Clinical characteristics: The spectrum of isolated sulfite oxidase deficiency ranges from classic early-onset (severe) disease to late-onset (mild) disease.
Classic ISOD is characterized in the first few hours to days of life by intractable seizures, feeding difficulties, and rapidly progressive encephalopathy manifest as abnormal tone (especially opisthotonus, spastic quadriplegia, and pyramidal signs) followed by progressive microcephaly and profound intellectual disability. Lens subluxation or dislocation, another characteristic finding, may be evident after the newborn period. Children usually die during the first few months of life.
Late-onset ISOD manifests between ages six and 18 months and is characterized by ectopia lentis (variably present), developmental delay/regression, movement disorder characterized by dystonia and choreoathetosis, ataxia, and (rarely) acute hemiplegia as a result of metabolic stroke. The clinical course may be progressive or episodic. In the episodic form encephalopathy, dystonia, choreoathetosis, and/or ataxia are intermittent.
Diagnosis/testing: Laboratory findings that suggest the diagnosis of ISOD are dipstick positive for urinary sulfite, elevated urinary thiosulfate and S-sulfocysteine, low urinary organic sulfate, and markedly reduced plasma levels of total homocysteine. The diagnosis is confirmed by identification of biallelic pathogenic variants in SUOX by molecular genetic testing.
Management: Treatment of manifestations: No treatment exists for the underlying metabolic defect. Symptomatic treatment can include: anti-seizure medication (ASM) for seizures; medications to reduce spasticity; and early consideration of gastrostomy tube placement to manage difficulties with swallowing, assure adequate caloric intake, and reduce risk of aspiration. Other measures can include vigorous chest physiotherapy to prevent respiratory complications. Treatment of vomiting, gastroesophageal reflux, and aspiration pneumonia are per routine.
Surveillance: Periodic assessment by a multidisciplinary team with particular attention to nutritional status, neurologic status (to evaluate dosages of ASMs and their side effects), and degree of spasticity and related complications.
Genetic counseling: ISOD is inherited in an autosomal recessive manner. The parents of an affected child are asymptomatic obligate heterozygotes (i.e., carriers of one SUOX pathogenic variant) and are not at risk of developing the disorder. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the SUOX pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
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