Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple carboxylase deficiency is characterized by deficient activities of three biotin-dependent enzymes, propionyl coenzyme A carboxylase, pyruvate carboxylase, and beta-methylcrotonyl coenzyme A carboxylase. A newborn infant was seen with metabolic ketoacidosis, hyperammonemia, organic aciduria, seizures, and coma. Multiple carboxylase deficiency was subsequently confirmed by enzyme activity determinations in his peripheral blood leukocytes and cultured skin fibroblasts. The infant's neurologic and metabolic status improved markedly within a few days of administration of pharmacologic doses of oral biotin. His EEG, which was distinctly abnormal, became normal; his extensive computed tomography scan changes resolved, with the exception of ventricular dilation, over the next two months. After two weeks of biotin treatment the excretion of abnormal organic acid metabolites was reduced and his carboxylase activities increased to the normal range. However, the activities of these enzymes increased only to 30% to 55% of normal in fibroblasts incubated in supplemental biotin. This partial correction of enzyme activity differs from that observed in other individuals with multiple carboxylase deficiency and suggests biochemical heterogeneity in this disorder. Prompt diagnosis and intervention can avert some of the pathologic complications of this biotin-responsive condition.
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PMID:Multiple carboxylase deficiency: clinical and biochemical improvement following neonatal biotin treatment. 678 61

A 15-year-old girl with a former clinical diagnosis of cerebral palsy was found to have isolated deficiency of 3-methylcrotonyl-CoA carboxylase (MCC) on gas chromatography-mass spectrometry (GC/MS) analysis and enzyme determination. Her symptoms included marked growth retardation from birth, profound mental retardation, tonic seizures, rigospastic quadriplegia with opisthotonic dystonia, gastroesophageal reflux with poor esophageal peristalsis, and recurrent episodes of aspiration pneumonia. Brain MRI revealed marked brain atrophy, involving both the gray and white matter. Although she did not exhibit acute metabolic decompensation or acute encephalopathy, her neurological symptoms continuously worsened. This patient is the oldest among reported cases of MCC deficiency who had symptoms at birth, and this case may have the severest sequelae of the longest known natural course of this inborn error of metabolism.
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PMID:Isolated 3-methylcrotonyl-CoA carboxylase deficiency in a 15-year-old girl. 918 84

Deficiency of 3-methylcrotonyl-CoA carboxylase (MCC) results in elevated excretion of 3-methylcrotonylglycine (3-MCG) and 3-hydroxyisovaleric acid (3-HIVA). MCC is a heteromeric mitochondrial enzyme comprising biotin-containing alpha subunits and smaller beta subunits, encoded by MCCA and MCCB, respectively. Mutations in these genes cause isolated MCC deficiency, an autosomal recessive disorder with a variable phenotype that ranges from severe neonatal to asymptomatic adult forms. No reported patients have responded to biotin therapy. Here, we describe two patients with a biochemical and, in one case, clinical phenotype of MCC deficiency, both of whom were responsive to biotin. The first patient presented at 3 months with seizures and progressive psychomotor retardation. Metabolic investigation at 2 years revealed elevated excretion of 3-MCG and 3-HIVA, suggesting MCC deficiency. High-dose biotin therapy was associated with a dramatic reduction in seizures, normalization of the electroencephalogram, and correction of the organic aciduria, within 4 weeks. MCC activity in fibroblasts was 25% of normal levels. The second patient, a newborn detected by tandem-mass-spectrometry newborn screening, displayed the same biochemical phenotype and remained asymptomatic with biotin up to the age of 18 months. In both patients, sequence analysis of the complete open reading frames of MCCA and MCCB revealed heterozygosity for MCCA-R385S and for the known polymorphic variant MCCA-P464H but revealed no other coding alterations. MCCA-R385S is unusual, in that it has a normal amount of MCC alpha protein but confers no MCC activity. We show that MCCA-R385S, but not other MCCA missense alleles, reduces the MCC activity of cotransfected MCCA-wild-type allele. Our results suggest that MCCA-R385S is a dominant negative allele and is biotin responsive in vivo.
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PMID:Isolated 3-methylcrotonyl-CoA carboxylase deficiency: evidence for an allele-specific dominant negative effect and responsiveness to biotin therapy. 1535 79

3-Methylcrotonylglycinuria is an inborn error of leucine catabolism with an autosomal recessive pattern of inheritance that results from a deficiency of 3-methylcrotonyl-CoA carboxylase (MCC). We report on a nine-year-old boy with severe psychomotor retardation who developed infantile spasms at the age of three weeks. Urine analysis at the age of two years revealed massive 3-methylcrotonylglycinuria and 3-hydroxyisovaleric aciduria suggesting MCC deficiency. Carnitine serum levels were decreased. Biotin therapy led to a dramatic decrease in the frequency of seizures, disappearance of hypsarrhythmia, and near normalisation of organic aciduria. Four months later a protein-restricted diet was introduced in addition and the boy remained clinically and metabolically stable. However, severe psychomotor delay persisted, and the seizures partially reoccurred. Biochemical findings showed partial MCC deficiency in cultured fibroblasts. Molecular genetic studies revealed a heterozygote missense mutation, MCCA-R385S, converting arginine to serine in a highly conserved region of the MCCA gene. This is the first patient with MCC deficiency caused by a heterozygote mutation and who demonstrated a substantial and sustained clinical and biochemical response to therapeutic doses of biotin. Sadly, this patient again also demonstrates that the main determinant of the outcome of even easily treatable metabolic diseases is timely diagnosis.
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PMID:The first case of 3-methylcrotonyl-CoA carboxylase (MCC) deficiency responsive to biotin. 1677 4

A patient with isolated 3-methylcrotonyl-CoA carboxylase (MCC) deficiency with an unusual clinical presentation is described. The patient presented with clusters of seizures with two or three months disease free interval in the first year of life which then evolved into attacks of status epilepticus after the age of 12 months. MCC deficiency was suspected because of elevated C5-OH-carnitine in tandem mass spectrometry and elevated 3-hydroxy-isovaleric acid in urine organic acid analysis. Deficiency of MCC was confirmed in cultured fibroblasts and mutation analysis revealed a novel mutation in MCCB, p.S39F. Attacks of status epilepticus as a predominant symptom have not been described before in isolated MCC deficiency.
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PMID:Recurrent attacks of status epilepticus as predominant symptom in 3-methylcrotonyl-CoA carboxylase deficiency. 1786 68