Molybdenum Cofactor Deficiency and Isolated Sulfite Oxidase Deficiency

48.1 Clinical Features

and Laboratory Investigations Molybdenum cofactor deficiency and sulfite oxidase deficiency are autosomal recessive inborn errors of metabolism with a similar clinical presentation. In molybdenum cofactor deficiency, not only sulfite oxi- dase but also xanthine dehydrogenase and aldehyde oxidase are deficient. Molybdenum cofactor deficien- cy occurs more frequently than isolated sulfite oxi- dase deficiency.

Patients with molybdenum cofactor deficiency usually present a few days after birth with feeding dif- ficulties, seizures, axial hypotonia, and limb hyperto- nia. The seizures are usually tonic–clonic and difficult to control. In patients who survive the neonatal peri- od, serious psychomotor retardation is seen. Many patients develop microcephaly. Lens dislocation de- velops in patients who survive the neonatal period.

Other ocular abnormalities include spherophakia, iris coloboma, nystagmus, and enophthalmos. Cere- bral blindness may occur.A few patients have a milder disease course, with onset after the neonatal period, usually precipitated by an infection. The clinical symptoms include hypotonia, extrapyramidal move- ment abnormalities, and sometimes lens dislocation.

Most patients die at an early age. Exceptional patients have a still milder disease with a Marfan-like habitus, dislocated lenses, learning problems, occasional stroke-like episodes with unilateral motor deficits, and survival into the third decade.

In patients with sulfite oxidase deficiency, the clin- ical picture is on the whole more variable than in molybdenum cofactor deficiency. At the severe end of the spectrum, patients display signs of serious en- cephalopathy soon after birth, with seizures and spas- ticity and subsequently serious psychomotor retarda- tion, lens dislocation, spherophakia, and early death, similar to the clinical picture of molybdenum cofac- tor deficiency. However, patients may also have a later onset, most often between the ages of 6 months and 1.5 years, and lack suggestive symptoms such as ec- topic lenses and seizures. The onset of the disease is often precipitated by an infection, which is followed by developmental regression, hypotonia, and dysto- nia or choreoathetosis. Microcephaly may develop.

An episodic course with stepwise deterioration has also been described.

Laboratory investigations in isolated sulfite oxi- dase deficiency reveal elevated urinary excretion of sulfite, thiosulfate, and taurine. Plasma and urinary amino acid profiles show the presence of S-sulfocys- teine. Plasma cystine levels are decreased. Urinary ex- cretion of xanthine and hypoxanthine are normal.

Sulfite oxidase activity is deficient in cultured fibro- blasts. In molybdenum cofactor deficiency, the same laboratory findings are present, with the exception of xanthine and hypoxanthine, which are elevated, and plasma and urinary uric acid, which are low to virtu- ally absent. DNA-based diagnosis is possible for both disorders. Elevated urinary sulfite can be detected us- ing dipsticks, but these are not very reliable and may show false negative results, because sulfite sponta- neously oxidizes to sulfate on standing. Prenatal diag- nosis is possible by enzyme assessment in chorionic villi or cultured amniotic cells. Prenatal diagnosis by DNA analysis is also an option.

48.2 Pathology

The neuropathology of both isolated sulfite oxidase deficiency and molybdenum cofactor deficiency is characterized by gross cerebral atrophy with deep sulci and dilated ventricles. The cerebral hemispheres are usually affected by multicystic degeneration, which involves the white matter and inner layer of the cortex. In some areas the cortex may show complete degeneration. The cavities are separated by thick glial scar tissue. The remaining white matter contains little myelin and is markedly gliotic. The basal ganglia, thalami, and cerebellum are atrophic and show neu- ronal loss and gliosis on microscopy. The basal gan- glia may also be partly cystic. Remaining white and gray matter structures may show diffuse spongiosis and may contain areas of mineralization. The brain stem is atrophic and contains little myelin, but is bet- ter preserved.

48.3 Pathogenetic Considerations

Sulfite oxidase is encoded by the gene SUOX, located on chromosome 12q13.2–13.3. Molybdenum cofactor consists of a unique pterin, molybdopterin, and the metal molybdenum. The cofactor is synthesized in

Molybdenum Cofactor Deficiency

and Isolated Sulfite Oxidase Deficiency

humans by a complex pathway that requires the prod- ucts of at least four different genes: MOCS1, MOCS2, MOCS3, and GEPH. Disease-causing mutations have been identified in three of these genes: MOCS1, MOCS2, and GEPH. MOCS1 is located on chromo- some 6p21.3, MOCS2 on chromosome 5q11, and GEPH on chromosome 14q24. MOCS1 and MOCS2 have a bicistronic architecture, which means that each gene encodes two proteins in different open reading frames. The gene products, MOCS1A and B and MOCS2A and B, are expressed either from different mRNAs generated by alternative splicing or by inde- pendent translation of a bicistronic mRNA. The gephyrin protein is required during cofactor assem- bly for insertion of the molybdenum into molyb- dopterin. To date, no disease-causing mutations have been found in MOCS3.

Molybdenum cofactor deficiency results in simul- taneous loss of all cofactor-dependent enzyme activ- ities, including sulfite oxidase, xanthine dehydroge- nase, and aldehyde oxidase. Sulfite oxidase catalyzes the oxidation of sulfite into sulfate. Xanthine oxidase catalyzes the decomposition of xanthine into uric acid. Aldehyde dehydrogenase catalyzes the forma- tion of xanthine from hypoxanthine. In addition, this enzyme is thought to be part of a general detoxifica- tion system. Combined deficiency leads to a pheno- type that is clinically quite similar to that of isolated sulfite oxidase deficiency. Therefore, it is likely that the neurological disease, characterized by a severe en- cephalopathy, results primarily from the sulfite oxi- dase deficiency. The pathological findings resemble those seen in severe perinatal asphyxia. The patho- genesis of the disease is not understood. It is not clear whether the damage arises from a toxic metabolite or from the deficit of a reaction product. The accumulat- ing sulfite may be toxic. However, its mode of action is unclear, and it is also unknown why the brain is most seriously affected. The reaction of sulfite with disul- fide bonds or with sulfhydryl groups is a general process that would be expected to occur in all organs.

Ocular lens subluxation may be related to a disrup- tion of cystine cross-linking by excess sulfite.

48.4 Therapy

No effective treatment is available for the severe vari- ants of either isolated sulfite oxidase deficiency or molybdenum cofactor deficiency. The cofactor is ex- ceedingly unstable and direct cofactor replacement is not feasible. Various therapeutic trials, including oral intake of molybdenum salts and low-sulfur amino acid diet, combined with oral sulfate supplementa- tion, have failed. However, some measures may bene- fit individual patients. In particular in patients with a milder clinical picture, restriction of the intake of the

precursor sulfur amino acids may lead to some im- provement. Cysteamine may be beneficial in absorb- ing excess sulfite.

Treatment of seizures is important. In particular vigabatrin has been successful in controlling the seizures.

48.5 Magnetic Resonance Imaging

Neuroimaging findings in patients with isolated sul- fite oxidase deficiency and molybdenum cofactor deficiency are similar. CT scan of the brain has been reported to show diffuse edema in the neonatal peri- od. Multicystic degeneration of the cerebral hemi- spheres and calcium deposits have been documented by follow-up CT.

In early postnatal presentation, MRI shows brain swelling and extensive areas of abnormal signal, con- sistent with edema and “hypoxic” changes within the cerebral cortex (Figs. 48.1 and 48.2). Follow-up MRI shows extensive cystic degeneration of the cerebral hemispheres, with large and smaller cysts within the white matter and enlargement of the ventricles and subarachnoid spaces (Fig. 48.2). The corpus callosum is thin. The cerebellum and brain stem are small, probably due to both hypoplasia and atrophy. The small cerebellum with enlarged pericerebellar spaces has been described as a Dandy–Walker variant, which is not correct, as the rest of the Dandy–Walker config- uration is lacking. The basal ganglia and thalami are atrophic and may contain cysts. On more prolonged follow-up, the large cysts in the cerebral white matter may collapse and a seriously atrophic brain may re- main. Not much myelin is deposited in the highly damaged, gliotic white matter. Because of the serious brain atrophy, subdural fluid collections develop eas- ily.

The above pattern is indistinguishable from that seen in multicystic encephalopathy after perinatal as- phyxia, neonatal presentations of a urea cycle defect, and some early-onset and severe mitochondrial dis- orders. It is essentially the pattern that is expected to develop in neonates after profound energy failure of any origin. It seems that serious edema preceding the multicystic degeneration is a common factor.

Some patients with milder forms of isolated sulfite oxidase deficiency or molybdenum cofactor deficien- cy have a much better preserved brain. Bilateral lesions in the globus pallidus with preservation of the rest of the brain have been found repeatedly (Fig. 48.3). In some patients more extensive abnor- malities are seen, with signal abnormality and swelling of the caudate nucleus, putamen, globus pallidus, and cerebral peduncles in the acute stage (Fig. 48.4) and less prominent signal abnormalities and atrophy of these structures in the chronic stage.

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Selective involvement of the globus pallidus is rare and has been observed in creatine synthesis defects, succinic semialdehyde dehydrogenase deficiency, mitochondrial defects, hyperbilirubinemia, and car- bon monoxide poisoning. Lesions in the globus pal- lidus are also relatively frequent in neurofibromatosis type I.

Fig. 48.1. Baby boy, 10 days old, with molybdenum cofactor deficiency.The T

-weighted images show serious involvement of the cortex and basal ganglia. These structures have a high

signal in parts on T

-weighted images, as seen in necrosis.

Courtesy of Dr. S. Blaser, Department of Diagnostic Imaging,

Hospital for Sick Children, Toronto, Canada

48.5 Magnetic Resonance Imaging 375

Fig. 48.2. Baby girl with isolated sulfite oxidase deficiency.

The T

-weighted images in the first row were obtained at the age of 5 days and show serious abnormalities of the cerebral cortex, white matter, and basal ganglia. The brain is diffusely swollen. The posterior fossa structures have a more normal appearance. The images in the second and third rows were

obtained at the age of 31 days and demonstrate cystic degen- eration of the cerebral white matter. The basal ganglia and cerebral cortex also contain signal abnormalities. The brain stem and cerebellum are preserved. From Dublin et al. (2002), with permission

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Fig. 48.3. Two brothers with isolated sulfite oxidase deficien- cy. Both are relatively mildly affected. The left and middle images represent the older brother at the age of 5 years. The

right image represents the younger brother, also at the age of 5 years. Both have isolated globus pallidus lesions

Fig. 48.4. Girl, 1 year and 9 months old, with molybdenum cofactor deficiency. Note the signal abnormality and swelling of the putamen, globus pallidus, caudate nucleus, substantia

nigra, and dentate nucleus. From Hughes et al. (1998), with

permission