Alternative titles; symbols
SNOMEDCT: 1003368009; ORPHA: 308393, 833, 99732; DO: 0111163;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q11.2 | Molybdenum cofactor deficiency B | 252160 | Autosomal recessive | 3 | MOCS2 | 603708 |
A number sign (#) is used with this entry because molybdenum cofactor deficiency type B (MOCODB) is caused by homozygous or compound heterozygous mutation in the MOCS2 gene (603708) on chromosome 5q11.
Molybdenum cofactor deficiency is a rare autosomal recessive metabolic disorder characterized by neonatal onset of intractable seizures, opisthotonus, and facial dysmorphism associated with hypouricemia and elevated urinary sulfite levels. Affected individuals show severe neurologic damage and often die in early childhood (summary by Reiss et al., 1999).
For a general phenotypic description and a discussion of genetic heterogeneity of MOCOD, see MOCODA (252150), which is clinically indistinguishable from MOCODB.
Leimkuhler et al. (2005) reported 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. 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.
Hahnewald et al. (2006) reported a Senegalese male infant with molybdenum cofactor deficiency. The child was born to a nonconsanguineous couple and appeared healthy at birth. From the third day of life, he developed feeding difficulties, hypotonia, and drug-resistant tonic and clonic seizures, and he had elevated sulfite and diminished uric acid in urine. He died 21 days after birth from cardiorespiratory arrest.
In 7 of 8 patients with MOCOD who were negative for mutations in the MOCS1 gene and in whom fibroblast studies confirmed complementation group B, Reiss et al. (1999) identified biallelic mutations in the MOCS2 gene (see, e.g., 603708.0001-603708.0005). A 2-bp deletion (726del; 603708.0001) accounted for 50% (7 of 14) of identified alleles.
In a Mexican infant with MOCODB, Leimkuhler et al. (2005) identified a mutation of the normal stop codon (X189Y; 603708.0008) in the MOCS2 gene.
In a Senegalese boy with molybdenum cofactor deficiency, Hahnewald et al. (2006) identified a 23-bp deletion at nucleotide 148 in exon 1a of the MOCS2 gene (603708.0009).
Reviews
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 mirrored the absence of mild or partial forms of MoCo deficiency and supported 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 (603930) genes, including several common to more than 1 family, that had been identified in molybdenum cofactor-deficient patients and their relatives.
Johnson et al. (2001) reported a 4-year-old patient with mild features of molybdenum cofactor deficiency. The patient had mild developmental delay, but no seizures or lens dislocation. Genetic analysis identified compound heterozygous mutations in the MOSC2 gene (Q6X; 603708.0006 and V7F; 603708.0007). 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.
Hahnewald, R., Leimkuhler, S., Vilaseca, A., Acquaviva-Bourdain, C., Lenz, U., Reiss, J. A novel MOCS2 mutation reveals coordinated expression of the small and large subunit of molybdopterin synthase. Molec. Genet. Metab. 89: 210-213, 2006. [PubMed: 16737835] [Full Text: https://doi.org/10.1016/j.ymgme.2006.04.008]
Johnson, J. L., Coyne, K. E., Rajagopalan, K. V., Van Hove, J. L. K., Mackay, M., Pitt, J., Boneh, A. Molybdopterin synthase mutations in a mild case of molybdenum cofactor deficiency. Am. J. Med. Genet. 104: 169-173, 2001. [PubMed: 11746050] [Full Text: https://doi.org/10.1002/1096-8628(20011122)104:2<169::aid-ajmg1603>3.0.co;2-8]
Johnson, J. L., Wuebbens, M. M., Mandell, R., Shih, V. E. Molybdenum cofactor biosynthesis in humans: identification of two complementation groups of cofactor-deficient patients and preliminary characterization of a diffusible molybdopterin precursor. J. Clin. Invest. 83: 897-903, 1989. [PubMed: 2522104] [Full Text: https://doi.org/10.1172/JCI113974]
Leimkuhler, S., Charcosset, M., Latour, P., Dorche, C., Kleppe, S., Scaglia, F., Szymczak, I., Schupp, P., Hahnewald, R., Reiss, J. Ten novel mutations in the molybdenum cofactor genes MOCS1 and MOCS2 and in vitro characterization of a MOCS2 mutation that abolishes the binding ability of molybdopterin synthase. Hum. Genet. 117: 565-570, 2005. [PubMed: 16021469] [Full Text: https://doi.org/10.1007/s00439-005-1341-9]
Reiss, J., Dorche, B., Stallmeyer, B., Mendel, R. R., Cohen, N., Zabot, M. T. Human molybdopterin synthase gene: genomic structure and mutations in molybdenum cofactor deficiency type B. Am. J. Hum. Genet. 64: 706-711, 1999. [PubMed: 10053004] [Full Text: https://doi.org/10.1086/302296]
Reiss, J., Johnson, J. L. Mutations in the molybdenum cofactor biosynthetic genes MOCS1, MOCS2, and GEPH. Hum. Mutat. 21: 569-576, 2003. [PubMed: 12754701] [Full Text: https://doi.org/10.1002/humu.10223]
Reiss, J. Genetics of molybdenum cofactor deficiency. Hum. Genet. 106: 157-163, 2000. [PubMed: 10746556] [Full Text: https://doi.org/10.1007/s004390051023]