SUOX – isolated sulfite oxidase deficiency

SUOX encodes the mitochondrial enzyme sulfite oxidase, whose deficiency causes isolated sulfite oxidase deficiency (SUOX; isolated sulfite oxidase deficiency). This autosomal recessive disorder presents in early infancy with intractable seizures, progressive neurodegeneration, cystic encephalomalacia on imaging, and often death within the first year. Biochemically, patients exhibit elevated urinary sulfite and S-sulfocysteine with normal uric acid levels.

Genetic analyses across multiple cohorts have identified over 32 pathogenic SUOX variants in more than 47 unrelated probands, confirming biallelic loss-of-function as causative ([PMID:28980090]). Segregation analysis in consanguineous and non-consanguineous families demonstrates consistent co-segregation of SUOX variants with disease; for example, three affected siblings with compound heterozygous variants in one pedigree ([PMID:31870341]).

The variant spectrum includes missense, nonsense, frameshift, splice-site, and founder mutations across SUOX. A representative variant is c.574C>T (p.Arg192Trp) identified in homozygous state in a prenatal case confirmed by chorionic villus sampling ([PMID:12001203]). Numerous other recurrent and private alleles have been reported, including c.1200C>G (p.Tyr400Ter) and c.1136A>G (p.Lys379Arg).

Functional studies reveal that many SUOX variants abrogate enzyme dimerization and catalytic efficiency. Recombinant R160Q protein shows a ~1,000-fold reduction in kcat/Km and altered molybdenum center geometry ([PMID:9600976]). The G473D variant is monomeric and catalytically inert in vitro ([PMID:16475804]). Impaired molybdenum cofactor insertion of G362S SO is rescued by molybdate supplementation in patient fibroblasts, demonstrating a maturation defect mechanism ([PMID:31127934]).

Phenotypic expansion includes late-onset mild presentations with ataxia and isolated ectopia lentis observed in siblings recovering spontaneously without dietary therapy ([PMID:31870341]). Prenatal neuroimaging may reveal poor gyration and early cystic changes in utero ([PMID:28629418]).

Integration of comprehensive genetic and functional data classifies the SUOX–isolated sulfite oxidase deficiency association as Definitive. Autosomal recessive SUOX sequencing and enzymatic activity assays underpin accurate diagnosis, enable prenatal and preimplantation genetic testing, and inform genetic counseling. Key take-home: Early molecular and biochemical testing for SUOX variants is critical for definitive diagnosis and family planning in isolated sulfite oxidase deficiency.

References

• European Journal of Paediatric Neurology • 2018 • Isolated sulfite oxidase deficiency. PMID:28980090
• Human Mutation • 2002 • Isolated sulfite oxidase deficiency: identification of 12 novel SUOX mutations in 10 patients. PMID:12112661
• Prenatal Diagnosis • 2002 • Isolated sulfite oxidase deficiency: mutation analysis and DNA-based prenatal diagnosis. PMID:12001203
• Proc Natl Acad Sci U S A • 1998 • Human sulfite oxidase R160Q: identification of the mutation in a sulfite oxidase-deficient patient and expression and characterization of the mutant enzyme. PMID:9600976
• Biochemistry • 2006 • The G473D mutation impairs dimerization and catalysis in human sulfite oxidase. PMID:16475804
• Hum Mol Genet • 2019 • Impaired mitochondrial maturation of sulfite oxidase in a patient with severe sulfite oxidase deficiency. PMID:31127934
• BMC Pediatrics • 2019 • Stable clinical course in three siblings with late-onset isolated sulfite oxidase deficiency: a case series and literature review. PMID:31870341
• Orphanet Journal of Rare Diseases • 2017 • Prenatal brain disruption in isolated sulfite oxidase deficiency. PMID:28629418

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