Chapter 128

Abstract

Abstract

1. The molybdenum cofactor is a low-molecular-weight prosthetic group in which the metal is complexed to a unique pterin species termed molybdopterin. The cofactor is essential for the function of the human enzymes sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase. Patients with molybdenum cofactor deficiency (MIM 252150 and 252150) are deficient in the activity of all three enzymes and exhibit symptoms that include severe neurologic abnormalities, dislocated ocular lenses, and mental retardation. They excrete elevated levels of sulfite, thiosulfate, S-sulfocysteine, taurine, xanthine, and hypoxanthine and low amounts of uric acid. Patients with isolated sulfite oxidase deficiency (MIM 272300) lack sulfite oxidase activity but are normal with respect to molybdenum cofactor and xanthine dehydrogenase and aldehyde oxidase functions. This form of sulfite oxidase deficiency produces clinical symptoms and neuropathology essentially indistinguishable from those of the combined deficiency disease.

2. More than 100 patients have been diagnosed with molybdenum cofactor deficiency or isolated sulfite oxidase deficiency. Molybdenum cofactor deficiency appears to be more prevalent than the isolated deficiency but is also more likely to be detected in routine screening programs. Patients with milder clinical symptoms and late onset are found more often among those with isolated sulfite oxidase deficiency. Both molybdenum cofactor deficiency and isolated sulfite oxidase deficiency are inherited as autosomal recessive traits, with obligate heterozygotes displaying no symptoms. Patients belong to a variety of ethnic groups and are found among the populations of Europe, North America, Northern Africa, Turkey, and Asia.

3. Although considerable variability in severity of symptoms and age of onset does occur, the key clinical symptom for molybdenum cofactor deficiency and isolated sulfite oxidase deficiency is severe convulsions, presenting early after birth. All patients with this presentation immediately should be subjected to metabolic screening procedures. Many patients display dysmorphic facial features that resemble those in patients with perinatal asphyxia. Patients with this presentation and no apparent hypoxic event at birth should be screened for these disorders.

4. Pathology studies in a number of cases of molybdenum cofactor deficiency and isolated sulfite oxidase deficiency have revealed a severe encephalopathy with marked neuronal loss and demyelination in the white matter accompanied by gliosis and diffuse spongiosis. The observation that neither isolated xanthinuria nor a combined loss of xanthine dehydrogenase and aldehyde oxidase results in encephalopathy supports the conclusion that these effects result from the absence of sulfite oxidase activity. A disturbed development and damage to the brain may occur as a result of accumulation of toxic levels of sulfite in cerebro.

5. Prenatal diagnosis of molybdenum cofactor deficiency and of isolated sulfite oxidase deficiency is accomplished by assay of sulfite oxidase activity in uncultured chorionic villus tissue or in cultured amniotic cells.

6. Molybdenum cofactor deficiency and isolated sulfite oxidase deficiency are serious and often fatal diseases for which no effective therapy is generally available. Some patients, especially those with milder forms of isolated sulfite oxidase deficiency, respond well to the administration of diets low in sulfur-containing amino acids. Some success in seizure control has been achieved with the antiepileptic drug vigabatrin.

7. The genes for sulfite oxidase and for most of the molybdenum cofactor biosynthetic enzymes have been cloned, and the mutations in a number of patients have been characterized at the molecular level. Deletions and insertions, as well as nonsense and missense mutations, have been identified in the sulfite oxidase gene, with one mutation, R160Q, identified in more than one patient. Patients with molybdenum cofactor deficiency comprise two complementation classes. Group B patients have mutations in molybdopterin synthase or molybdopterin synthase sulfurylase, whereas group A patients are most likely defective in genes coding for early steps in the biosynthetic pathway, MOCS1A or MOCS1B.

8. The extreme instability of the isolated molybdenum cofactor precludes its use as effective therapy for correction of molybdenum cofactor deficiency. However, as more is learned of the pathways of biosynthesis and metabolism of this molecule in human tissues, more stable intermediates may be identified with potential efficacy for cofactor replacement therapy in some patients.

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