Sulfite Oxidase Deficiency and Molybdenum Cofactor Deficiency 

Updated: Feb 18, 2019
Author: Reena Jethva, MD; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG 

Overview

Background

Sulfite oxidase deficiency is an inborn error of the metabolism of sulfated amino acids. Individuals affected with sulfite oxidase deficiency most commonly present in the neonatal period with intractable seizures, characteristic dysmorphic features, and profound intellectual disability. Molybdenum cofactor deficiency, which affects the functioning of sulfite oxidase, leads to a similar phenotype.

Pathophysiology

Inherited defects in the sulfite oxidase enzyme can cause the phenotype of sulfite oxidase deficiency. However, many cases of this disorder are associated with deficiency of the molybdenum-containing pterin cofactor (molybdenum cofactor deficiency). Molybdenum cofactor is associated with the enzymes sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase (see the image below).[1]

Molybdenum cofactor deficiency. Molybdenum cofactor deficiency.

Sulfite oxidase is located in the mitochondrial intermembranous space and is involved in electron transport. It leads to oxidation of sulfite to sulfate.[2] The enzyme sulfite oxidase depends on the molybdenum-containing pterin cofactor, as do the enzymes xanthine dehydrogenase and aldehyde oxidase. Xanthine dehydrogenase catalyzes the hydroxylation of xanthine and hypoxanthine to produce uric acid.[3] Aldehyde oxidase hydroxylates hypoxanthine into xanthine and functions in detoxification. Deficiency of xanthine oxidase and aldehyde oxidase is not known to cause neurologic disease and may not produce symptoms.[4]

As sulfite oxidase deficiency and molybdenum cofactor deficiency have virtually identical phenotypes, the CNS toxicity appears to be secondary to loss of function of sulfite oxidase. Methionine and cysteine normally are metabolized to sulfite and then are oxidized to sulfate by the enzyme sulfite oxidase (see the image below).

Sulfite oxidase deficiency and molybdenum cofactor Sulfite oxidase deficiency and molybdenum cofactor deficiency in the metabolism of sulfated amino acids.

When sulfite oxidase is deficient, alternate metabolic pathways for sulfite are augmented, including formation of metabolites s-sulfocysteine and thiosulfate. S-sulfocysteine probably substitutes for cysteine in connective tissues. This substitution appears to weaken the zonule of the lens (a tissue normally rich in cysteine) and results in the characteristic dislocated lenses. The pathogenesis of the brain damage in those with sulfite oxidase deficiency is not known but may be related to sulfite accumulation or lack of sulfate in the CNS.

Epidemiology

Frequency

United States

The frequencies of sulfite oxidase deficiency and molybdenum cofactor deficiency are unknown; however, these disorders are probably underdiagnosed.

International

Worldwide, approximately 50 cases of sulfite oxidase deficiency have been reported.[4] The preponderance of reported cases in Europe and the United States most likely represents increased recognition in these countries. Closer to 100 cases of molybdenum cofactor deficiency have been reported. The estimated prevalence of molybdenum cofactor deficiency 1 per 100,000-200,000 newborns worldwide.[5]

Mortality/Morbidity

In most cases, sulfite oxidase deficiency is fatal in infancy or early childhood. Survivors of sulfite oxidase deficiency often have profound intellectual disability. Some later-onset cases with more favorable outcomes have been reported. Of note, some types of molybdenum cofactor deficiency have been responsive to treatment, leading to better longer-term outcomes.

Race

Molybdenum cofactor deficiency and sulfite oxidase deficiency are panethnic.

Sex

Both sexes are equally affected.

Age

Traditionally, infants with sulfite oxidase deficiency were reported to present in the neonatal period.[6] However, an increasing number of patients have been reported with later onset or deterioration after an intercurrent illness.

Prognosis

Most cases of sulfite oxidase deficiency are fatal in infancy or early childhood. The prognosis may be more variable for later-onset cases. Survivors of this disorder often have profound intellectual disability. Some later-onset cases with more favorable outcomes have been reported. Of note, some types of molybdenum cofactor deficiency have been responsive to treatment, leading to better longer-term outcomes. Individuals with molybdenum cofactor deficiency type A who are eligible for and treated early with cPMP replacement may have a better prognosis.

Patient Education

Sulfite oxidase deficiency is inherited in an autosomal-recessive manner. Two parents who are both carriers of pathogenic variants have a 25% recurrence risk for sulfite oxidase deficiency in future children. Genetic counseling is encouraged, including information about prenatal and preimplantation diagnosis to parents of individuals with this disorder.

 

Presentation

History

Pregnancy and delivery history are typically normal, although numerous infants with sulfite oxidase deficiency have had depressed Apgar scores.

The "classic presentation" of sulfite oxidase deficiency includes intractable seizures in the first days or weeks of life and abnormal tone (particularly opisthotonos). Feeding difficulties are common shortly after birth. Poor growth may ensue. Affected individuals are at risk for severe psychomotor retardation, spasticity, and/or hypotonia. Most individuals have profound intellectual disability. Strokelike episodes (”metabolic stroke”) have been reported in cases of isolated sulfite oxidase deficiency.

Later or milder presentations of sulfite oxidase deficiency are being reported with increasing frequency. These presentations include neurologic regression with loss of previously acquired milestones or movement disorders. A review of 22 cases of isolated sulfite oxidase deficiency noted that age of onset was after the first month of life in 9 cases (10 weeks to 15 months) and that the oldest onset cases were more likely to have mild or no developmental delays; in some cases, movement or tone abnormalities were presenting symptoms instead of seizures.[2]

Other reported systemic issues include renal stones and ocular abnormalities such as lens dislocation. Hypertrophic cardiomyopathy was reported in a patient with molybdenum cofactor deficiency.[5]

Physical

Birth weight, height, and head circumference are usually normal in individuals with sulfite oxidase deficiency. Progressive microcephaly is commonly described to develop in infancy.

Neurologic examination may note the following[7] :

  • Axial hypotonia with peripheral hypertonia
  • Intractable tonic/clonic seizures
  • Myoclonus
  • Opisthotonos
  • Movement disorder
  • Hyperekplexia

The following characteristic craniofacial anomalies may be observed (see the image below):

Pictured is an infant with sulfite oxidase deficie Pictured is an infant with sulfite oxidase deficiency. Note the narrow bifrontal diameter and deep-set eyes.

See the list below:

  • Narrow bifrontal diameter
  • Frontal bossing
  • Depressed nasal bridge
  • Deep-set eyes
  • Full cheeks

The following ocular abnormalities are also common:

  • Dislocated lenses (may develop after the neonatal period)
  • Lack of response to light

Causes

Both isolated sulfite oxidase deficiency[8] and molybdenum cofactor deficiency are autosomal-recessive disorders. Two complementation groups are involved in molybdenum cofactor synthesis.

When sulfite oxidase is deficient, alternate metabolic pathways for sulfite are augmented, including formation of the metabolites S-sulfocysteine and thiosulfate. S-sulfocysteine probably substitutes for cysteine in connective tissues, which appears to weaken the zonule of the lens (a tissue normally rich in cysteine) and to result in the characteristic dislocated lenses. The pathogenesis of brain damage in individuals with sulfite oxidase deficiency is unknown but may be related to sulfite accumulation or lack of sulfate in the CNS. Animal studies have found that elevated sulfite levels have neurotoxic effects in rats.

Complications

Neurologic complications of sulfite oxidase deficiency include poor seizure control, spasticity, and profound intellectual disabilities. Other systemic complications include abnormal respiratory drive, poor feeding that requires a gastrostomy tube, vomiting, gastroesophageal reflux, and aspiration pneumonia.

 

DDx

Differential Diagnoses

 

Workup

Approach Considerations

Enzymatic proof of diagnosis may not be available in a timely fashion, necessitating invasive studies. Molecular testing of the known genes is available for diagnosis confirmation. However, in the acute phase, a diagnosis of sulfite oxidase deficiency is generally based on the presence or absence of physical findings and characteristic metabolites. Molecular testing is recommended early for suspected cases, particularly as treatment options have emerged for some types of molybdenum cofactor deficiency. Targeted multigene panels or broader molecular testing options can be considered depending on the clinical situation.

Laboratory Studies

A positive sulfite dipstick finding of very fresh urine is highly suggestive of sulfite oxidase deficiency; however, a negative dipstick finding should not eliminate suspicion, as urinary sulfite is an unstable compound and prone to false-negative results related to drugs and bacterial degradation.

For quantitative plasma and urine amino acids, alert the laboratory to look for characteristic cysteine metabolite S-sulfocysteine, which may not be detected or reported unless specifically requested. S-sulfocysteine elutes in the early part of the chromatogram, before the main amino acids of interest do. Special techniques may be required to differentiate the peak from other more common substances.

Plasma levels of homocysteine are reduced. Plasma lactate and pyruvate levels may be highly elevated, although this finding is nonspecific.

Urine organic acids may reveal lactate (a nonspecific finding) but may help assess for common organic acidemias. Urinary urothion (a degradation product of molybdopterin), if low, is virtually diagnostic for molybdenum cofactor deficiency (except in cases of profound molybdenum deficiency). Urinary thiosulfate (a metabolite of cysteine) can also be measured in a selected laboratories. An elevated urinary thiosulfate level is essentially diagnostic of sulfite oxidase deficiency or molybdenum cofactor deficiency.

Laboratory findings that are typically seen in molybdenum cofactor deficiency but not isolated sulfite oxidase deficiency include low or low-normal levels of plasma uric acid level (within reference range in individuals with isolated sulfite oxidase deficiency) and elevated levels of urinary xanthine and hypoxanthine (within reference range in individuals with sulfite oxidase deficiency).

Mutations in the SUOX gene (sulfite oxidase) and in the component of the molybdenum cofactor (MOCS1, MOCS2,MOCS3, GEPH) have been described.[5] Mutations in MOCS1 and MOCS2 are much more common. The caring clinicians must determine if a targeted molecular analysis (single gene versus multigene) or broader multigene panel (ie, for genes associated with infantile seizures) versus whole-exome sequencing is indicated depending on clinical suspicion.

Imaging Studies

Cranial CT or MRI may reveal the following:

  • Abnormal gyration
  • Cerebral atrophy
  • Decreased density of white matter
  • White matter gliosis
  • Dilated ventricles
  • Multicystic cerebral hemispheres and subcortical cystic changes
  • Cystic lesions (in basal ganglia and/or cerebellum)
  • Wide interhemispheric fissures
  • Thinning of corpus callosum
  • Calcifications
  • Cerebral edema

Magnetic resonance spectroscopy (MRS) findings in 3 cases revealed a reduced peak area N -acetylaspartate–to–total creatine ratio, an increased peak choline–to–total creatine ratio, increased lactate and lipid levels, and pronounced elevation of glutamate and glutamine levels.[9]

Other Tests

Prenatal diagnosis has been achieved by measurement of sulfite oxidase activity in chorionic villi or by DNA analysis in families in whom the mutation is known in the index case.

Histologic Findings

Neuropathological findings include cerebral atrophy or edema; microgyri and abnormal sulci; multicystic subcortical and juxtacortical focal lesions in white matter; microscopic lesions in frontal, temporal, and occipital cortex; demyelination; spongiosis; and microcavitation.

 

Treatment

Approach Considerations

A multidisciplinary team is recommended for the treatment of sulfite oxidase deficiency and molybdenum cofactor deficiency. While treatment is available for some types of molybdenum cofactor deficiency, no long-term effective therapy is available for other cases. Various medications have been attempted. Supportive symptomatic care may include the following:

  • Medications to manage seizures and spasticity
  • Monitoring and management of gastrointestinal complications (ie, vomiting, gastroesophageal reflux, poor nutrition, aspiration)
  • Monitoring and management of respiratory complications (ie, aspiration pneumonia)

Medical Care

No medical treatments that improve neurologic outcome are known, but cyclic pyranopterin monophosphate (cPMP) has shown promise in the treatment of molybdenum cofactor deficiency type A. Human trials of cysteine-restricted and methionine-restricted diets have been conducted, but the clinical benefits have varied. Low-protein diets have also been attempted.

Intravenous cyclic pyranopterin monophosphate (cPMP) treatment in a patient with MOCS1 deficiency has shown promise. Reduction in sulfite, S-sulfocysteine, thiosulfate, xanthine, and uric acid levels were noted within one week of treatment and a reduction of seizures within two weeks of treatment. The child continued to be developmentally delayed with spastic quadriplegia and hypertonicity. Brain MRI demonstrated cerebral atrophy with a characteristic cystic appearance.[10] A child who was prenatally diagnosed with sulfite oxidase deficiency and received early treatment was found to have only mild cognitive delays and normal fine/gross motor delays at 21 months.[5] The FDA has granted breakthrough therapy designation to cPMP replacement.

Consultations

Involve a metabolic specialist and a neurologist in evaluation and management of individuals with this disorder. Involve other specialists depending on the symptomatic care required for the patient.

Diet

Diets restricted in cysteine and methionine have been used in a few cases of sulfite oxidase deficiency. In some reported cases, biochemical improvement has been observed, but clinical improvement has been infrequently reported. The value of these diets and low-protein diets for individuals who present with mild or late cases of this disorder remains to be further studied but may be more effective.

Prospective diet treatment of siblings of known cases has not improved outcome.

 

Medication

Medication Summary

Cyclic pyranopterin monophosphate (cPMP) has shown promise in the treatment of molybdenum cofactor deficiency type A. The FDA has granted breakthrough therapy designation to cPMP replacement.

Various other drug treatments have been attempted. Doses are experimental and are not listed in this article. Attempt drug therapy with the assistance of a metabolic specialist or a neurologist. No drug treatments have proven effective in reversing profound brain damage in individuals with sulfite oxidase deficiency.

Betaine has been used to increase remethylation of homocysteine back to methionine, thus decreasing cysteine and, ultimately, sulfite levels (see the image below).

Sulfite oxidase deficiency and molybdenum cofactor Sulfite oxidase deficiency and molybdenum cofactor deficiency in the metabolism of sulfated amino acids.

High-dose thiamine has been used to replace thiamine destroyed by sulfite.

Cysteamine and penicillamine have been used to chelate sulfite. Cysteamine has been shown to have some biochemical effect; however, no clinical effect has been observed with use of this drug.

Supplementation with sulfate, molybdenum cofactor, tetrahydrobiopterin, and uric acid has been proposed in order to replace body stores. Molybdenum cofactor is not sufficiently stable for administration, and tetrahydrobiopterin supplementation has not been effective. Currently, no reports of effectiveness of sulfate and uric acid administration are available.