprise a large class of genetic diseases involving disorders of metabolism. Presentation is usually in the neonatal period or infancy but can occur at any time, even in adulthood. Seizures are frequent symptom in inborn errors of metabolism, with no specific seizure types or EEG signatures. The diagnosis of a genetic defect or an inborn error of metabolism often results in requests for a vast array of biochemical and molecular tests leading to an expensive workup. However a specific diagnosis of metabolic disorders in epileptic patients may provide the possibility of specific treatments that can improve seizures. In a few metabolic diseases, epilepsy responds to specific treatments based on diet or supplementation of cofactors (vitaminresponsive epilepsies), but for most of them specific treatment is unfortunately not available, and conventional antiepileptic drugs must be used, often with no satisfactory success. In this review we present an overview of metabolic epilepsies based on various criteria such as treatability, age of onset, seizure type, and pathogenetic background. (A. Spalice).
Ketogenic diet in pyruvate dehydrogenase complex deficiency: short- and long-term outcomes
Journal of Inherited Metabolic Disease
Objectives Our aime was to study the short-and long-term effects of ketogenic diet on the disease course and diseaserelated outcomes in patients with pyruvate dehydrogenase complex deficiency, the metabolic factors implicated in treatment outcomes, and potential safety and compliance issues. Methods Pediatric patients diagnosed with pyruvate dehydrogenase complex deficiency in Sweden and treated with ketogenic diet were evaluated. Study assessments at specific time points included developmental and neurocognitive testing, patient log books, and investigator and parental questionnaires. A systematic literature review was also performed. Results Nineteen patients were assessed, the majority having prenatal disease onset. Patients were treated with ketogenic diet for a median of 2.9 years. All patients alive at the time of data registration at a median age of 6 years. The treatment had a positive effect mainly in the areas of epilepsy, ataxia, sleep disturbance, speech/language development, social functioning, and frequency of hospitalizations. It was also safeexcept in one patient who discontinued because of acute pancreatitis. The median plasma concentration of ketone bodies (3-hydroxybutyric acid) was 3.3 mmol/l. Poor dietary compliance was associated with relapsing ataxia and stagnation of motor and neurocognitive development. Results of neurocognitive testing are reported for 12 of 19 patients. Conclusion Ketogenic diet was an effective and safe treatment for the majority of patients. Treatment effect was mainly determined by disease phenotype and attainment and maintenance of ketosis.
Metabolic Causes of Epileptic Encephalopathy
Epilepsy Research and Treatment, 2013
Epileptic encephalopathy can be induced by inborn metabolic defects that may be rare individually but in aggregate represent a substantial clinical portion of child neurology. These may present with various epilepsy phenotypes including refractory neonatal seizures, early myoclonic encephalopathy, early infantile epileptic encephalopathy, infantile spasms, and generalized epilepsies which in particular include myoclonic seizures. There are varying degrees of treatability, but the outcome if untreated can often be catastrophic. The importance of early recognition cannot be overemphasized. This paper provides an overview of inborn metabolic errors associated with persistent brain disturbances due to highly active clinical or electrographic ictal activity. Selected diseases are organized by the defective molecule or mechanism and categorized as small molecule disorders (involving amino and organic acids, fatty acids, neurotransmitters, urea cycle, vitamers and cofactors, and mitochondr...
Epilepsy in inborn errors of metabolism: two cases with unusual presentation
International Journal of Epilepsy, 2014
Inherited metabolic disorders are a rare cause of epilepsy in children. We describe a case of Glutaric aciduria type 1 presenting with West syndrome and a case of intermittent Maple syrup urine disease presenting with epileptic encephalopathy. Early diagnosis and institution of appropriate therapy may be life saving and may improve the long term neurodevelopmental outcome in children with inherited metabolic disorders.
Metabolic Testing in the Pediatric Epilepsy Unit
Pediatric Neurology, 2008
Unexplained mental retardation is noted in up to 3% of the general population, and upwards of 30% of these patients manifest epilepsy. There is no standardized approach to metabolic testing in these patients. In a first step toward a standardized approach for our center, we performed a retrospective evaluation of testing of our patients in the past. Records of 429 children admitted to our pediatric epilepsy-monitoring center in 2005 were reviewed. We noted whether they had developmental delay, their type of epilepsy, and the extent of metabolic testing. Ninety percent of our patients had developmental delay, and 20% received some form of metabolic testing. Abnormal results suggesting mitochondrial dysfunction were found in 28% of our patients without a previous underlying diagnosis. Metabolic abnormalities were found in 75% of those with multifocal interictal discharges. Secondary carnitine deficiency was identified in 22%; these patients were taking valproic acid. Primary or secondary metabolic abnormalities likely represent a prominent finding in these patients. Differential diagnoses involving mitochondrial dysfunction should receive serious consideration. Findings such as carnitine deficiency can be identified and treated. A systematic approach for such testing is needed. A prospective evaluation at our institution is planned.
Multiple sources of metabolic disturbance in ETHE1-related ethylmalonic encephalopathy
Journal of Inherited Metabolic Disease, 2010
Ethylmalonic encephalopathy (EE) is a rare metabolic disorder caused by dysfunction of ETHE1, a mitochondrial dioxygenase involved in hydrogen sulfide (H 2 S) detoxification. Patients present in infancy with psychomotor retardation, chronic diarrhea, orthostatic acrocyanosis and relapsing petechiae. High levels of lactic acid, ethymalonic acid (EMA) and methylsuccinic acid (MSA) are detected in body fluids. Several pathways may contribute to the pathophysiology, including isoleucine, methionine and fatty acid metabolism. We report on a 15-month-old male presenting with typical EE associated with a homozygous ETHE1 mutation. We investigated oral isoleucine (150 mg/kg), methionine (100 mg/kg), fatty acid loading tests and isoleucine-restricted diet (200 mg/day) for any effects on several metabolic parameters. Before loading tests or specific dietary interventions, EMA, C4-C5 acylcarnitines and most acylglycines were elevated, indicating functional deficiency of short chain acyl-CoA (SCAD) as well as all branched acyl-CoA dehydrogenases. Excretion of EMA and n-butyrylglycine increased following each of the loads, and isoleucine led to increased levels of derivative Communicated by: Georg Hoffmann Competing interest: None declared.