Encephalopathy due to sulfite oxidase deficiency (ORPHA:833)
Encephalopathy due to sulfite oxidase deficiency is a rare neurometabolic disorder characterized by seizures, progressive encephalopathy and lens dislocation.
Epidemiology
The prevalence is unknown but is very rare. At least 100 patients with sulfite oxidase deficiency have been reported with approximately 75% of cases being related to molybdenum cofactor (MoCo) deficiency.
Clinical description
Symptoms usually occur within the first week after birth with feeding difficulties, vomiting and seizures which are difficult to control. The majority of patients exhibit facial dysmorphism (prominent forehead, narrow bifrontal diameter, sunken eyes, elongated palpebral fissures, puffy cheeks, small nose and long philtrum and thick lips). The course is progressive, with spasticity, severe intellectual deficit, and microcephaly seen in survivors. Lens dislocation usually occurs late in infancy but has been observed as early as two months of age. A late onset form with a milder phenotype has also been described.
Etiology
Isolated sulfite oxidase deficiency is caused by a mutation in the SUOX gene (12q13.13) (see this term). The SUOX gene encodes the enzyme sulfite oxidase which catalyzes sulfite to sulfate, a process essential for the catabolism of sulfur-containing amino acids. MoCo deficiency secondary to mutations in either the MOCS1 (6p21.2) or MOCS2 (5q11) genes also causes sulfite oxidase deficiency (see this term). These genes encode two of the biosynthetic MoCo pathway enzymes. Impaired synthesis of MoCo leads to the combined deficiencies in sulfite oxidase, xanthine dehydrogenase, mitochondrial amidoxime reducing component (mARC) and aldehyde oxidase (the four human molybdoenzymes). The GPHN (14q23.3) gene has also been identified as the cause in one case of MoCo deficiency (see this term).
Diagnostic methods
A sulfite test strip in a fresh urine sample is a simple screening test but false positive and negative results can occur. Hypouricemia is seen in the MoCo deficiency form of the disease. A third test involves detection of low levels of plasma homocysteine. Diagnosis is confirmed by a skin fibroblast culture showing the absence of sulphite oxidase and/or MoCo activity in cultured fibroblasts. Magnetic resonance imaging shows diffuse cystic lesions within the white matter, basal ganglia and thalamus along with ulegyric changes in the cerebral cortex and cerebellar hypoplasia.
Differential diagnosis
Isolated sulfite oxidase deficiency is clinically indistinguishable from MoCo deficiency (see these terms). Hypoxic-ischemic encephalopathy (see this term) and neonatal hyperekplexia should be eliminated. Feeding difficulties can mimic amino acid intolerances.
Antenatal diagnosis
Antenatal diagnosis is possible by measuring the enzyme activity in chorionic villus samples or s-sulfocysteine levels in amniotic fluid, or by DNA analysis.
Genetic counseling
The disease follows an autosomal recessive pattern of inheritance and genetic counseling is possible.
Management and treatment
There is no cure for sulfite oxidase deficiency. Antiepileptic drugs in various combinations are used for control of seizures. Administration of diets low in sulfur containing amino acids along with sulfate supplementation have been attempted with positive biochemical responses but with no lasting neurological improvement. MoCo type A defective individuals have benefited from precursor Z (cPMP), a precursor to MoCo. Although it cannot reverse the cerebral injury that has already occurred, seizures are stopped and neurotoxicity and further cerebral damage is prevented. Genetic therapy with a MOCS1 expression cassette being carried by AAV vectors is now being studied as a future treatment.
Prognosis
The prognosis of the disease is poor. For those who survive infancy, new treatments have led to improvement in some patients.

                            Last update: 
                            January 2012


                            - Expert reviewer(s): 
                            Dr Parayil Sankaran BINDU