molybdenum-cofactor and Seizures

Hereditary xanthinuria is a rare autosomal recessive disorder, with xanthine oxidase deficiency. Patients often display renal symptoms because they excrete a large amounts of xanthine in urine. An high-fluid-intake, alow-purine-food, and alkalinization of urine are effective in the patients. Molybdenum cofactor is essential for xanthine oxidase, sulfite oxidase and aldehyde oxidase. Patients with molybdenum cofactor deficiency display severe neurological symptoms, such as severe convulsions. The patients increase urinary excretions of xanthine and sulfite. Treatments are ineffective for neurological symptoms.

Topics: Central Nervous System Diseases; Coenzymes; Diagnosis, Differential; Diet Therapy; Humans; Infant, Newborn; Metalloproteins; Molybdenum Cofactors; Pteridines; Purine-Pyrimidine Metabolism, Inborn Errors; Seizures; Uric Acid; Xanthine; Xanthine Oxidase; Xanthines

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.

Topics: Amino Acid Metabolism, Inborn Errors; Brazil; Coenzymes; Diagnosis, Differential; DNA Mutational Analysis; Encephalomalacia; Female; Humans; Infant, Newborn; Infant, Newborn, Diseases; Metalloproteins; Molybdenum Cofactors; Pteridines; Seizures; Sulfite Oxidase; Turkey

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.

Topics: Carbon-Carbon Lyases; Carrier Proteins; Coenzymes; Developmental Disabilities; Feeding Behavior; Female; Humans; Infant; Male; Membrane Proteins; Metabolism, Inborn Errors; Metalloproteins; Microcephaly; Molybdenum Cofactors; Mothers; Nuclear Proteins; Polymorphism, Single Nucleotide; Pteridines; Seizures; Sulfurtransferases; Uniparental Disomy

Anomalous hippocampal inhibition is involved in temporal lobe epilepsy, and reduced gephyrin immunoreactivity in the temporal lobe epilepsy hippocampus has been reported recently. However, the mechanisms responsible for curtailing postsynaptic gephyrin scaffolds are poorly understood. Here, we have investigated gephyrin expression in the hippocampus of patients with intractable temporal lobe epilepsy. Immunohistochemical and western blot analyses revealed irregular gephyrin expression in the cornu ammonis of patients with temporal lobe epilepsy and four abnormally spliced gephyrins lacking several exons in their G-domains were isolated. Identified temporal lobe epilepsy gephyrins have oligomerization deficits and they curtail hippocampal postsynaptic gephyrin and GABA(A) receptor α2 while interacting with regularly spliced gephyrins. We found that cellular stress (alkalosis and hyperthermia) induces exon skipping in gephyrin messenger RNA, which is responsible for curtailed postsynaptic gephyrin and GABA(A) receptor α2 scaffolds. Accordingly, we did not obtain evidence for gephyrin gene mutations in patients with temporal lobe epilepsy. Cellular stress such as alkalosis, for example arising from seizure activity, could thus facilitate the development of temporal lobe epilepsy by reducing GABA(A) receptor α2-mediated hippocampal synaptic transmission selectively in the cornu ammonis.

Topics: Alternative Splicing; Animals; Blotting, Western; Carrier Proteins; Cells, Cultured; Coenzymes; DNA; Electroencephalography; Electrophysiological Phenomena; Epilepsy, Temporal Lobe; Fluorescent Antibody Technique; Gene Expression Regulation; Green Fluorescent Proteins; Hippocampus; Humans; Membrane Proteins; Metalloproteins; Microscopy, Confocal; Molybdenum Cofactors; Patch-Clamp Techniques; Pteridines; Rats; Receptors, GABA-A; Reverse Transcriptase Polymerase Chain Reaction; Seizures; Synapses; Transfection

We ascertained a patient with the full-blown phenotype of isolated sulfite oxidase deficiency in a consanguineous Arab family. The proband's phenotype included the presence of intractable seizures in the neonatal period, some dysmorphic features, neuroradiologic findings reminiscent of hypoxic ischemic encephalopathy and rapidly progressive brain destruction leading to severe neurodevelopmental impairment. Biochemically, the patient excreted a large amount of S-sulfocysteine with normal amounts of xanthene and hypoxanthine and had normal plasma uric acid, which was consistent with isolated sulfite oxidase deficiency. We report the identification of the first Arab mutation in SUOX, the gene for sulfite oxidase enzyme, in the ascertained family. The newly identified Arab mutation in the SUOX gene (a single nucleotide deletion, del G1244) is predicted to cause a frame shift at amino acid 117 of the translated protein with the generation of a stop codon and total truncation of the molybdo-pterin- and the dimerizing-domain(s) of SUOX protein expressed from the mutant allele. The identification of this new Arab SUOX mutation should facilitate pre-implantation genetic diagnosis and selection of unaffected embryos for future pregnancy in the ascertained family with the mutation and related families with the same mutation.

Topics: Abnormalities, Multiple; Arabs; Base Sequence; Binding Sites; Coenzymes; Consanguinity; Dimerization; DNA; DNA Mutational Analysis; Ear; Family Health; Frameshift Mutation; Humans; Infant; Male; Metalloproteins; Microcephaly; Molybdenum Cofactors; Mutation; Organometallic Compounds; Oxidoreductases Acting on Sulfur Group Donors; Proteins; Pteridines; Seizures; Sequence Deletion

Normally, ventricular cerebrospinal fluid (CSF) contains low levels of all metabolite signals on proton magnetic resonance spectroscopic imaging (MRSI). We present here three cases (two with seizure disorders, one with a central nervous system lymphoma) who presented with unusually elevated CSF signals on MRSI. Based on chemical shifts and in vitro studies (in one case), the signals were assigned to propan-1,2-diol (PD), acetone, and lactate, respectively. These compounds were either exclusively, or more readily, detected in CSF than in brain. Proton MRSI conveniently screens both brain and CSF for abnormal metabolism simultaneously.

Topics: Adult; Cerebral Ventricles; Cerebrospinal Fluid; Child; Coenzymes; Fatal Outcome; Female; Humans; Infant; Lymphoma, AIDS-Related; Magnetic Resonance Spectroscopy; Male; Metalloproteins; Molybdenum Cofactors; Protons; Pteridines; Seizures

We report three infants with the diagnosis of molybdenum cofactor deficiency. The key findings leading to diagnosis were neonatal seizures unresponsive to treatment, craniofacial dysmorphic features, hyperexcitability, low blood uric acid levels, and neuroimaging findings. The parents were consanguineous in two of these patients. The diagnosis was established by the presence of low blood uric acid levels, positive urine sulfite reaction, quantitative aminoacid analysis, and high-voltage electrophoresis of the urine sample showing a typical increase of S-sulfo-L-cysteine. Skin fibroblast cultures confirmed the diagnosis. Magnetic resonance imaging findings were suggestive of encephalomalacia with cystic changes due to hypoxic-ischemic encephalopathy. We conclude that molybdenum cofactor deficiency must be included in the differential diagnosis of patients presenting with intractable seizures in the newborn period who have computed tomography and magnetic resonance imaging findings reminiscent of those of hypoxic-ischemic encephalopathy, and the urine sulfite dipstick test can be a part of the evaluation of these infants in neonatal intensive care units.

Topics: Coenzymes; Diagnosis, Differential; Female; Humans; Hypoxia-Ischemia, Brain; Infant; Infant, Newborn; Magnetic Resonance Imaging; Male; Metalloproteins; Molybdenum Cofactors; Pteridines; Seizures; Sulfites; Tomography, X-Ray Computed; Uric Acid; Urinalysis

Topics: Coenzymes; Encephalomalacia; Hematuria; Humans; Infant; Male; Metabolism, Inborn Errors; Metalloproteins; Molybdenum Cofactors; Pteridines; Seizures; Uric Acid

Topics: Antioxidants; Coenzymes; Diagnosis, Differential; Free Radical Scavengers; Free Radicals; Humans; Hypoxia, Brain; Infant, Newborn; Magnetic Resonance Imaging; Metalloproteins; Molybdenum; Molybdenum Cofactors; Pteridines; Reactive Oxygen Species; Seizures; Sulfites; Tomography, X-Ray Computed; Uric Acid

Topics: Child, Preschool; Coenzymes; Diagnosis, Differential; Humans; Infant; Infant, Newborn; Metalloproteins; Molybdenum; Molybdenum Cofactors; Oxidoreductases Acting on Sulfur Group Donors; Pteridines; Purines; Reagent Strips; Reproducibility of Results; Seizures; Uric Acid; Xanthine Dehydrogenase

Topics: Asphyxia; Coenzymes; False Negative Reactions; Fatal Outcome; Female; Humans; Infant, Newborn; Metalloproteins; Molybdenum Cofactors; Neonatal Screening; Oxidoreductases Acting on Sulfur Group Donors; Pteridines; Seizures; Thiosulfates

Topics: Coenzymes; Diagnostic Errors; Humans; Infant, Newborn; Male; Metalloproteins; Molybdenum Cofactors; Pteridines; Reagent Strips; Seizures; Sulfites; Uric Acid

We describe a new case of molybdenum cofactor deficiency, an underrecognized inborn error of metabolism that results in neonatal seizures and neurologic abnormalities. Characteristic biochemical defects in affected individuals include hypouricemia, elevated urine sulfate (detectable by dipstick), and elevated S-sulfocysteine (detectable by anion exchange chromatography). This disorder should be considered in the differential diagnosis of neonatal seizures.

Topics: Coenzymes; Female; Genes, Recessive; Humans; Infant, Newborn; Metabolism, Inborn Errors; Metalloproteins; Molybdenum; Molybdenum Cofactors; Pteridines; Seizures

A newborn infant exhibiting seizures and spastic tetraparesis at the age of 1 week was shown to excrete excessive quantities of sulphite, taurine, S-sulphocysteine and thiosulphate, characteristic of sulphite oxidase deficiency. In addition, increased renal excretion of xanthine and hypoxanthine combined with a low serum and urinary uric acid was consistent with xanthine dehydrogenase deficiency. Both deficiencies could be established at the enzyme level. The primary defect giving rise to the combined abnormalities is the absence of a molybdenum cofactor, a molybdenum-containing pterin being an essential component of both enzymes. The patient developed a severe neurological syndrome, brain atrophy and lens dislocation and died at the age of 22 months. Attempts at treatment, such as oral administration of ammonium molybdate, sodium sulphate, D-penicillamine, 2-mercaptoethane sulphonic acid, pyridoxine and thiamine did not influence the clinical course.

Topics: Abnormalities, Multiple; Coenzymes; Humans; Infant; Ketone Oxidoreductases; Male; Metalloproteins; Molybdenum Cofactors; Oxidoreductases; Oxidoreductases Acting on Sulfur Group Donors; Pteridines; Seizures; Xanthine Dehydrogenase

Topics: Coenzymes; Humans; Infant, Newborn; Metabolism, Inborn Errors; Metalloproteins; Molybdenum Cofactors; Pteridines; Seizures; Uric Acid