molybdenum-cofactor and Metabolism--Inborn-Errors

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

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.

Topics: Alternative Splicing; Base Sequence; Carbon-Carbon Lyases; Child; Coenzymes; DNA Mutational Analysis; Exons; Humans; Male; Metabolism, Inborn Errors; Metalloproteins; Models, Biological; Molecular Sequence Data; Molybdenum Cofactors; Nuclear Proteins; Polymorphism, Genetic; Pteridines

The molybdenum cofactor is essential for the function of sulphite oxidase, xanthine dehydrogenase, and aldehyde oxidase enzymes. Molybdenum cofactor deficiency (MoCD) is a fatal disease resulting in severe neurological damage and death in early childhood. MoCD is an autosomal recessive condition which may mimic ischaemic encephalopathy. Although milder cases with later onset and less severe symptoms have been identified, the classic presentation involves neonatal seizures, progressive encephalopathy and death at an early age. There is currently no effective therapy, and the prognosis is poor. The disorder should be considered in all cases of intractable seizures in the newborn period and infants with clinical and radiological features of ischaemic encephalopathy, especially when no obvious lesion is detected. Blood uric acid measurement should be included in the battery of tests to be performed in all neonates' refractory seizures. We reported here an infant with MoCD who presented with hypoxic ischaemic encephalopathy and identified a novel mutation, c.130C>T in cDNA of the MOCS2 gene from the infant.

Topics: Adult; Brain Diseases, Metabolic, Inborn; Coenzymes; DNA Mutational Analysis; Family Health; Female; Humans; Infant; Magnetic Resonance Imaging; Male; Metabolism, Inborn Errors; Metalloproteins; Molybdenum Cofactors; Mutation; Pteridines; Sulfurtransferases; Turkey

Molybdenum cofactor (MoCo) deficiency is a progressive neurological disorder that inevitably leads to early childhood death because of the lack of any effective therapy. In a mouse model of MoCo deficiency type A, the most frequent form of this autosomal recessively inherited disease, the affected animals show the biochemical characteristics of sulphite and xanthine intoxication and do not survive >2 wk after birth. We have constructed a recombinant-expression cassette for the gene MOCS1, which, via alternative splicing, facilitates the expression of the proteins MOCS1A and MOCS1B, both of which are necessary for the formation of a first intermediate, cyclic pyranopterin monophosphate (cPMP), within the biosynthetic pathway leading to active MoCo. A recombinant adeno-associated virus (AAV) vector was used to express the artificial MOCS1 minigene, in an attempt to cure the lethal MOCS1-deficient phenotype. The vector was used to transduce Mocs1-deficient mice at both 1 and 4 d after birth or, after a pretreatment with purified cPMP, at 40 d after birth. We report here that all Mocs1-deficient animals injected with a control AAV-enhanced green fluorescent protein vector died approximately 8 d after birth or after withdrawal of cPMP supplementation, whereas AAV-MOCS1-transduced animals show significantly increased longevity. A single intrahepatic injection of AAV-MOCS1 resulted in fertile adult animals without any pathological phenotypes.

Topics: Animals; Animals, Newborn; Carbon-Carbon Lyases; Coenzymes; Dependovirus; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Metabolism, Inborn Errors; Metalloproteins; Mice; Mice, Knockout; Molybdenum Cofactors; Nuclear Proteins; Pteridines

Molybdenum cofactor is essential for the function of three human enzymes: sulphite oxidase, xanthine dehydrogenase, and aldehyde oxidase. Molybdenum cofactor deficiency is a rare autosomal recessively inherited disease. Disturbed development and damage to the brain may occur as a result of accumulation of toxic levels of sulphite. The CT and MRI findings include severe early brain abnormalities and have been widely reported, but the cranial US imaging findings have seldom been reported. We report a chronological series of cranial US images obtained from an affected infant that show the rapid development of cerebral atrophy, calcifications and white matter cysts. Our report supports the utility of cranial US, a noninvasive bed-side technique, in the detection and follow-up of these rapidly changing lesions.

Topics: Atrophy; Brain Diseases; Calcinosis; Coenzymes; Echoencephalography; Humans; Infant, Newborn; Male; Metabolism, Inborn Errors; Metalloproteins; Molybdenum Cofactors; Pteridines; Syndrome

Molybdenum cofactor deficiency leads to combined deficiency of sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase enzyme activities. The major clinic symptom is intractable seizures seen soon after birth. No definite therapy is available. We report here a newborn with molybdenum cofactor deficiency-associated Dandy-Walker malformation who presented with severe lactic acidosis and intracranial hemorrhage.

Topics: Acidosis, Lactic; Coenzymes; Dandy-Walker Syndrome; Female; Humans; Infant, Newborn; Intracranial Hemorrhages; Metabolism, Inborn Errors; Metalloproteins; Molybdenum Cofactors; Pteridines

Serum transthyretin has several isoforms, most of which are caused by disulfide linkage with cysteine residue at position 10. We found an ion peak 80 D larger than unmodified transthyretin by electrospray ionization mass spectrometry and assigned it to S-sulfonated transthyretin. The peak height was <2% of total transthyretin in control sera from more than 200 individuals including infants. Transthyretin from a patient with molybdenum cofactor deficiency was analyzed, and the peak was prominent, higher than 85% of total transthyretin. In patients with this disease, the presence of elevated levels of sulfite leads to the formation of S-sulfonated cysteine. The peak can be used as a diagnostic marker for molybdenum cofactor deficiency, although more sera from patients with this disease should be tested.

Topics: Child, Preschool; Coenzymes; Humans; Infant; Male; Metabolism, Inborn Errors; Metalloproteins; Molybdenum; Molybdenum Cofactors; Prealbumin; Pteridines; Spectrometry, Mass, Secondary Ion; Sulfonic Acids

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

All molybdoenzymes other than nitrogenase require molybdopterin as a metal-binding cofactor. Several genes necessary for the synthesis of the molybdenum cofactor (MoCo) have been characterized in bacteria and plants. The proteins encoded by the Escherichia coli genes moaA and moaC catalyse the first steps in MoCo synthesis. The human homologues of these genes are therefore candidate genes for molybdenum cofactor deficiency, a rare and fatal disease. Using oligonucleotides complementary to a conserved region in the moaA gene, we have isolated a human cDNA derived from liver mRNA. This transcript contains an open reading frame (ORF) encoding the human moaA homologue and a second ORF encoding a human moaC homologue. Mutations can be found in the majority of MoCo-deficient patients that confirm the functional role of both ORFs in the corresponding gene MOCS1 (for 'molybdenum cofactor synthesis-step 1'). Northern-blot analysis detected only full-length transcripts containing both consecutive ORFs in various human tissues. The mRNA structure suggests a translation reinitiation mechanism for the second ORF. These data indicate the existence of a eukaryotic mRNA, which as a single and uniform transcript guides the synthesis of two different enzymatic polypeptides with disease-causing potential.

Topics: Amino Acid Sequence; Base Sequence; Carbon-Carbon Lyases; Coenzymes; Conserved Sequence; Female; Humans; Male; Metabolism, Inborn Errors; Metalloproteins; Molecular Sequence Data; Molybdenum Cofactors; Mutation; Nuclear Proteins; Open Reading Frames; Pedigree; Pteridines; RNA, Messenger; Sequence Alignment; Sequence Homology, Amino Acid

Topics: Amino Acids; Brain; Coenzymes; Humans; Metabolism, Inborn Errors; Metalloproteins; Molybdenum Cofactors; Pteridines

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.

Topics: Amino Acid Sequence; Carbon-Carbon Lyases; Coenzymes; Europe; Exons; Genes, Recessive; Genetic Complementation Test; Genetic Testing; Heterozygote; Homozygote; Humans; Israel; Metabolism, Inborn Errors; Metalloproteins; Molecular Sequence Data; Molybdenum; Molybdenum Cofactors; Mutation; Nuclear Proteins; Pteridines; RNA Splicing

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

Topics: Anticonvulsants; Child, Preschool; Coenzymes; Dextromethorphan; Epilepsy; Humans; Male; Metabolism, Inborn Errors; Metalloproteins; Molybdenum Cofactors; N-Methylaspartate; Pteridines

The objectives of this study were to find additional diagnostic information for the evaluation of xanthine dehydrogenase deficiency and molybdenum cofactor deficiency. Patients were given an oral loading test with 10 mg/kg 5,6,7,8-tetrahydrobiopterin. Urine excretion of pterin and isoxanthopterin was measured by HPLC. Control subjects had a fairly constant ratio of urinary pterin/isoxanthopterin before (0.57-5.32) and after (0.55-4.55) 5,6,7,8-tetrahydrobiopterin loading. These ratios were increased to 33 and 22 in a patient with hereditary xanthinuria and to 570 and 8030 in a patient with molybdenum cofactor deficiency. Obligate heterozygotes had an entirely normal test result. Evidence was obtained for the in vivo involvement of xanthine dehydrogenase in the conversion of pterin to isoxanthopterin. This test could be a sensitive marker for the establishment of residual enzyme activity.

Topics: Administration, Oral; Adult; Antioxidants; Biopterins; Child, Preschool; Coenzymes; Female; Heterozygote; Humans; Infant; Infant, Newborn; Male; Metabolism, Inborn Errors; Metalloproteins; Middle Aged; Molybdenum Cofactors; Pregnancy; Pteridines; Pterins; Xanthine Dehydrogenase; Xanthopterin

Topics: Coenzymes; Female; Fibroblasts; Humans; Hypoxanthine; Infant; Metabolism, Inborn Errors; Metalloproteins; Molybdenum; Molybdenum Cofactors; Nervous System Diseases; Oxidoreductases Acting on Sulfur Group Donors; Pteridines; Uric Acid; Xanthine; Xanthine Oxidase; Xanthines

Sulphite oxidase deficiency occurs in man in two forms, as the isolated deficiency and as a syndrome of combined molybdoenzyme deficiency. This latter pleiotropic condition has as its underlying cause a defect in the synthesis of the molybdenum cofactor required for the activity of all molybdoenzymes in humans. Difficulties in diagnosis of sulphite oxidase deficiency are often encountered. A new method for detection of a key diagnostic metabolite, S-sulphocysteine, is outlined. The procedure is based on precolumn derivatization of urinary amino acids with dimethylaminoazobenzene sulphonyl chloride (Dabsyl-Cl) and resolution of the modified S-sulphocysteine by reversed-phase HPLC. A number of affected patients and control individuals with similar clinical symptoms have been studied, and a clear demarcation between the two groups has been noted.

Topics: Amino Acids; Biomarkers; Chromatography, High Pressure Liquid; Coenzymes; Cysteine; Humans; Metabolism, Inborn Errors; Metalloproteins; Molybdenum; Molybdenum Cofactors; Oxidoreductases Acting on Sulfur Group Donors; Pteridines; Taurine

Topics: Allopurinol; Coenzymes; Female; Humans; Male; Metabolism, Inborn Errors; Metalloproteins; Molybdenum; Molybdenum Cofactors; Pteridines; Purine-Pyrimidine Metabolism, Inborn Errors; Xanthine; Xanthine Dehydrogenase; Xanthines

Molybdenum cofactor deficiency was diagnosed in a 3-month-old girl who presented with microcephaly, developmental delay, severe irritability, and lactic acidosis. Dietary methionine restriction, with cysteine supplementation, was associated with moderate short-term clinical improvement, including a resumption in predicted head growth, modest developmental progress, and a reduction in irritability. Clinical relapse was associated with noncompliance of dietary therapy 2 months later. Urinary sulfite levels measured by commercial dipsticks were useful in following therapy. Molybdenum cofactor deficiency is probably frequently underdiagnosed due to the lack of specific clinical or laboratory features. Screening of infants at risk for the presence of urinary sulfites or serum hypouricemia, or both, is both rapid and inexpensive.

Topics: Acidosis, Lactic; Coenzymes; Cysteine; Developmental Disabilities; Female; Food, Fortified; Humans; Infant; Lactates; Metabolism, Inborn Errors; Metalloproteins; Methionine; Microcephaly; Molybdenum Cofactors; Pteridines

Topics: Biomarkers; Coenzymes; Humans; Metabolism, Inborn Errors; Metalloproteins; Molybdenum; Molybdenum Cofactors; Pteridines; Pterins

Topics: Coenzymes; Escherichia coli; Humans; Liver; Metabolism, Inborn Errors; Metalloproteins; Molybdenum; Molybdenum Cofactors; Neurospora crassa; Pteridines; Sulfurtransferases

Two siblings with molybdenum cofactor deficiency are presented. They showed clinical, biochemical and neuroradiological features very similar to those of the few previously described cases. Difficulties in diagnosis are emphasised.

Topics: Coenzymes; Female; Humans; Infant, Newborn; Male; Metabolism, Inborn Errors; Metalloproteins; Molybdenum Cofactors; Oxidoreductases Acting on Sulfur Group Donors; Pteridines; Taurine

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

Topics: Amidohydrolases; Amino Acid Metabolism, Inborn Errors; Biotinidase; Child; Child, Preschool; Coenzymes; Female; Humans; Infant, Newborn; Lysine; Male; Metabolism, Inborn Errors; Metalloproteins; Molybdenum; Molybdenum Cofactors; Multiple Carboxylase Deficiency; Pteridines

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

Increased urinary excretion of xanthine, hypoxanthine, sulphite, thiosulphate and decreased serum uric acid were observed in an infant with profound failure to thrive. Other clinical findings included refractory seizures, spastic quadriplegia and profound psychomotor retardation. The patient died at 20 months of age. There were no detectable activities for xanthine oxidase and sulphite oxidase in the postmortem liver. Urothione, which is the metabolic excretory product of the molybdenum cofactor for molybdoenzymes was not present in the urine. A deficiency of the molybdenum cofactor which is common to both xanthine and sulphite oxidase is presumed to be the metabolic defect responsible for the absent activities of both enzymes.

Topics: Coenzymes; Humans; Infant, Newborn; Liver; Male; Metabolism, Inborn Errors; Metalloproteins; Molybdenum Cofactors; Oxidoreductases; Oxidoreductases Acting on Sulfur Group Donors; Pteridines; Sulfites; Xanthine; Xanthine Oxidase; Xanthines

Topics: Coenzymes; Humans; Infant, Newborn; Male; Metabolism, Inborn Errors; Metalloproteins; Molybdenum; Molybdenum Cofactors; Oxidoreductases; Oxidoreductases Acting on Sulfur Group Donors; Pteridines; Sulfites; Uric Acid; Xanthine Oxidase

Topics: Coenzymes; Female; Humans; Infant; Metabolism, Inborn Errors; Metalloproteins; Methods; Molybdenum; Molybdenum Cofactors; Oxidoreductases; Oxidoreductases Acting on Sulfur Group Donors; Pteridines; Sulfites; Uric Acid; Xanthine Oxidase

There are many causes of lens dislocation in man. Amongst these are two inborn errors of sulfur amino acid metabolism, viz., homocystinuria and sulfite oxidase deficiency. To date nine patients have been found in whom a combined deficiency of sulfite oxidase and xanthine dehydrogenase was observed. This inherited disease is due to a defective synthesis of molybdenum cofactor, an essential component for the assembly of both enzymes. The main clinical symptoms of these patients were: facial dysmorphic features, severe feeding difficulties, mental retardation, abnormal muscle tone, severe seizures and myoclonia. Four out of nine patients had dislocated eye lenses. The main biochemical findings included hypouricemia, xanthinuria, an increased excretion of sulfite, thiosulfate, S-sulfocysteine, taurine and a decreased excretion of inorganic sulfate. The prognosis of the disease is poor; various attempts at treatment were not successful so far. Prenatal diagnosis by assay of sulfite oxidase in cultured amniotic fluid cells and by direct measurement of amniotic fluid S-sulfocysteine is possible.

Topics: Coenzymes; Female; Humans; Infant; Infant, Newborn; Lens Subluxation; Liver; Male; Metabolism, Inborn Errors; Metalloproteins; Molybdenum; Molybdenum Cofactors; Pregnancy; Prenatal Diagnosis; Pteridines