Sulfite Oxidase Deficiency and Molybdenum Cofactor Deficiency Workup

Updated: Feb 18, 2019
  • Author: Reena Jethva, MD; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG  more...
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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.