Metabolic Metabolism Disorders

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

Homocysteine is an intermediate metabolite of methionine; it is either re-methylated to form methionine, or it combines with serine in a cascade of transsulfuration reactions, forming cystathionine and then cysteine. Cysteine is then metabolized to sulphite, taurine and glutathione. Various defects of remethylation or transsulfuration can lead to the accumulation of homocysteine, which leads to the disease.

The first step in the metabolism of methionine is its conversion into adenosylmethionine; for this, a methionine oxidase enzyme enzyme is required. Deficiency of this enzyme leads to an increase in the level of methionine, which is not clinically significant, except that it leads to false positive results in a screening of newborns for homocystinuria.

[1], [2], [3], [4], [5],

Classical homocystinuria

Homocystinuria - this disease is a consequence of a deficiency of cystathionine-beta-synthetase, which catalyzes the formation of cystathion from homocysteine and serine, is inherited by autosomal recessive type. Homocysteine accumulates and dimerizes, forming a homocysteine disulfide, which is excreted in the urine. Since remethylation is not disrupted, part of the additional homocysteine is converted to methionine, which accumulates in the blood. Excess homocysteine predisposes to thrombosis and has a negative effect on connective tissue (probably acting on fibrillin), especially the eyes and skeleton; The negative effect on the nervous system can be a consequence of thrombosis and direct exposure.

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

The diagnosis is based on neonatal screening for elevated serum methionine levels; confirms the diagnosis of an elevated level of homocysteine in the plasma. Also, the use of enzymes in skin fibroblasts is used. Treatment includes a diet with a low content of methionine in combination with high doses of pyridoxine (co-factor of cystathion synthetase) 100-500 mg orally once a day. Since about half of patients have an effect on the appointment of only high doses of pyridoxine, some doctors do not limit the intake of methionine in such patients. Betaine (trimethylglycine), which enhances remethylation, can also help reduce homocysteine levels; The dose is 100-120 mg / kg orally twice a day. Also prescribed folic acid is 500-1000 mcg once a day. At an early start of treatment, intellectual development is normal or almost normal.

[6], [7], [8], [9], [10]

Other forms of homocystinuria

Various defects in the remeliation process can lead to homocystinuria. Defects include a deficiency of methionine synthase (MS) and MS reductase (MCP), an insufficient intake of methyl cobalamin and adenosylcobalamin, and a deficiency of methylenetetrahydrofolate reductase (MTHFR, which is necessary for the formation of 5-methylenetetrahydrofolate required for the action of methionine synthase). Since no methionine is raised in these forms of homocystinuria, they are not detected in neonatal screening.

Symptoms are similar to manifestations of other forms of homocystinuria. In addition, the deficiency of MS and MSR is accompanied by neurologic disorders and megaloblastic anemia. Clinical manifestations of the deficit of MTHFR vary, including mental retardation, psychosis, weakness, ataxia and spasticity.

The diagnosis of MS and MCP 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 methylmalone acidemia are noted. Deficiency of MTHFR is diagnosed by DNA testing.

Carry out hydroxy cobalamin replacement therapy 1 mg intramuscularly once a day (in patients with MS, MCP and cobalamin deficiency) and folic acid at doses as in classical homocystinuria.

Cystathionuria

This disease is caused by a deficiency of cystathionase, which converts cystathionine to cystine. Accumulation of cystathionine leads to an increased excretion of it with urine, but there are no clinical manifestations.

[11], [12], [13], [14]

Deficiency of sulfite oxidase

Sulfite oxidase converts sulfite to sulfate in the last stage of degradation of cysteine and methionine; this requires the presence of cofactor - molybdenum. Deficiency of both the enzyme and the cofactor causes similar clinical manifestations; the type of inheritance in both variants is autosomal recessive. In the most severe forms, clinical manifestations develop during the neonatal period and include convulsions, hypotension and myoclonus, progressing up to the early death of the child. Patients with lighter forms may develop clinical manifestations similar to infantile cerebral palsy, and chorea-like movements may occur. The diagnosis is based on an increase in the urinary sulfite and is confirmed by determining the level of the enzyme in the fibroblasts, as well as the level of co-factor in the liver tissue. Treatment is supportive.

[15], [16], [17], [18], [19], [20]