Homocystinuria

homocystinuria

1. Dr: Mohamed Abed EGH

2. Homocystinuria Homocystinuria is a disorder of methionine metabolism, leading to an abnormal accumulation of homocysteine and its metabolites ( homocystine , homocysteine-cysteine complex, and others) in blood and urine. Normally, these metabolites are not found in appreciable quantities in blood or urine .

3. Homocystinuria Homocystinuria is inherited as an autosomal recessive trait. prevalence of 1 in 200,000 to 1 in 350,000 live births has been estimated. The condition seems more common in New South Wales, Australia (1 in 60,000 live births), and Ireland. Prenatal diagnosis is feasible by performing an enzyme assay of cultured amniotic cells or chorionic villi or by DNA analysis.

4. Metabolic cycle of methionine Methionine is an essential, non-polar α- amino acid. Under normal conditions methionine undergoes conversion to homocysteine. This in turn undergoes trans- sulfuration to ultimately yield cysteine. This step is catalyzed by the enzyme Cystathionine beta synthase (CBS). People suffering from this disease are unable to synthesize CBS, hence leading to an inability to metabolize methionine.

5. Metabolic cycle of methionine Due to the absence of CBS enzyme , homocysteine accumulates in the blood serum leading to an increased excretion of homocystine in the urine

6. Metabolic cycle of methionine Normally, most homocysteine , an intermediate compound of methionine degradation, is remethylated to methionine . This methionine sparing reaction is catalyzed by the enzyme methionine synthase , which requires a metabolite of folic acid (5-methyltetrahydrofolate) as a methyl donor and a metabolite of vitamin B12( methylcobalamin ), as well as S- adenosylcobalamin , as cofactors

7. Only approximately 20% of total homocysteine (and its dimer homocystine ) is in free form in the plasma of normal individuals. The rest is bound to proteins as mixed disulfides. 3 major forms of homocystinemia and homocystinuria have been identified

8. Homocystinuria Caused by Cystathionine β- Synthase Deficiency (Classic Homocystinuria ) Homocystinuria Caused by Defects in Methylcobalamin Formation Homocystinuria Caused by Deficiency of Methylene tetrahydrofolate Reductase

9. Homocystinuria Caused by Cystathionine β- Synthase Deficiency ( ( ClassicHomocystinuria This is the most common inborn error of methionine metabolism is an autosomal recessive inherited disorder Approximately 40% of affected patients respond to high doses of vitamin B6 and usually have milder clinical manifestations than those who are unresponsive to vitamin B6 therapy. These patients possess some residual enzyme activity.

10. Clinical Infants with this disorder are normal at birth. Clinical manifestations during infancy are nonspecific and may include: failure to thrive and developmental delay . The diagnosis is usually made after 3 yr of age, when subluxation of the ocular lens ( ectopia lentis )occurs. retinal detachment, and optic atrophy may develop later in life. Progressive intellectual disabilityis common.

11. Normal intelligence has been reported. Higher IQ scores are seen in vitamin B6 responsive patients. Psychiatric and behavioral disorders ( 50% ) Convulsions (20%)

12. skeletal abnormalities resembling those of Marfan syndrome they are usually tall and thin, with elongated limbs and arachnodactyly . Scoliosis, pectus excavatum or carinatum , genu valgum , pes cavus , high-arched palate, and crowding of the teeth are commonly seen. These children usually have fair hair, blue eyes, and a peculiar malar flush. Generalized osteoporosis, especially of the spine

13. Thromboembolic episodes which is caused by changes in the vascular walls and increased platelet adhesiveness secondary to elevated homocystine levels involving both large and small vessels, especially those of the brain, are common and may occur at any age. Optic atrophy, paralysis, cor pulmonale , and severe hypertension (from renal infarcts) . The risk of thromboembolism increases after surgical procedures. Spontaneous pneumothorax and acute pancreatitis are rare complications

14. Homocytinuria (downward dislocation= low IQ), Marfan syndrome, upward (upward= normal IQ)

15. diagnosis Elevations of both methionine and homocystine in body fluids are the diagnostic laboratory findings. Freshly voided urine should be tested for homocystine because this compound is unstable and may disappear as the urine is stored. Cystine is low or absent in plasma .

16. Clotting studies are normal The diagnosis may be established by assay of the enzyme in liver biopsy specimens , cultured fibroblasts, or phytohemagglutinin -stimulated lymphocytes or by DNA analysis

17. Treatment with high doses of vitamin B6 (200-1,000 mg/24 hr) causes dramatic improvement in most patients who are responsive this therapy. The degree of response to vitamin B6 treatment may be different in different families. Some patients may not respond because of folate depletion; a patient should not be considered unresponsive to vitamin B6 until folic acid (1-5 mg/24 hr) has been added to the treatment regimen. .

18. Restriction of methionine intake in conjunction with cysteine supplementation is recommended for patients who are unresponsive to vitamin B6 The need for dietary restriction and its extent remains controversial in patients with vitamin B6 responsive form. Dislocation of the lens seemed to be prevented in some patients.

19. Betaine ( trimethylglycine , 200-250 mg/kg/day ) lowers homocysteine levels in body fluids This treatment has produced clinical improvement (preventing vascular events) in patients who are unresponsive to vitaminB6 therapy. Cerebral edema has occurred in a patient with vitamin B6 nonresponsive homocystinuria and dietary noncompliance during betaine therapy. Administration of large doses of vitamin C (1 g/day) has improved endothelial function; long-term clinical efficacy is not known

20. Homocystinuria Caused by Defects in Methylcobalamin Formation Methylcobalamin is the cofactor for the enzyme methionine synthase , which catalyzes remethylation of homocysteine to methionine . There are at least 7 distinct defects in the intracellular metabolism of cobalamin that may interfere with the formation of methylcobalamin .

21. The clinical manifestationsare similar in patients with all of these defects. Vomiting, poor feeding, failure to thrive, lethargy, hypotonia , seizures, and developmental delay may occur in the first few months of life. One patient with the cblG defect was not symptomatic (except for mild developmental delay) until she was 21 yr old when she developed difficulty in walking and numbness of the hands

22. Laboratory findings include megaloblastic anemia, homocystinuria , and hypomethioninemia . The presence of megaloblastic anemia differentiates these defects from homocystinuria due to methylene tetrahydrofolate reductase deficiency . Renal artery thrombosis, hemolytic uremic syndrome, pulmonary hypertension and optic nerve atrophy have been reported in some patients with these defects

23. Diagnosis is established by complementation studies performed in cultured fibroblasts. Prenatal diagnosis has been accomplished by studies in amniotic cell cultures Treatment with vitamin B12 in the form of hydroxycobalamin (1-2 mg/24 hr) is used to correct the clinical and biochemical findings.

24. Homocystinuria Caused by Deficiency of Methylene tetrahydrofolate Reductase This enzyme reduces 5,10-methylene tetrahydrofolate to form 5-methyltetrahydrofolate, which provides the methyl group needed for remethylation of homocysteine to methionine The severity of the enzyme defect and the clinical manifestations varies considerably in different families

25. Clinical findings vary from apnea, seizure, microcephaly , coma, and death to developmental delay, ataxia, and motor abnormalities or even psychiatric manifestations. Premature vascular disease or peripheral neuropathy has been reported as the only manifestation of this enzyme deficiency in some patients.

26. Adults with severe enzyme deficiency may even be completely asymptomatic. Exposure to the anesthetic nitrous oxide (which inhibits methionine synthase ) in patients with methylenetetrahydrofolate reductase (MTHFR) deficiency may result in neurologic deterioration and death.

27. diagnosis Laboratory findings include moderate homocystinemia and homocystinuria . The methionine concentration is low or low normal. Thromboembolism of vessels has also been observed in these patients. Diagnosis may be confirmed by the enzyme assay in cultured fibroblasts or leukocytes or by finding causal mutation in the MTHRgene

28. diagnosis Prenatal diagnosis can be offered by measuring MTHFR enzyme activity in cultured chorionic villus cells or amniocytes , by linkage analysis in informative families, or by DNA analysis of the mutation

29. Treatment Treatment of severe MTHFR deficiency with a combination of folic acid, vitamin B6, vitamin B12, methionine supplementation, and betaine has been tried. Of these, early treatment with betaine seems to have the most beneficial effect