Molybdenum Cofactor Deficiency Type B via the MOCS2 Gene

Molybdenum cofactor deficiency type B is an inborn error in metabolism that results in defective synthesis of the molybdopterin cofactor required for the function of the sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase enzymes. Patients with molybdenum cofactor deficiency excrete elevated levels of sulfite, thiosulfate, S-sulfocysteine, taurine, xanthine, and hypoxanthine, while also exhibiting hypouricemia (Johnson and Duran, 2014). Isolated deficiency of the xanthine dehydrogenase or aldehyde oxidase enzymes is a benign biochemical condition in most patients, while sulfite oxidase deficient patients present with a severe disease course. Clinical presentations in isolated sulfite oxidase deficiency and molybdenum cofactor deficiencies are almost indistinguishable (Mendel, 2009. PubMed ID: 19623604; Johnson and Duran, 2014).

Many times molybdenum cofactor deficiency will be misdiagnosed as infantile encephalopathy due to the brain anomalies and neurologic symptoms. Typically, presentation will occur early after birth with severe convulsions that are difficult to suppress (Reiss et al., 1998. PubMed ID: 9731530; Johnson and Duran, 2014). Pathological studies have shown there is marked neuronal loss and demyelination in the white matter accompanied by gliosis and diffuse spongiosis. Patients with milder clinical symptoms and later onset (6-15 months) have also been reported, although less than 10% of patients fall into this group. In many cases, an infection will trigger the first symptoms in later onset patients (Johnson and Duran, 2014). Patients with molybdenum cofactor deficiency or isolated sulfite oxidase deficiency also have dysmorphic features that include long face with puffy cheeks, widely spaced eyes, elongated palpebral fissures, thick lips, a long philtrum, and a small nose, which can resemble perinatal asphyxia. Patients also present with psychomotor retardation, ophthalmologic abnormalities such as lens dislocation, peripheral hypertonicity, and axial hypotonia (Johnson and Duran, 2014). Irreversible neurological damage occurs due to sulfite toxicity and/or sulfate deficiency, and most patients die during the neonatal period or early childhood (Reiss et al., 1998. PubMed ID: 9731530; Macaya et al., 2005. PubMed ID: 16429380).

All molybdenum cofactor deficiencies are inherited in an autosomal recessive manner. Molybdenum cofactor deficiency type B is caused by pathogenic variants in the MOCS2 gene, which is located on chromosome 5 at 5q11.2. Reported pathogenic variants in this gene include missense and nonsense variants as well as small frameshift deletions and duplications (Reiss and Johnson, 2003. PubMed ID: 12754701; Reiss and Hahnewald, 2011. PubMed ID: 21031595; Human Gene Mutation Database).

The MOCS2 gene encodes a bicistronic mRNA with two overlapping open reading frames that are shifted relative to each other. It is thought that two distinct proteins are generated: MOCS2A and MOCS2B (Hahnewald et al., 2006. PubMed ID: 16737835; Reiss and Hahnewald, 2011. PubMed ID: 21031595; Johnson and Duran, 2014). The nomenclature of variants in the MOCS2 gene is complicated by the overlapping protein coding regions, and thus sequence variants in this gene are best described using the accepted terminology reported by Reiss and Hahnewald (2011). Using this nomenclature, the most prevalent MOCS2 variant is designated c.726_727del (Reiss and Johnson, 2003. PubMed ID: 12754701; Reiss and Hahnewald, 2011. PubMed ID: 21031595).

Biosynthesis of the molybdopterin cofactor begins with the conversion of guanosine triphosphate (GTP) to a precursor molecule designated Precursor Z. The MOCS2A and MOCS2B proteins are responsible for conversion of Precursor Z to the molybdopterin intermediate, MPT (Arenas et al., 2009. PubMed ID: 19544009; Johnson and Duran, 2014).

In the largest report of biochemically confirmed molybdenum cofactor deficient patients, ~58% were found to have variants in the MOCS1 gene, ~38% in MOCS2, and 2% in GPHN (Reiss and Johnson, 2003. PubMed ID: 12754701). Analytical sensitivity should be near 100% because all reported pathogenic variants are detectable by sequencing.

This test provides full coverage of all coding exons of the MOCS2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).