molybdenum-cofactor and Purine-Pyrimidine-Metabolism--Inborn-Errors

Topics: Allopurinol; Coenzymes; Diagnosis, Differential; Humans; Liver Diseases; Metalloproteins; Molybdenum Cofactors; Prognosis; Pteridines; Purine-Nucleoside Phosphorylase; Purine-Pyrimidine Metabolism, Inborn Errors; Ribose-Phosphate Pyrophosphokinase; Uric Acid; Xanthine

Topics: Coenzymes; Genes, Recessive; Humans; Metalloproteins; Molybdenum Cofactors; Mutation; Pteridines; Purine-Pyrimidine Metabolism, Inborn Errors; Uric Acid; Xanthine; Xanthine Dehydrogenase

Topics: Aldehyde Oxidase; Aldehyde Oxidoreductases; Coenzymes; Diagnosis, Differential; Humans; Metalloproteins; Molybdenum Cofactors; Mutation; Oxidoreductases Acting on Sulfur Group Donors; Prognosis; Pteridines; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Urinary Calculi; Xanthine; Xanthine Dehydrogenase

Topics: Aldehyde Oxidase; Aldehyde Oxidoreductases; Amino Acid Metabolism, Inborn Errors; Coenzymes; Diagnosis, Differential; Humans; Metalloproteins; Molybdenum Cofactors; Oxidoreductases Acting on Sulfur Group Donors; Prognosis; Pteridines; Purine-Pyrimidine Metabolism, Inborn Errors; Xanthine Oxidase

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

Molybdenum cofactor deficiency (MoCD) is a rare metabolic disorder characterized by severe and rapidly progressive neurologic damage caused by the functional loss of sulfite oxidase, 1 of 4 molybdenum-dependent enzymes. To date, no effective therapy is available for MoCD, and death in early infancy has been the usual outcome. We report here the case of a patient who was diagnosed with MoCD at the age of 6 days. Substitution therapy with purified cyclic pyranopterin monophosphate (cPMP) was started on day 36 by daily intravenous administration of 80 to 160 microg of cPMP/kg of body weight. Within 1 to 2 weeks, all urinary markers of sulfite oxidase (sulfite, S-sulfocysteine, thiosulfate) and xanthine oxidase deficiency (xanthine, uric acid) returned to almost normal readings and stayed constant (>450 days of treatment). Clinically, the infant became more alert, convulsions and twitching disappeared within the first 2 weeks, and an electroencephalogram showed the return of rhythmic elements and markedly reduced epileptiform discharges. Substitution of cPMP represents the first causative therapy available for patients with MoCD. We demonstrate efficient uptake of cPMP and restoration of molybdenum cofactor-dependent enzyme activities. Further neurodegeneration by toxic metabolites was stopped in the reported patient. We also demonstrated the feasibility to detect MoCD in newborn-screening cards to enable early diagnosis.

Topics: Brain Diseases, Metabolic, Inborn; Coenzymes; Diagnosis, Differential; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Infant, Newborn; Infusions, Intravenous; Metalloproteins; Molybdenum Cofactors; Organophosphorus Compounds; Pteridines; Pterins; Purine-Pyrimidine Metabolism, Inborn Errors; Sulfite Oxidase

Drosophila ma-l gene was suggested to encode an enzyme for sulfuration of the desulfo molybdenum cofactor for xanthine dehydrogenase (XDH) and aldehyde oxidase (AO). The human molybdenum cofactor sulfurase (HMCS) gene, the human ma-l homologue, is therefore a candidate gene responsible for classical xanthinuria type II, which involves both XDH and AO deficiencies. However, HMCS has not been identified as yet. In this study, we cloned the HMCS gene from a cDNA library prepared from liver. In two independent patients with classical xanthinuria type II, we identified a C to T base substitution at nucleotide 1255 in the HMCS gene that should cause a CGA (Arg) to TGA (Ter) nonsense substitution at codon 419. A classical xanthinuria type I patient and healthy volunteers lacked this mutation. These results indicate that a functional defect of the HMCS gene is responsible for classical xanthinuria type II, and that HMCS protein functions to provide a sulfur atom for the molybdenum cofactor of XDH and AO.

Topics: Aged; Aldehyde Oxidase; Aldehyde Oxidoreductases; Cloning, Molecular; Coenzymes; DNA Mutational Analysis; Exons; Humans; Introns; Japan; Liver; Male; Metalloproteins; Middle Aged; Molecular Sequence Data; Molybdenum Cofactors; Mutation; Polymorphism, Genetic; Pteridines; Purine-Pyrimidine Metabolism, Inborn Errors; RNA, Messenger; Sequence Analysis, DNA; Sequence Homology, Amino Acid; Sulfurtransferases; Xanthine Dehydrogenase; Xanthines

Topics: Coenzymes; Diagnosis, Differential; Fatal Outcome; Humans; Infant, Newborn; Male; Metalloproteins; Molybdenum Cofactors; Pteridines; Purine-Pyrimidine Metabolism, Inborn Errors; Uric Acid

Hereditary xanthinuria is classified into three categories. Classical xanthinuria type I lacks only xanthine dehydrogenase activity, while type II and molybdenum cofactor deficiency also lack one or two additional enzyme activities. In the present study, we examined four individuals with classical xanthinuria to discover the cause of the enzyme deficiency at the molecular level. One subject had a C to T base substitution at nucleotide 682 that should cause a CGA (Arg) to TGA (Ter) nonsense substitution at codon 228. The duodenal mucosa from the subject had no xanthine dehydrogenase protein while the mRNA level was not reduced. The two subjects who were siblings with type I xanthinuria were homozygous concerning this mutation, while another subject was found to contain the same mutation in a heterozygous state. The last subject who was also with type I xanthinuria had a deletion of C at nucleotide 2567 in cDNA that should generate a termination codon from nucleotide 2783. This subject was homozygous for the mutation and the level of mRNA in the duodenal mucosa from the subject was not reduced. Thus, in three subjects with type I xanthinuria, the primary genetic defects were confirmed to be in the xanthine dehydrogenase gene.

Topics: Adult; Aged; Codon; Coenzymes; DNA Primers; Duodenum; Humans; Intestinal Mucosa; Male; Metalloproteins; Molybdenum; Molybdenum Cofactors; Point Mutation; Polymerase Chain Reaction; Pteridines; Purine-Pyrimidine Metabolism, Inborn Errors; RNA, Messenger; Sequence Deletion; Xanthine; Xanthine Dehydrogenase; Xanthines

Molybdenum cofactor deficiency is an autosomal recessive disorder characterized by lack of activity of the enzymes sulfite oxidase, aldehyde oxidase, and xanthine dehydrogenase or oxidase. The clinical manifestations are indistinguishable from those of isolated sulfite oxidase deficiency: craniofacial alterations, intractable neonatal convulsions, very severe mental retardation, lens dislocation, and death in the first decade of life. Lens dislocation is found in nearly all patients after neonatal age. In the present case it developed late (at the age of 8 years) and was preceded by bilateral spherophakia. We hypothesize that an abnormal relaxation of the zonular fibers is the cause of spherophakia in this disease; this causes lens dislocation eventually, after days, months, or years.

Topics: Child; Coenzymes; Fatal Outcome; Genes, Recessive; Humans; Lens Subluxation; Lens, Crystalline; Male; Metalloproteins; Molybdenum Cofactors; Pteridines; Purine-Pyrimidine Metabolism, Inborn Errors

A patient with molybdenum cofactor deficiency (producing the biochemical abnormalities associated with deficiencies of sulphite oxidase and xanthine dehydrogenase) clinically expressed Marfan-like habitus with dislocated lenses, vertebral abnormality, learning disability, moderate hemiplegia, increased medial lentiform MRI signal and intermittent microscopic haematuria. S-Sulphocysteine was present in plasma and urine, and the oxidized derivative of a molybdopterin precursor (precursor Z), together with xanthine and hypoxanthine, were elevated in urine. Blood uric acid was < 1 mg/dl, while urinary urothione was not detected. These data indicate a functionally inadequate terminal enzyme for converting precursor Z to active molybdopterin (complementation group B of general molybdenum cofactor deficiency). Although the biochemical parameters were indicative of a severe deficiency state, the patient has survived into the third decade with a less severe clinical spectrum than has generally been associated with this disease.

Topics: Adult; Coenzymes; Humans; Male; Metalloproteins; Molybdenum; Molybdenum Cofactors; Pteridines; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Radiography; Spine; Sulfur

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

A female patient is described with combined deficiency of sulphite, zanthine and aldehyde oxidase. She presented at the age of four weeks with intractable seizures. Initially the diagnosis was suspected because of a very low serum urate level (23 mumol/1-1). This condition can be easily missed and it is proposed that measurement of serum urate be included in the metabolic assessment of neonates with unexplained seizures and developmental delay.

Topics: Aldehyde Oxidase; Aldehyde Oxidoreductases; Chromosome Aberrations; Chromosome Disorders; Coenzymes; Female; Genes, Recessive; Humans; Infant; Intellectual Disability; Metalloproteins; Molybdenum Cofactors; Oxidoreductases Acting on Sulfur Group Donors; Pteridines; Purine-Pyrimidine Metabolism, Inborn Errors; Uric Acid; Xanthine Oxidase

A case of combined deficiency of sulphite-oxidase and xanthine-oxidase with a defect of the molybdenum cofactor, which is vital to the activity of sulphite-, xanthine- and aldehyde-oxidase, is reported here. Seven cases of combined deficiencies have been described with regard to both clinical and laboratory findings. The clinical, laboratory and anatomo-pathological features and, in particular, the central nervous system lesions of the present case correspond exactly to those in the case described Rosenblum in which an isolated deficiency in sulphite-oxidase was present. As the cerebral alterations in the present case are comparable to those described in Rosenblum's case, they probably result from the defect in sulphite-oxidase activity.

Topics: Amino Acid Metabolism, Inborn Errors; Amino Acids, Sulfur; Brain; Child, Preschool; Coenzymes; Female; Humans; Liver; Metalloproteins; Microcephaly; Molybdenum; Molybdenum Cofactors; Oxidoreductases; Oxidoreductases Acting on Sulfur Group Donors; Pteridines; Purine-Pyrimidine Metabolism, Inborn Errors; Sulfates; Syndrome; Xanthine Oxidase; Xanthines

The clinical features and biological results in a second patient with a metabolic defect of the molybdenum cofactor are described. The first case was reported in 1978 by Duran et al. Their clinical description was similar with early encephalopathy and myoclonial and dislocation of the lens. Biologically, this condition is characterised by secondary hypo-uricemia and hypo-uricuria due to xanthine oxidase deficiency and by sulphituria, resulting from sulphite oxidase deficiency. These two enzymes have a common hepatic molybdenum cofactor, the structure and metabolism of which are only partially known.

Topics: Brain Diseases, Metabolic; Coenzymes; Consanguinity; Female; Humans; Infant; Metalloproteins; Molybdenum; Molybdenum Cofactors; Oxidoreductases; Oxidoreductases Acting on Sulfur Group Donors; Pteridines; Purine-Pyrimidine Metabolism, Inborn Errors; Xanthine Oxidase