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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Molybdenum cofactor (MoCo) deficiency is a rare and devastating disease resulting in neonatal seizures and other neurological symptoms identical to those of sulphite oxidase deficiency. It is an autosomal recessive disease and no therapy is known. Most patients harbour MOCS1 mutations, which are found in both open reading frames of this unusual gene encoding the first two enzymes required in the MoCo biosynthesis pathway, MOCS1 A and MOCS1 B, in a single transcript. We describe genomic details as a prerequisite for comprehensive mutation analysis. In an initial cohort of 24 MoCo deficiency patients, we identified 13 different mutations on 34 chromosomes, with a mutation detection rate of 70%. Five mutations were observed in more than one patient and together accounted for two thirds of detected mutations. These comprise the most frequent mutation, R319Q, which is restricted to England, two Danish/German mutations (one missense and one splice site mutation), a missense mutation found in England and Germany, and a "Mediterranean" frameshift mutation. All patients with identified mutations are either homozygous or compound heterozygous for mutations in either of the two open reading frames corresponding to MOCS1 A and MOCS1 B, respectively. This observation suggests the existence of more than the two previously described complementation groups in MoCo biosynthesis.
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PMID:Genomic structure and mutational spectrum of the bicistronic MOCS1 gene defective in molybdenum cofactor deficiency type A. 992 96

Molybdenum cofactor (MoCo) deficiency leads to a combined deficiency of the molybdo-enzymes sulphite oxidase, xanthine dehydrogenase and aldehyde oxidase. No therapy is known for this rare disease, which results in neonatal seizures and other neurological symptoms identical to sulphite oxidase deficiency. It is inherited autosomal-recessively and leads to early childhood death. Prenatal diagnosis has been performed since 1983 by the measurement of sulphite oxidase activity, but no enzymatic carrier diagnosis is possible. The human genes necessary for MoCo biosynthesis have recently been cloned and mutations in the bicistronic MOCS1 gene could be identified in most European patients. In a Danish family we have now performed enzymatic and molecular genetic analysis in parallel after chorionic villus sampling. The sulphite oxidase activity in uncultured CVS material was found to be normal. A MOCS1 splice site mutation, found homozygous in the affected patient, was found in a heterozygous state in cultured chorionic cells. This confirmed that the fetus was not affected, since heterozygous carriers of a MoCo deficiency allele do not display any symptoms.
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PMID:Molybdenum cofactor deficiency: first prenatal genetic analysis. 1032 49

Molybdenum cofactor (MoCo) deficiency leads to a combined deficiency of the molybdoenzymes sulphite oxidase, xanthine dehydrogenase and aldehyde oxidase. Effective therapy is not available for this rare disease, which results in neonatal seizures and other neurological symptoms identical to those of sulphite oxidase deficiency. It is an autosomal recessive trait and leads to early childhood death. Biosynthesis of MoCo can be divided into the formation of a precursor and its subsequent conversion to the organic moiety of MoCo by molybdopterin synthase. These two steps are the molecular basis of the two observed complementation groups A and B and of two types of MoCo deficiency with an identical phenotype. MOCS1 is defective in the majority of patients (group A) and was shown to encode two enzymes functioning in the formation of a precursor. The corresponding transcript is bicistronic with two consecutive open reading frames (ORFs). MOCS2 encodes the small and large subunits of molybdopterin synthase via a single transcript with two overlapping reading frames. This gene carries lesions in the B complementation group less frequently observed in patients. Both genes, MOCS1 and MOCS2, share the unusual bicistronic architecture, have identical and very low expression profiles and extremely conserved C-terminal ends in their 5'-ORF. These observations point to a novel form of microcompartmentalization and render the MOCS genes ideal candidates for a somatic gene therapy approach.
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PMID:Genetics of molybdenum cofactor deficiency. 1074 56

Human molybdenum cofactor deficiency is a rare and devastating autosomal-recessive disease for which no therapy is known. The absence of active sulfite oxidase-a molybdenum cofactor-dependent enzyme-results in neonatal seizures and early childhood death. Most patients harbor mutations in the MOCS1 gene, whose murine homolog was disrupted by homologous recombination with a targeting vector. As in humans, heterozygous mice display no symptoms, but homozygous animals die between days 1 and 11 after birth. Biochemical analyis of these animals shows that molydopterin and active cofactor are undetectable. They do not possess any sulfite oxidase or xanthine dehydrogenase activity. No organ abnormalities were observed and the synaptic localization of inhibitory receptors, which was found to be disturbed in molybdenum cofactor deficient-mice with a Gephyrin mutation, appears normal. MOCS1(-/-) mice could be a suitable animal model for biochemical and/or genetic therapy approaches.
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PMID:Molybdenum cofactor-deficient mice resemble the phenotype of human patients. 1247 Oct 57

We report a newborn with exaggerated startle reactions and stiffness of neonatal onset, the prototypical signs of hyperekplexia. Startle and flexor spasms, leading to apnoea, did not respond to treatment with clonazepam but did partially to sodium valproate. Molecular analysis of GLRA1 revealed no mutations. The incidental finding of hypouricemia led to a work-up for molybdenum cofactor (MoCo) deficiency; the diagnosis was confirmed by the altered urine chemistries, including elevated urine S-sulphocysteine. Despite persistence of the spasms, clinical or electrographic seizures were never detected before the infant died at age 1 month. In this patient, the concurrence of hyperekplexia and MoCo deficiency was suggestive of impaired gephyrin function. GPH mutational analysis, however, showed no abnormalities. The patient was eventually found to harbour a novel c.1064T > C mutation in exon 8 of the MOCS1 gene. Despite extensive sequence analysis of the gene, the second causative mutation of this recessive trait still awaits identification. MoCo deficiency should be considered in the differential diagnosis of neonatal hyperekplexia, particularly in the instances of refractoriness to clonazepam, an early demise in infancy or the evidence of no mutations in the GLRA1 gene.
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PMID:Molybdenum cofactor deficiency presenting as neonatal hyperekplexia: a clinical, biochemical and genetic study. 1642 80

Molybdenum cofactor deficiency (MOCOD) is a rare inherited metabolic disorder resulting in the combined deficiency of aldehyde oxidase (AO, EC 1.2.3.1), xanthine dehydrogenase (XDH, EC 1.1.1.204), and sulfite oxidase (SUOX, EC 1.8.3.1). The majority of patients typically present soon after birth with intractable seizures, developmental delay and lens dislocation and do not survive early childhood. Milder cases have been reported. We report an unusual mutation in the MOCS1 gene associated with a relatively mild clinical phenotype, in a patient who presented with normal uric acid (UA) levels in plasma. We also report a new MOCS1 mRNA splice variant in the 5' region of the gene. MOCS1 genomic DNA and cDNA from peripheral blood leukocytes were sequenced. MOCS1 mRNA splice variants were amplified with fluorescently labelled primers and quantitated. A novel homozygous mutation MOCS1c.1165+6T > C in intron 9 resulting in miss-splicing of exon 9 was found. Multiple alternatively spliced MOCS1 transcripts have been previously reported. A new MOCS1 transcript in the 5' - exon 1 region was identified in both patient and controls. This new transcript derived from the Larin variant and lacked exon 1 d.
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PMID:An unusual genetic variant in the MOCS1 gene leads to complete missplicing of an alternatively spliced exon in a patient with molybdenum cofactor deficiency. 1954 9

Sulfite oxidase is a mitochondrial enzyme encoded by the SUOX gene and essential for the detoxification of sulfite which results mainly from the catabolism of sulfur-containing amino acids. Decreased activity of this enzyme can either be due to mutations in the SUOX gene or secondary to defects in the synthesis of its cofactor, the molybdenum cofactor. Defects in the synthesis of the molybdenum cofactor are caused by mutations in one of the genes MOCS1, MOCS2, MOCS3 and GEPH and result in combined deficiencies of the enzymes sulfite oxidase, xanthine dehydrogenase and aldehyde oxidase. Although present in many ethnic groups, isolated sulfite oxidase deficiency and molybdenum cofactor deficiency are rare inborn errors of metabolism, which makes awareness of key clinical and laboratory features of affected individuals crucial for early diagnosis. We report clinical, radiologic, biochemical and genetic data on a Brazilian and on a Turkish child with sulfite oxidase deficiency due to the isolated defect and impaired synthesis of the molybdenum cofactor, respectively. Both patients presented with early onset seizures and neurological deterioration. They showed no sulfite oxidase activity in fibroblasts and were homozygous for the mutations c.1136A>G in the SUOX gene and c.667insCGA in the MOCS1 gene, respectively. Widely available routine laboratory tests such as assessment of total homocysteine and uric acid are indicated in children with a clinical presentation resembling that of hypoxic ischemic encephalopathy and may help in obtaining a tentative diagnosis locally, which requires confirmation by specialized laboratories.
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PMID:Functional deficiencies of sulfite oxidase: Differential diagnoses in neonates presenting with intractable seizures and cystic encephalomalacia. 1979 32

Molybdenum cofactor (MoCo) deficiency is a rare autosomal recessive inherited metabolic disorder resulting in the combined deficiency of aldehyde oxidase, xanthine dehydrogenase, and sulfite oxidase. We report a male infant with MoCo deficiency whose clinical findings consisted of microcephaly, intractable seizures soon after birth, feeding difficulties, and developmental delay. Sequencing of MOCS1, MOCS2, and GEPH genes, and single nucleotide polymorphism genotyping array analysis showed, to our knowledge, unusual inheritance of MoCo deficiency/maternal uniparental isodisomy for the first time in the literature. At 10 months of age, he now has microcephaly and developmental delay, and his seizures are controlled with phenobarbital, clonozepam, and vigabatrin therapy.
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PMID:Maternal uniparental isodisomy is responsible for serious molybdenum cofactor deficiency. 2057 77

Molybdenum cofactor deficiency is a rare autosomal recessive disorder that may present during the neonatal period with intractable seizures and be mistaken for ischemic encephalopathy. We describe a patient whose prenatal sonography at 35 weeks' gestation revealed diffuse brain damage with multiple subcortical cavities, ventriculomegaly, dysgenesis of the corpus callosum, and a hypoplastic cerebellum with an enlarged cisterna magna. Magnetic resonance imaging (MRI) later revealed brain atrophy, and multicystic encephalomalacia with hypoplastic vermis and cerebellum. Neurological examination at 10 months showed microcephaly, profound mental retardation, and spasticity. Uric acid was low, and taurine and xanthine were increased in the urine. A sulfite test was positive. The diagnosis of molybdenum cofactor deficiency was made. Sulfite oxidase activity in fibroblasts was undetectable. The patient was found to be homozygous for the 251-418del in the MOCS1 gene. This is the first description of the prenatal development of severe brain disruption in molybdenum cofactor deficiency.
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PMID:Prenatal brain disruption in molybdenum cofactor deficiency. 2177 22

Molybdenum cofactor deficiency is a rare inborn error of metabolism. The major clinical symptoms are intractable neonatal seizures, progressive encephalopathy, facial dysmorphic features and feeding difficulties. Most of the patients are misdiagnosed as hypoxic ischemic encephalopathy. The majority of patients have mutations in the MOCS1 and MOCS2 genes. Although the therapeutic treatment strategies have not been improved, genetic analysis is essential to elucidate the disease. Here, we report a review of 12 patients with Molybdenum cofactor deficiency reported from Turkey.
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PMID:Molybdenum cofactor deficiency: review of 12 cases (MoCD and review). 2312 24


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