A number of disorders of the methionine metabolism leads to an accumulation of homocysteine ??and its dimer Homozystin with undesirable effects such as thrombosis, lens dislocation and CNS and skeletal abnormalities.

There are many disorders of methionine and sulfur metabolism (see table) and many other amino acid and organic acid metabolism disorders. See also Procedure in a patient with suspected congenital metabolic disorder and investigation for suspected inherited metabolic disorders.

A number of disorders of the methionine metabolism leads to an accumulation of homocysteine ??and its dimer Homozystin with undesirable effects such as thrombosis, lens dislocation and CNS and skeletal abnormalities. There are many disorders of methionine and sulfur metabolism (see table) and many other amino acid and organic acid metabolism disorders. See also Procedure in a patient with suspected congenital metabolic disorder and investigation for suspected inherited metabolic disorders. Homocysteine ??is an intermediate in methionine metabolism; it will either remethylated to regenerate methionine, or combined in a number of Transsulfurationsreaktionen with serine to form Zystathionin and cysteine. Cysteine ??is then metabolized to sulfite, taurine and glutathione. Various defects of Remethylation or transsulphuration can cause the homocysteine ??accumulates and causes a disease. Deficiency of this enzyme leads to an increase of methionine. The first step in the methionine metabolism is the conversion to adenosylmethionine required by the enzyme Methioninadenosyltransferase. This is not of clinical significance, except that it gives a false positive neonatal testing for homocystinuria. Methionine and sulfur metabolism disorders disease (OMIM number) defects proteins or enzymes defective gene or genes (chromosomal location) Remarks homocystinuria (236200) Cystathionine ?-synthase (CBS 21q22.3) * Biochemical Profile: Methioninurie, homocystinuria Clinical features: osteoporosis, scoliosis, pale complexion, ectopia lentis, progressive mental retardation, thromboembolism treatment: pyridoxine, folic acid, betaine in patients who do not respond to, reducing methionine in countries ingestion, L-cysteine ??supplementation Methylenetetrahydrofolate reductase deficiency (236250) methylenetetrahydrofolate MTHFR (1p36.3) * Biochemical Profile: Low to normal methionine in the blood, Homozystinämie, homocystinuria Clinical features: varies from asymptomatic to microcephaly, hypotension, seizures, abnormal gait, mental retardation, apnea, coma and death treatment: pyridoxine, folic acid, hydroxycobalamin, methionine, betaine-methylmalonic homocystinuria (cble; 236270) Methioninsynthasereduktase MTRR (5p15) * Biochemical Profile: homocystinuria, Homozystinämie, low methionine in the blood, no methylmalonic, normal B12 and folic acid Clinical features: difficulties in feeding, growth disorders, mental retardation, ataxia, cerebral atrophy treatment: hydroxycobalamin, folic acid, L -methionine-methylmalonic homocystinuria (cblG; 250940) methylenetetrahydrofolate homocysteine ??methyltransferase MTR (1q43) * As with methylmalonic-homocystinuria cble hypermethioninemia (250850) Methionina denosyltransferase I and III MAT1A (10q22) * biochemical profile: increased methionine in the blood Clinical features: Mainly asymptomatic; Halitosis treatment: Not required Zystathioninurie (219500) ?-Zystathionase CTH (16) * Biochemical Profile: Zystathioninurie Clinical characteristics: Usually normal; of mental retardation is reported treatment: Pyridoxine sulfite oxidase deficiency (606887) sulfite SUOX (12q13) * Biochemical profile: Elevated sulfite, thiosulfate and S-sulfocysteine ??in the urine; reduced sulphate Clinical features: developmental delay, ectopia lentis, eczema, delayed teeth, fine hair, hemiplegia, infantile hypotension, hypertension, convulsions, choreo, ataxia, dystonia, death Treatment: There is no effective therapy. Molybdenum cofactor deficiency (252150) and MOCS1A- MOCS1B proteins MCOS1 (14q24) * biochemical profile: Elevated sulfite, thiosulfate, S-sulfocysteine, taurine, hypoxanthine and xanthine in the urine; reduced sulfate and urate Clinic: Similar demm oxidase deficiency, in addition urinary Treatment: There is no effective therapy. A low sulfur diet may be helpful in patients with mild symptoms Molybdopterinsynthase MCOS2 (6p21.3) * gephyrin GEPH (5q21) * * The gene was identified, and the molecular basis has been elucidated. OMIM = Online Mendelian Inheritance in Man (see OMIM database). Classical homocystinuria This disorder is caused by an autosomal recessive defect in Zystathionin-?-synthase, which catalyzes the Zystathioninbildung by homocysteine ??and serine. Homocysteine ??accumulates and dimerized to form Disulfidhomozystin, which is excreted in the urine. Since the remethylation is intact, homocysteine ??is converted to methionine in addition, which accumulates in the blood. Unwanted neurological effects may come about because of thrombosis and by direct action. The excess homocysteine ??predisposed to thrombosis and has adverse effects on the connective tissue (perhaps involves fibrillin), especially to the eyes and the skeleton. Arterial and venous thromboembolic phenomena can occur at any age. Many developing an ectopic lenses, mental retardation and osteoporosis. Patients may have a marfanoid habit, although they are not particularly large. The diagnosis of classical homocystinuria is provided by the Neonatal Screening with increased Methioninspiegeln, an increase in the homocysteine ??level in the serum to confirm the diagnosis. Enzyme assays with skin fibroblasts can also be performed. The treatment of a classical homocystinuria is a diet low methionine, combined with high doses of pyridoxine (a cofactor for the Zystathioninsynthetase) 100-500 mg / day. Since half of the patients respond to high-dose pyridoxine sole, some doctors do not limit the intake of methionine in these patients. The dosage is 100-125 mg / kg p.o. 2 times a day. Betaine (trimethyl glycine), which increases the Remethylation, may also be helpful to lower homocysteine ??levels. Also, folic acid are given daily 500-1000 micrograms once. With timely treatment mental development is normal or nearly normal. Other forms of homocystinuria Various defects in Remethylisierungsprozess can lead to homocystinuria. The defects include a lack of methionine synthase (MS) and MS-reductase (MSR), the provision of methylcobalamin and adenosylcobalamin and a lack of methylenetetrahydrofolate reductase (MTHFR, which is needed to 5-methyltetrahydrofolate for Methioninsynthasereaktion provide) a. Because there is no Methioninerhöhung in these forms of homocystinuria, they are not detected in neonatal screening. The clinical manifestations are similar to the other two forms of homocystinuria. In addition, at the MS and MSR deficiency neurological symptoms and megaloblastic anemia occur. The clinical manifestations in MTHFR deficiency vary (u. A. Mental retardation, psychosis, weakness, ataxia and spasticity). The diagnosis of MS and MSR defect is suspected in the presence of homocystinuria and megaloblastic anemia and confirmed by DNA diagnostics. Patients with Cobalamindefekt develop a megaloblastic anemia and methylmalonic acidemia. A MTHFR deficiency is diagnosed by a DNA test. The treatment consists of 1 mg i.m. in the substitution of hydroxycobalamin once a day (in patients with MS, MSR and Cobalamindefekten) and folic acid substitution, similar to the classical homocystinuria. Zystathioninurie This disorder is caused by a lack of Zystathionase that converts Zysthionin to cysteine. The accumulation of Zystathionin resulting in increased urine output without clinical symptoms. Sulfitoxidasemangel converts sulphite in the last step of the Zystein- and Methioninreduzierung sulfite to sulfate; this is required as a cofactor molybdenum. Inheritance occurs as an autosomal recessive in both cases. The lack each of these enzymes of the cofactor or causes the same disease. In its most severe form, the clinical symptoms (seizures, hypotension, and myoclonus) manifest already in the newborn and lead to premature death. Patients with milder forms have symptoms similar to those of cerebral palsy and can choreatic movements have. The diagnosis of Sulfitoxidasemangel is believed due to the increased Sulfitspiegel in urine and confirmed by the measurement of enzyme levels in fibroblasts and by determining the Kofaktorspiegels in liver biopsy. Treatment is supportive.

Health Life Media Team

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