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.

1. HOMOCYSTINURIA Dr. V. MAGENDIRA MANI., M.Sc., M.Phil., Ph.D.,TNSET Assistant Professor of Biochemistry Islamiah College (Autonomous), Vaniyambadi [email protected] ; 9486000227

2. Inborn errors of metabolism are inherited metabolic disorders that result from defects in genes coding for specific enzymes. This defect generates abnormal chemical reactions that disrupt the normal metabolic pathways resulting in the toxic accumulation of the substrate behind the block or a deficiency in the product. Inborn errors of metabolism

3. Homocystinuria is a disorder of methionine metabolism, leading to an abnormal accumulation of homocysteine and its metabolites (homocystine, homocysteine-cysteine complex) in blood and urine.

4. Homocystinuria is inherited as an autosomal recessive trait. Prevalence of 1 in 200,000 to 350,000 live births has been estimated. Homocystinuria is accompanied by a variety of clinical and pathological abnormalities, which show major involvement in four organ systems:- the eye, skeletal, central nervous system, and vascular system

5. If both parents carry the faulty gene, for each child, there is a: 25% chance the child will be born with the disorder 50% chance the child will be a carrier of the faulty gene 25% chance the child will neither have disorder nor would be the carrier. Inheritance of Homocystinuria

6. Homocystinuria Caused by Cystathionine β-Synthase Deficiency (Classic Homocystinuria) 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).

7. People suffering from this disease are unable to synthesize CBS , hence leading to an inability to metabolize methionine Due to the absence of CBS enzyme, homocysteine accumulates in the blood serum leading to an increased excretion of homocystine in the urine

8. 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

9. Other causes Homocystinuria Caused by Defects in Methylcobalamin Formation Homocystinuria Caused by Deficiency of Methylene tetrahydrofolate Reductase

10. 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.

11. 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

12. Symptoms Delayed development or failure to thrive, Increasing visual problems As the child grows, physical deformities become more evident, such as a peaked or hollowed chest, scoliosis, high arches of the feet, fine brittle hair, a high palate with crowded teeth, knock knees, and long thin limbs and fingers. Mental retardation, Dislocation of the lens of the eye Brittle bones that are prone to breaking Seizures, movement disorders, and anemia. Abnormal Blood clotting, strokes, heart disease and heart attacks

13. osteoporosis, or weakening of the bones Learning disabilities Long, spindly arms and legs Scoliosis - is a sideways curvature of the spine. Coronary artery disease - e.g., myocardial infarction Fatty infiltration of liver Blood clotting which could lead to heart strokes.

14. DIAGNOSIS The test usually looks for high levels of MET, homocystine, and other sulphur-containing amino acids Tests also detect an enzyme deficiency (such as cystathionine synthetase) can be done as well. x-rays to detect osteoporosis, and an eye exam to check for a dislocated lens.

15. Cystine is low or absent in plasma Genetic testing may additionally be helpful to identify carriers in the family and for either prenatal or neonatal screening for children at high risk of developing the disease.

16. TREATMENT No specific cure has been discovered for homocystinuria Lifelong vitamin B6 supplements (also called pyridoxine) Those who do not respond to B6 will need to eat a lifelong low-methionine diet. No meat, fish, dairy, or eggs are allowed, and flour, beans, and nuts must be restricted A normal dose of folic acid supplement and occasionally adding cysteine to the diet

17. Betaine (N,N,N-trimethylglycine) is used to reduce concentrations of homocysteine by promoting the conversion of homocysteine back to methionine Special low-methionine flours, breads, and pastas are often eaten, as well as a highprotein methionine-free formula. Administration of large doses of vitamin C (1 g/day) has improved endothelial function

18. The re-formed methionine is then gradually removed by incorporation into body protein. The methionine that is not converted into protein is converted to S-adenosyl-methionine which goes on to form homocysteine again.

19. Prevention Genetic counseling is recommended for prospective parents with a family history of homocystinuria. Prenatal diagnosis of homocystinuria is available and is made by culturing amniotic cells or chorionic villi to test for the presence or absence of cystathionine synthase Screen for homocystinuria in all newborns