Homocystinuria

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Homocystinuria

  1. 1. Homocystinuria Homocystinuria or cystathionine beta synthase deficiency is an autosomal recessive inherited disorder of methionine metabolism. 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.
  2. 2. Symptoms 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. Ectopia lentis and high myopia are the major ocular manifestation of classical homocystinuria. The most striking changes however is that of skeleton. As puberty nears the limbs grow out of proportion to the trunk, anterior chest wall deformities may occur. The facial appearance may be altered by prominence and protrusion of upper teeth due to overcrowding . One of the distinguishing features of classical homocystinuria patients is the presence of osteoporosis, especially spinal osteoporosis.
  3. 3. Other Symptoms Another well known symptom of homocystinuria is thromboembolism, affecting both large and small arteries and veins. It is also the most striking cause of serious complications and mortality in the disease. Mental Retardation is the most frequent Central Nervous System abnormality and Is often the first recognizable sign of homocystinuria. These patients show a wide variation in their IQ levels with a median IQ of 64. Episodic depression, behavioral disorders, OCD, schizophrenia, etc. are some of the most common mental disorders appearing in these patients
  4. 4. Symptoms in a Nutshell
  5. 5. Incidence According to the data collected from countries that have screened over 2,00,000 newborns, the current cumulative detection rate of homocystinuria is 1 in 3,44,000. However this figure is considered by many as an underestimation of the true rate of occurrence. This is mainly due to the fact that in pyridoxine- responsive cases, the most readily treatable form is preferentially missed by newborn screening methods. The true rate of incidence is considered by many to be as high as 1 in 45,000, based on the mutation rate formula.
  6. 6. Normal metabolism of Methionine
  7. 7.  Homocysteine produced in the third step of the pathway is either regenerated into methionine or converted to cystathionine by combining serine and homocysteine  The reaction is catalysed by the enzyme , Cystathionine-β-synthase (CBS)  The deficiency of CBS due inherited defects causes homocystinuria  Due to the absence of CBS enzyme , homocysteine accumulates in the blood serum leading to an increased excretion of homocystine in the urine
  8. 8.  In absence of CBS enzyme Cystathionine is not formed and the second part of the pathway does not take place
  9. 9. DIAGNOSIS • Newborns are tested for homocystinuria before they leave the hospital. The test usually looks for high levels of MET. If the test is positive, blood or urine tests can be done to confirm the diagnosis. These tests can detect high levels of MET, homocystine, and other sulphur-containing amino acids. Tests to detect an enzyme deficiency (such as cystathionine synthetase) can be done as well. • If a child is not tested at birth, a doctor may later discover the disorder based on symptoms. At that point, the following may be done: • Blood tests to confirm the diagnosis • X-rays to look for bone problems • An eye exam to look for eye problems
  10. 10. TREATMENT  No specific cure has been discovered for homocystinuria; however, many people are treated using high doses of vitamin B6 i.e. pyridoxine. Slightly less than 50% respond to this treatment and need to intake supplemental vitamin B6 for the rest of their lives. Those who do not respond require a low methionine diet, and most will need treatment with trimethylglycine. A normal dose of folic acid supplement and occasionally adding cysteine to the diet.  Betaine (N,N,N-trimethylglycine) is used to reduce concentrations of homocysteine by promoting the conversion of homocysteine back to methionine. 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.
  11. 11.  Betaine is, therefore, only effective if the quantity of methionine to be removed is small. Hence treatment includes both betaine and a diet low in methionine. In classical homocystinuria (CBS, or cystathione beta synthase deficiency) the plasma methionine usually increases above the normal range of 30 micromoles/L and the concentrations should be monitored as potentially toxic levels (more than 400 micromole/l) may be reached.
  12. 12. Prevention is better than cure  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 (the enzyme that is missing in homocystinuria).  If the diagnosis is made while a patient is young, a low methionine diet started promptly and strictly adhered to can spare some mental retardation and other complications of the disease. For this reason, some states screen for homocystinuria in all newborns

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