Disorder of methionine metabolism

A number of defects in methionine metabolism lead to accumulation of homocysteine (and its dimer, homocystine) with adverse effects including a tendency toward thrombosis, lens dislocation, and nervous system and skeletal disorders.

Homocysteine is an intermediate metabolite of methionine; it is either remethylated to form methionine or combined with serine in the transsulfuration cascade to form cystathionine and then cysteine. Cysteine is then metabolized to sulfite, taurine, and glutathione. Various defects in remethylation or transsulfuration can lead to accumulation of homocysteine, which is the cause of disease.

The first step in the metabolism of methionine is its conversion to adenosylmethionine; this requires the enzyme methionine adenosyltransferase. Deficiency of this enzyme results in elevated methionine levels that are not clinically significant except that they result in false-positive results in newborn screening for homocystinuria.

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Classic homocystinuria

Homocystinuria is a disorder resulting from a deficiency of cystathionine beta synthetase, which catalyzes the formation of cystathione from homocysteine and serine, and is inherited in an autosomal recessive manner. Homocysteine accumulates and dimerizes to form homocysteine disulfide, which is excreted in the urine. Since remethylation is not impaired, some of the extra homocysteine is converted to methionine, which accumulates in the blood. Excess homocysteine predisposes to thrombosis and has a negative effect on connective tissue (probably by acting on fibrillin), especially the eyes and skeleton; negative effects on the nervous system may result from thrombosis and direct exposure.

Arterial and venous thromboembolism can occur at any age. Many have ectopia lentis (subluxation of the lens), mental retardation, and osteoporosis. Patients may have a Marfan-like phenotype even though they are not usually tall.

Diagnosis is by neonatal screening for elevated serum methionine; elevated plasma homocysteine confirms the diagnosis. Enzyme assays in skin fibroblasts are also used. Treatment involves a low-methionine diet plus high-dose pyridoxine (a cofactor for cystathionine synthetase) 100–500 mg orally once daily. Because about half of patients respond to high-dose pyridoxine alone, some clinicians do not restrict methionine in these patients. Betaine (trimethylglycine), which enhances remethylation, may also help lower homocysteine; the dose is 100–120 mg/kg orally twice daily. Folic acid 500–1000 mcg once daily is also given. Intellectual development is normal or near normal when treatment is started early.

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Other forms of homocystinuria

Various defects in the remethylation process can lead to homocystinuria. Defects include methionine synthase (MS) and MC reductase (MCP) deficiencies, inadequate methylcobalamin and adenosylcobalamin intake, and deficiency of methylenetetrahydrofolate reductase (MTHFR, which is required to form 5-methylenetetrahydrofolate, which is necessary for the action of methionine synthase). Because methionine is not elevated in these forms of homocystinuria, they are not detected by neonatal screening.

Symptoms are similar to those of other forms of homocystinuria. In addition, MS and MCP deficiency are associated with neurological impairment and megaloblastic anemia. Clinical manifestations of MTHFR deficiency vary, including mental retardation, psychosis, weakness, ataxia, and spasticity.

The diagnosis of MS and MSR deficiency is suggested by the presence of homocystinuria and megaloblastic anemia and confirmed by DNA testing. In the presence of cobalamin defects, interregional anemia and methylmalonic acidemia are noted. MTHFR deficiency is diagnosed by DNA testing.

Replacement therapy is carried out with hydroxycobalamin 1 mg intramuscularly once a day (in patients with a defect in MS, MCP and cobalamin) and folic acid in doses as for classical homocystinuria.

Cystathioninuria

This disease is caused by a deficiency of cystathionase, which converts cystathionine to cystine. The accumulation of cystathionine leads to increased excretion in the urine, but there are no clinical manifestations.

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Sulfite oxidase deficiency

Sulfite oxidase converts sulfite to sulfate in the final step of cysteine and methionine degradation; this requires the cofactor molybdenum. Deficiency of either the enzyme or the cofactor causes similar clinical manifestations; both are inherited autosomal recessively. In the most severe forms, clinical manifestations develop in the neonatal period and include seizures, hypotonia, and myoclonus, progressing to early death. Patients with milder forms may develop clinical manifestations resembling cerebral palsy and may have choreiform movements. Diagnosis is suggested by elevated urinary sulfite and confirmed by measuring enzyme levels in fibroblasts and cofactor levels in liver tissue. Treatment is supportive.

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