Sulfite oxidase deficiency
Sulfite oxidase deficiency is a rare genetic disorder characterized by the absence or malfunction of the enzyme sulfite oxidase, which is essential for the metabolism of sulfur-containing amino acids. This deficiency leads to severe neurological issues, including seizures, intellectual disabilities, and various physical abnormalities, often resulting in death during infancy. The condition is inherited in an autosomal recessive manner, meaning that both parents must carry a gene mutation for a child to be affected. Despite its rarity, it has been underdiagnosed, with only about fifty cases reported globally, predominantly in Europe and the United States. Symptoms typically manifest shortly after birth, but some individuals may have later-onset forms of the disorder. Diagnosis often involves identifying elevated urinary sulfite levels and characteristic metabolites, alongside imaging techniques to assess brain abnormalities. Unfortunately, there are no effective treatments for sulfite oxidase deficiency, and supportive care is the primary approach. The prognosis is generally poor, with most affected individuals not surviving past early childhood, although a few cases may present with milder symptoms and better outcomes.
Sulfite oxidase deficiency
ALSO KNOWN AS: Isolated sulfite oxidase deficiency; sulphite oxidase deficiency
DEFINITION Sulfite oxidase deficiency is a rare deficiency disease in which there is a defect in the enzyme sulfite oxidase, which metabolizes sulfur amino acids. Isolated sulfite oxidase deficiency is characterized by severe neurological abnormalities, seizures, intellectual disability, physical malformations, and dislocation of ocular lenses and is often fatal in infancy.
Risk Factors
Inheritance of sulfite oxidase deficiency is autosomal recessive. Individuals who are for this condition have no symptoms. Individuals with this disorder belong to both genders and to various ethnic groups. There is a 25 percent risk of sulfite oxidase deficiency occurring in future children of parents who already have a child with this disorder.
Etiology and Genetics
Sulfite oxidase catalyzes the final reaction in oxidative degradation of sulfur amino acids. Defects in activity result in sulfite oxidase deficiency. Two conditions that affect enzyme activity include mutations in the enzyme itself and a genetic defect that results in absence of a required molybdenum cofactor.
Normally, the amino acids methionine and cysteine are metabolized to sulfite followed by oxidation to sulfite through the activity of the enzyme sulfite oxidase in a step that requires a molybdenum cofactor. Deficiency of either the enzyme or the cofactor results in similar disease symptoms. A defect in the pathway results in buildup of sulfite, which increases activity of alternate metabolic pathways for sulfite degradation. This results in formation of metabolites, S-sulfocysteine and thiosulfate, which can be used as diagnostic indicators of sulfite oxidase deficiency. The metabolite S-sulfocysteine probably substitutes for cysteine in connective tissues. This substitution weakens the zonule, a tissue in the lens that is normally rich in cysteine, and results in characteristic dislocated lenses associated with this disorder. The pathogenesis of brain damage associated with sulfite oxidase deficiency is not known but is likely related to toxic sulfite accumulation in the brain. As reported by Orphanet (January 2012), isolated sulfite oxidase deficiency cases are more rare than those associated with deficiency of the molybdenum cofactor. Individuals with isolated sulfite oxidase deficiency lack sulfite oxidase activity, but are normal with respect to molybdenum cofactor.
Inheritance of isolated sulfite oxidase deficiency is autosomal recessive. Mutations in the gene that codes for sulfite oxidase, SUOX, and in genes that code for molybdenum cofactor components (MOCS1 or MOCS2 have been described, although no mutation is clearly predominant. Some mutations in the sulfite oxidase gene have been characterized at the molecular level, with deletions, insertions, and both nonsense and missense mutations identified.
Symptoms
In isolated sulfite oxidase deficiency, severe convulsions begin soon after birth. Individuals with this disorder generally show symptoms such as seizures, neurological disorders, intellectual disability, and physical malformations as newborns. Other symptoms include hypotonia and myclonus. Choreiform movements and symptoms similar to cerebral palsy may be present in individuals with milder forms. Brain pathology in affected individuals shows brain degradation, severe encephalopathy, marked neuronal loss, and white matter demyelination.
Screening and Diagnosis
Although the frequency of sulfite oxidase deficiency is unknown, this disorder is likely underdiagnosed. The condition is rare, with only about fifty cases reported worldwide. A predominance of reported cases in Europe and the United States most likely reflects increased recognition in these areas. Sulfite oxidase deficiency has traditionally been identified in patients during the neonatal period, although an increasing number of diagnoses with later onset have been reported. Elevated urinary sulfite is one indicator used to diagnose sulfite oxidase deficiency; it can be measured using commercially available dipsticks. Enzyme activity in fibroblasts and cofactor levels in liver biopsies are used for confirmation. Sophisticated laboratory techniques can identify characteristic metabolites, S-sulfocysteine and thiosulfate, present in urine or plasma of patients with this disorder. Cranial CT scans or magnetic resonance imaging (MRI) may show characteristic brain abnormalities such as cerebral atrophy, decreased white matter density, neuronal loss, or cerebral edema. Sulfite oxidase activity in chorionic villi or DNA analysis in families known to carry a mutation in the sulfite oxidase gene have been used in prenatal diagnosis.
Treatment and Therapy
There are no effective medical treatments known for sulfite oxidase deficiency, particularly for patients diagnosed in infancy. Treatment for this disorder is supportive. Although diets restricted in cysteine and methionine have been tried and resulted in biochemical improvements, clinical gains were not substantial. Various drug treatments have also been tried, with limited success. High-dose thiamine has been used to replace thiamine destroyed by sulfite. Compounds such as cysteamine and penicillamine have been used to chelate excess sulfite, with some biochemical effects but few or no clinical effects. Some success in controlling seizures has been achieved with the antiepileptic drug vigabatrin.
Prevention and Outcomes
Sulfite oxidase deficiency is almost always associated with severe brain damage and death in early childhood, and is generally fatal in infancy. Survival beyond two years is often associated with development of dislocation of the ocular lens and profound intellectual disability. Some cases of individuals with later presentation of sulfite oxidase deficiency symptoms have more favorable outcomes.
Bibliography
Bosley, Thomas, et al. "Neurologic Injury in Isolated Sulfite Oxidase Deficiency." Neurology 82.10 (2014): P4. Print.
Clarke, Joe T. R. A Clinical Guide to Inherited Metabolic Diseases. Cambridge: Cambridge UP, 2002. Print.
"Encephalopathy Due to Sulfite Oxidase Deficiency." Orphanet. Orphanet, Jan. 2012. Web. 8 Aug. 2014.
Fernandes, John, Jean-Marie Saudubray, Geroges Van Den Berghe, and John H. Walter. Inborn Metabolic Diseases. 4th ed. Berlin: Springer, 2006. Print.
Hoffmann, Georg F., J. Zshocke and W. L. Nyhan.Inherited Metabolic Diseases: A Clinical Approach. Berlin: Springer, 2010. Print.
Milunksy, Aubrey. Genetic Disorders and the Fetus. Baltimore: Johns Hopkins UP, 2004. Print.
Schwahn, Bernd C., et al. "Consensus Guidelines for the Diagnosis and Management of Isolated Sulfite Oxidase Deficiency and Molybdenum Cofactor Deficiencies." Journal of Inherited Metabolic Disease, Apr. 2024, www.researchgate.net/publication/379872566‗R‗E‗V‗I‗E‗W‗Consensus‗guidelines‗for‗the‗diagnosis‗and‗management‗of‗isolated‗sulfite‗oxidase‗deficiency‗and‗molybdenum‗cofactor‗deficiencies. Accessed 6 Sept. 2024.