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)

Mitochondrial DNA depletion syndrome (MDS) is characterized by a reduction in mtDNA copy number and has been associated with mutations in eight nuclear genes, including enzymes involved in mitochondrial nucleotide metabolism (POLG, TK2, DGUOK, SUCLA2, SUCLG1, PEO1) and MPV17. Recently, mutations in the RRM2B gene, encoding the p53-controlled ribonucleotide reductase subunit, have been described in seven infants from four families, who presented with various combinations of hypotonia, tubulopathy, seizures, respiratory distress, diarrhea, and lactic acidosis. All children died before 4 months of age. We sequenced the RRM2B gene in three unrelated cases with unexplained severe mtDNA depletion. The first patient developed intractable diarrhea, profound weakness, respiratory distress, and died at 3 months. The other two unrelated patients had a much milder phenotype and are still alive at ages 27 and 36 months. All three patients had lactic acidosis and severe depletion of mtDNA in muscle. Muscle histochemistry showed RRF and COX deficiency. Sequencing the RRM2B gene revealed three missense mutations and two single nucleotide deletions in exons 6, 8, and 9, confirming that RRM2B mutations are important causes of MDS and that the clinical phenotype is heterogeneous and not invariably fatal in infancy.
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PMID:Mitochondrial DNA depletion syndrome due to mutations in the RRM2B gene. 1850 29

Mitochondrial DNA depletion syndrome (MDS) is a severe recessively inherited disease of childhood. It manifests most often in infancy, is rapidly progressive and leads to early death. MDS is caused by an increasing number of nuclear genes leading to multisystemic or tissue-specific decrease in mitochondrial DNA (mtDNA) copy number. Thymidine kinase 2 (TK2) has been reported to cause a myopathic form of MDS. We report here the clinical, autopsy and molecular genetic findings of rapidly progressive fatal infantile mitochondrial syndrome. All of our seven patients had rapidly progressive myopathy/encephalomyopathy, leading to respiratory failure within the first 3 years of life, with high creatine kinase values and dystrophic changes in the muscle with cytochrome c oxidase-negative fibres. In addition, two patients also had terminal-phase seizures, one had epilepsia partialis continua and one had cortical laminar necrosis. We identified two different homozygous or compound heterozygous mutations in the TK2 gene in all the patients: c.739 C s -> T and c.898 C -> T, leading to p.R172W and p.R225W changes at conserved protein sites. R172W mutation led to myopathy or encephalomyopathy with the onset during the first months of life, and was associated with severe mtDNA depletion in the muscle, brain and liver. Homozygosity for R225W mutation manifested during the second year of life as a myopathy, and showed muscle-specific mtDNA depletion. Both mutations originated from single ancient founders, with Finnish origin and enrichment for the new R172W mutation, and possibly Scandinavian ancestral origin for the R225W. We conclude that TK2 mutations may manifest as infantile-onset fatal myopathy with dystrophic features, but should be considered also in infantile progressive encephalomyopathy with wide-spread mtDNA depletion.
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PMID:Thymidine kinase 2 defects can cause multi-tissue mtDNA depletion syndrome. 1881 85

An 11 months old boy, developed liver failure after febrile status epilepticus while being treated with valproic acid for myoclonic epilepsy and recurrent partial and generalized seizures. The diagnosis of Alpers-Huttenlocher disease was considered. A muscle biopsy showed mitochondrial dysfunction. Mitochondrial DNA depletion was ruled out. Sequencing of the polymerase gamma gene (POLG1) did not detect any mutations. Sequencing of the alpha-1 subunit gene of the voltage-gated neuronal sodium channel (SCN1A) revealed a novel, de novo amino acid change p.Val 1637 Glu. This case expands the spectrum of clinical presentations related to mutations in SCN1A. We warn that children with SCN1A mutations may be at risk for developing liver failure following status epilepticus, due to mitochondrial dysfunction.
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PMID:Hepatic coma culminating in severe brain damage in a child with a SCN1A mutation. 2039 57