Table of Contents - #252150
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#252150
ICD+
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| MOLYBDENUM COFACTOR DEFICIENCY | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| MOCOD SULFITE OXIDASE, XANTHINE DEHYDROGENASE, AND ALDEHYDE OXIDASE, COMBINED DEFICIENCY OF | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Other entities represented in this entry: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| MOLYBDENUM COFACTOR DEFICIENCY, COMPLEMENTATION GROUP A, INCLUDED | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| MOLYBDENUM COFACTOR DEFICIENCY, COMPLEMENTATION GROUP B, INCLUDED MOLYBDENUM COFACTOR DEFICIENCY, COMPLEMENTATION GROUP C, INCLUDED | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because of evidence that molybdenum cofactor deficiency can be caused by mutation at either of 2 separate steps in the formation of molybdenum cofactor. MOCS1 (603707) encodes 2 enzymes for synthesis of the precursor via a bicistronic transcript with 2 consecutive open reading frames. The conversion of the precursor into the organic moiety of molybdenum cofactor is catalyzed by molybdopterin synthase (MOCS2; 603708), which encodes the small and large subunits of this heteromeric enzyme via a single transcript with 2 overlapping reading frames. MOCS1 is defective in patients with complementation group A deficiency. MOCS2 is defective in patients with complementation group B deficiency. The phenotype is identical in both complementation groups. In addition, a third type of molybdenum cofactor deficiency, complementation group C, is caused by mutation in the gephyrin gene (GEPH; 603930). A molybdenum-containing cofactor is essential to the function of 3 enzymes: sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase. Johnson et al. (1980) described a severely retarded girl with deficient activity of both sulfite oxidase and xanthine dehydrogenase, secondary to deficient synthesis of the molybdenum cofactor. In addition to serious neurologic abnormalities, the patient displayed dislocated lenses and severe mental retardation. Urinary xanthine stones were presumably the only manifestation of the xanthine oxidase deficiency. Urinary excretion of sulfite, thiosulfate, S-sulfocysteine, taurine, hypoxanthine, and xanthine was increased, whereas sulfate and urate excretion was markedly reduced. The loss of 2 enzyme activities because of deficiency of the cofactor occurs also with the defect in cobalamin synthesis leading to methylmalonic acidemia and homocystinuria (277400). Aldehyde oxidase was probably deficient also in the patient of Johnson et al. (1980). Beemer (1981) identified this disorder in a second patient, a male newborn, whose parents were born in the same region of Holland as the parents of the first patient, with at least 2 links between the pedigrees. By 1983, according to Wadman et al. (1983), there were more cases of sulfite oxidase deficiency due to defect in the molybdenum cofactor than cases of isolated sulfite oxidase deficiency (272300). Convulsions, feeding difficulties, mental retardation, and lens dislocation occur in both the isolated and the combined forms. In the combined form, abnormal muscle tone, myoclonic spasms and an abnormal physiognomy have been reported also. Wadman et al. (1983) called attention to a very simple screening test for urinary sulfite, which was originally developed for the semiquantitative determination of sulfite in wine and fruit juices and is available as a 'strip test.' Aukett et al. (1988) described a patient presenting with seizures at age 4 weeks in whom the stick sulfite test, by 2 techniques, was negative. They suggested that low serum urate may be a better pointer to the diagnosis than the sulfite test. Johnson and Rajagopalan (1982) showed that urothione, a sulfur-containing pterin, is the normal metabolic degradation product of the molybdenum cofactor that is deficient in this disorder. Johnson et al. (1980) found that no detectable urothione was excreted by a patient with this disorder. Roesel et al. (1986) described an additional case of combined xanthine and sulfite oxidase deficiency and showed that there was no detectable urinary urothione. Endres et al. (1988) reported a newborn infant with seizures and spastic tetraparesis at the age of 1 week who excreted excessive amounts of sulfite, taurine, S-sulfocysteine and thiosulfate, characteristic of sulfite 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 were established at the enzyme level. Attempts at treatment were unsuccessful. The patient developed a severe neurologic syndrome, brain atrophy, and lens dislocation, and died at the age of 22 months. Coskun et al. (1998) presented a case of MOCOD and stressed the value of serum uric acid concentration in reaching the diagnosis. A very low serum uric acid level reflects the deficiency of xanthine dehydrogenase, one of the enzymes whose function is affected in this disorder. From studies of cocultured fibroblasts from affected individuals, Johnson et al. (1989) identified 2 complementation groups, A and B. Coculture of group A and group B cells, without heterokaryon formation, led to the appearance of active sulfite oxidase. Use of conditioned media indicated that a relatively stable form of diffusible precursor produced by group B cells could be used to repair sulfite oxidase in group A recipient cells. Although the extremely low level of precursor produced by group B cells precluded its direct characterization, studies with a heterologous in vitro reconstitution system suggested that the precursor that accumulates in group B cells is the same as a molybdopterin precursor identified in a molybdopterin mutant of Neurospora crassa, and that a converting enzyme is present in group A cells which catalyzes an activation reaction analogous to that of a converting enzyme identified in a molybdopterin mutant of E. coli. Gray et al. (1990) described prenatal diagnosis by demonstrating sulfite oxidase deficiency in uncultured chorionic villus material. Slot et al. (1993) reported 2 unrelated patients with neonatal convulsions. The parents in one case were second cousins. One infant died at the age of 10 days and was found to have severe loss of neocortical neurons, predominantly affecting the deeper layers, well-established gliosis of the white matter and areas of cystic lysis in the white matter. In the case of the second infant, death occurred at the age of about 1 year. Postmortem examination, like clinical examination, disclosed no lens luxation. Parini et al. (1997) described a patient with molybdenum cofactor deficiency in which lens dislocation developed late (at the age of 8 years) and was preceded by bilateral spherophakia. The authors hypothesized that the cause of spherophakia in this disorder is an abnormal relaxation of the zonular fibers, which eventually causes lens dislocation. The mutations described by Reiss et al. (1998) in the MOCS1 gene (603707) were in cases of complementation group A and involved 2 enzymes for synthesis of the precursor of molybdopterin. The 2 enzymes are encoded by a bicistronic transcript with 2 consecutive open reading frames, MOCS1A and MOCS1B. Mutations were identified in each. Reiss et al. (1999) noted that molybdenum cofactor deficiency comes to clinical attention through neonatal seizures unresponsive to therapy, opisthotonos, and facial dysmorphism (Johnson and Wadman, 1995). Elevated sulfite levels may be found in fresh urine samples. Other biochemical findings include hypouricemia, which is not observed in the otherwise similar phenotype of isolated sulfite oxidase deficiency, as well as abnormal sulfur and purine metabolites. Sulfite oxidase deficiency is demonstrable in fibroblast cultures. Reiss et al. (1999) identified mutations in molybdopterin synthase (603708) as the cause of complementation type B molybdenum cofactor deficiency. Molybdenum cofactor deficiency results in neonatal seizures and other neurologic symptoms identical to those of sulfite oxidase deficiency (272300). Reiss et al. (1999) pointed out that since 1983 the prenatal diagnosis of molybdenum cofactor deficiency had been made by measurement of sulfite oxidase activity, but no enzymatic carrier diagnosis was possible. With the cloning of the MOCS1 gene, it was possible for Reiss et al. (1999) to perform enzymatic and molecular genetic analysis in parallel after chorionic villus sampling in a Danish family. The sulfite oxidase activity in uncultured CVS material was found to be normal. A MOCS1 splice site mutation (603707.0004), found to be homozygous in the proband, was found to be heterozygous in cultured chorionic cells. This confirmed that the fetus was not affected, since heterozygous carriers of the molybdenum cofactor deficiency do not display any symptoms. Reiss (2000) reviewed the genetics of molybdenum cofactor deficiency. Both MOCS1 and MOCS2 have an unusual bicistronic architecture, have identical very low expression profiles, and show extremely conserved C-terminal ends in their 5-prime open reading frames. MOCS1 mutations are responsible for two-thirds of cases. Reiss (2000) pointed out that all described MOCS1 and MOCS2 mutations affect one or several highly conserved motifs. No missense mutations of a less conserved residue were identified. This mirrors the absence of mild or partial forms of MoCo deficiency and supports the hypothesis of a qualitative 'yes or no' mechanism rather than quantitative kinetics for MoCo function, i.e., this function is either completely abolished or sufficient for a normal phenotype. The minimal expression of the MOCS genes concurs with this theory and would predict a low level of transfected or expressing cells that would be adequate for somatic gene therapy. Furthermore, precursor-producing cells seem to be capable of feeding their precursor-deficient neighbor cells (Johnson et al., 1989). Johnson et al. (2001) reported a 4-year-old patient with mild features of molybdenum cofactor deficiency (mild developmental delay, but no seizures or lens dislocation). The patient was heterozygous for 2 single-base substitutions in the MOCS2 gene: Q6X (603708.0006) on one allele and V7F (603708.0007) on the other. The authors postulated that a low level of residual molybdopterin synthase activity derived from the V7F allele may have been responsible for the milder clinical symptoms. In a patient with symptoms identical to those of MoCo deficiency, Reiss et al. (2001) identified a mutation in the GEPH gene (603930.0001). In a 9-month-old Mexican infant with an unusual phenotype of molybdenum cofactor deficiency involving static encephalopathy, microcephaly, and dysmorphic features but no evidence of seizure disorder, lens dislocation, or progressive psychomotor retardation, Leimkuhler et al. (2005) identified a mutation of the normal stop codon (X189Y; 603708.0008) in the MOCS2 gene. On examination, the patient had spastic quadriparesis, opisthotonos, nystagmus, and irritability; brain MRI revealed diffuse cerebral atrophy, gliotic white matter, and a thinned corpus callosum. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Nomenclature | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The mutations of MOCS1 causing molybdenum cofactor deficiency occur in either MOCS1A or MOCS1B, and similarly the mutations in MOCS2 can occur in either the A or the B gene product. Therefore, in order to avoid confusion, the form of molybdenum cofactor deficiency caused by mutation in MOCS1 is called here complementation group A (not type A); molybdenum cofactor deficiency due to mutation in MOCS2 is referred to as complementation group B; and molybdenum cofactor deficiency due to mutation in gephyrin (GPH; 603930) is referred to as complementation group C. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Animal Model | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Lee et al. (2002) constructed a transgenic mouse model of molybdenum cofactor deficiency in which the MOCS1 gene was disrupted by homologous recombination with a targeting vector. As in humans, heterozygous mice displayed no symptoms, but homozygous animals died between days 1 and 11 after birth. Biochemical analysis of these animals showed that molybdopterin and active cofactor were undetectable. The animals did 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 Geph mutation, appeared normal. Schwarz et al. (2004) described the isolation of a pterin intermediate from bacteria that was successfully used for the therapy of molybdenum cofactor deficiency in a mouse model. An intermediate of this pathway, designated 'precursor Z,' is more stable than the cofactor itself and has an identical structure in all phyla. Schwarz et al. (2004) overproduced precursor Z in E. coli and injected purified precursor Z-deficient knockout mice, which displayed a phenotype resembling the human deficiency state. Precursor Z-substituted mice reached adulthood and fertility. Biochemical analyses further suggested that the described treatment may lead to the alleviation of most symptoms associated with human molybdenum cofactor deficiency. The mouse model of MoCo deficiency type A (Lee et al., 2002; Schwarz et al., 2004) showed the biochemical characteristics of sulphite and xanthine intoxication and a failure to survive more than 2 weeks after birth. Kugler et al. (2007) constructed an expression cassette for the gene MOCS1 which, by 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 monophosphatate (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 days after birth or, after a pretreatment with purified cPMP, at 40 days after birth. They found that all deficient animals injected with control AAV-enhanced green fluorescent protein vector died approximately 8 days after birth or after withdrawal of cPMP supplementation, whereas AAV-MOCS1-transduced animals showed significantly increased longevity. A single intrahepatic injection of AAV-MOCS1 resulted in fertile adult animals without any pathologic phenotypes. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See Also: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Beemer and Delleman (1980); Reiss et al. (1998); Van Gennip et al. (1994) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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