Sulfite Oxidase Deficiency via the SUOX Gene

Sulfite oxidase deficiency is an inborn error in metabolism that results in the accumulation of sulfite and a reduced production of sulfate. Sulfite oxidase is the terminal enzyme in the sulfur amino acids catabolic pathway that oxidizes sulfite to sulfate. Sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase all require molybdenum as a cofactor. Therefore, this enzyme is also non-functional in molybdenum cofactor deficiencies. Patients with isolated sulfite oxidase deficiency excrete elevated levels of sulfite, thiosulfate, S-sulfocysteine, and taurine while the levels of xanthine, hypoxanthine, and uric acid are normal (Tan et al., 2005. PubMed ID: 16140720; Johnson and Duran, 2014).

Clinical presentation in isolated sulfite oxidase deficiency and molybdenum cofactor deficiencies is almost indistinguishable. Many times this disorder will be misdiagnosed as infantile encephalopathy due to the brain anomalies and neurologic symptoms. Typically, presentation will occur shortly after birth with severe convulsions that are difficult to suppress (Johnson et al., 2002. PubMed ID: 12112661; Tan et al., 2005. PubMed ID: 16140720; 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, and in many cases an infection will trigger symptoms. 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 et al., 2002. PubMed ID: 12112661; Johnson and Duran, 2014).

Sulfite oxidase deficiency is inherited in an autosomal recessive manner and is caused by pathogenic variants in the SUOX gene (Johnson et al., 2002. PubMed ID: 12112661; Johnson and Duran, 2014). Reported pathogenic variants include missense, nonsense, and small frameshift deletions and insertions. Many of these variants have only been reported in a single patient (Human Gene Mutation Database; Johnson and Duran, 2014). Only the Arg160Gln variant has been seen in more than one patient, and is thought be located in a mutational hotspot (Johnson and Duran, 2014).

The sulfite oxidase protein functions as a dimer and includes a heme domain, molybdenum cofactor domain, and a C-terminal domain necessary for dimerization (Kisker et al., 1997. PubMed ID: 9428520). Missense variants (Ser370Tyr, Gly473Asp) in the C-terminal domain have been shown to result in a monomeric protein with no catalytic activity. Other missense variants (Arg160Gln, Ala208Asp, Arg212Cys), occur in the catalytic active site of the enzyme (Kisker et al., 1997. PubMed ID: 9428520; Johnson and Duran, 2014).

Clinical sensitivity cannot be estimated precisely because large cohort studies have not been conducted. However, in a small cohort of ten patients presenting clinically and biochemically with isolated sulfite oxidase deficiency, all ten patients had a molecular diagnosis (Johnson et al., 2002. PubMed ID: 12112661). 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 SUOX 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).