Alternative titles; symbols
SNOMEDCT: 1003367004, 29692004; ORPHA: 308386, 833, 99732; DO: 0111164;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6p21.2 | Molybdenum cofactor deficiency A | 252150 | Autosomal recessive | 3 | MOCS1 | 603707 |
A number sign (#) is used with this entry because molybdenum cofactor deficiency of complementation group A (MOCODA) is caused by homozygous or compound heterozygous mutation in the MOCS1 gene (603707) on chromosome 6p21.
Molybdenum cofactor deficiency (MOCOD) is a rare autosomal recessive metabolic disorder characterized by onset in infancy of poor feeding, intractable seizures, and severe psychomotor retardation. Characteristic biochemical abnormalities include decreased serum uric acid and increased urine sulfite levels due to the combined enzymatic deficiency of xanthine dehydrogenase (XDH; 607633) and sulfite oxidase (SUOX; 606887), both of which use molybdenum as a cofactor. Most affected individuals die in early childhood (summary by Reiss, 2000; Reiss et al., 2011).
Genetic Heterogeneity of Molybdenum Cofactor Deficiency
See also MOCOD, complementation group B (MOCODB; 252160), caused by mutation in the MOCS2 gene (602708) on chromosome 5q11; and MOCOD, complementation group C (MOCODC; 615501), caused by mutation in the GPHN gene (603930) on chromosome 14q24.
Duran et al. (1978) reported a female infant with a combination of sulfite oxidase deficiency (272300) and xanthine oxidase deficiency (278300). She presented at age 10 days with poor feeding, tonic-clonic seizures, EEG abnormalities, and dysmorphic features, including frontal bossing, asymmetry of the skull, and subtle medio-facial dysplasia. She also had nystagmus, enophthalmos, and dislocated lenses. Laboratory studies showed low serum uric acid, and urinary analysis showed increased excretion of xanthine, hypoxanthine, S-sulfocysteine, and taurine. At age 14 months, she was noted to have excretion of xanthine stones. At age 2 years, she had poor head control, hypertonia, no reaction to light, and essentially no psychomotor development. Xanthine oxidase activity was demonstrated to be absent in patient cells, but sulfite oxidase activity was difficult to determine. However, the excretion of sulfur-containing metabolites was consistent with decreased sulfite oxidase activity. Serum molybdenum concentration was normal. Johnson et al. (1980) reported further studies on the patient reported by Duran et al. (1978), who was bedridden and had not achieved any milestones by age 3 years. Hepatic tissue from the patient showed deficient activities of both sulfite oxidase and xanthine dehydrogenase, secondary to deficient synthesis of the molybdenum cofactor. Molybdenum was absent in the liver sample despite normal serum levels of the metal; however, the active molybdenum cofactor was not detectable in the liver. The clinical features were attributed mainly to the deficiency of sulfite oxidase; urinary xanthine stones were presumably the only manifestation of the xanthine oxidase deficiency. There was also indirect biochemical evidence of aldehyde oxidase (AOX1; 602841) deficiency. Johnson et al. (1980) concluded that the patient had a primary defect in an essential step of the biosynthesis of the active molybdenum cofactor.
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 a defect in the molybdenum cofactor than cases of isolated sulfite oxidase deficiency. Convulsions, feeding difficulties, mental retardation, and lens dislocation occurred in both the isolated and the combined forms. In the combined form, abnormal muscle tone, myoclonic spasms, and an abnormal physiognomy had also been reported.
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.
Slot et al. (1993) reported 2 unrelated patients with MOCOD who presented 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.
Patients with MOCOD have recognizable dysmorphic facial features, including long face with puffy cheeks, widely spaced eyes, elongated palpebral fissures, thick lips, long philtrum, and small nose. Some patients develop progressive microcephaly, whereas others have macrocephaly secondary to hydrocephalus. Neuropathologic findings include brain atrophy, neuronal loss, astrocytic gliosis, cystic changes in the subcortical white matter, thin corpus callosum, enlarged ventricles, and demyelination (summary by Johnson and Duran, 2001).
Mechler et al. (2015) reported a natural history of molybdenum cofactor deficiency with pooled data. Of 82 children, 70% were classified as MOCD not otherwise specified because the molecular basis was not known; 15% were MOCODA, 10% were MOCODB, and 6% were MOCODC. In this cohort, 42% were female, 45% were male, and 13% were of unknown sex. Affected sibs were present in 38%, absent in 60%, and unknown in 2%. At last follow-up, 51% were alive and 49% had died. The median survival overall was 36 months. The initial cardinal disease features at onset were seizures (72%) as well as feeding difficulties (25%) and hypotonia (11%). In addition, developmental delay (9%), hemiplegia (2%), lens dislocation (2%), and hyperreflexia (1%) were reported. Reported median age of onset of the disease was the first day of life; the median age at diagnosis was 4.5 months. The median time to diagnosis (diagnostic delay) was 89 days.
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. Roesel et al. (1986) found no detectable urinary urothione in a patient with combined xanthine and sulfite oxidase deficiency.
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.
The transmission pattern of molybdenum cofactor deficiency is consistent with autosomal recessive inheritance (summary by Reiss, 2000).
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.
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.
Prenatal Diagnosis
Gray et al. (1990) described prenatal diagnosis by demonstrating sulfite oxidase deficiency in uncultured chorionic villus material.
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.
By use of homozygosity mapping in 2 unrelated consanguineous kindreds of Israeli Arab origin, Shalata et al. (1998) demonstrated linkage of MOCODA to an 8-cM region on chromosome 6p21.3, between markers D6S1641 and D6S1672. Linkage analysis generated the highest combined lod score, 3.6, at a recombination fraction of 0.0, with marker D6S1575. In 1 extensive kindred, 11 homozygotes in 9 sibships related as cousins were reported. The first affected member of this family had been reported by Van Gennip et al. (1994). In a second kindred, 2 sibs were homozygous. An immediate benefit of the mapping effort was the ability to perform prenatal diagnosis and carrier detection by use of microsatellite markers.
In 2 unrelated patients with molybdenum cofactor deficiency of complementation group A, Reiss et al. (1998) identified 2 different homozygous truncating mutations in the MOCS1 gene (603707.0001 and 603707.0002); one mutation occurred in the MOCS1A transcript and the other occurred in the MOCS1B transcript. These findings indicated the existence of a eukaryotic mRNA which, as a single and uniform transcript, guides the synthesis of 2 different enzymatic polypeptides with disease-causing potential. Thus the MOCS1 gene is bicistronic.
In an initial cohort of 24 patients with molybdenum cofactor deficiency, Reiss et al. (1998) identified 13 different mutations on 34 of the 48 chromosomes, giving a mutation detection rate of 70%. Five mutations were observed in more than 1 patient and together accounted for two-thirds of detected mutations. All patients with identified mutations were either homozygous or compound heterozygous for mutations in either of the 2 open reading frames corresponding to MOCS1A and MOCS1B, respectively.
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).
Reiss and Johnson (2003) collected a total of 32 different disease-causing mutations in the MOCS1, MOCS2, or GPHN genes, including several common to more than 1 family, that had been identified in molybdenum cofactor-deficient patients and their relatives.
The mutations of MOCS1 causing molybdenum cofactor deficiency occur in either the MOCS1A or MOCS1B isoforms, and similarly the mutations in MOCS2 can occur in either the MOCS2A or MOSC2B isoforms. 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 the GPHN gene is referred to as complementation group C.
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 sulfite 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 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 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.
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