Homocystinuria

Sample for Homocystinuria

1. This test is done on the urine sample.
2. The estimation of methionine can be done on serum as well.

Purpose of the test (Indications) for Homocystinuria

• To diagnose the complications due to homocystinuria.

Definition of Homocystinuria

It is characterized by increased plasma concentration of methionine, free homocysteine, and cysteine-homocysteine disulfide together with low cystine.

Pathophysiology of Homocystinuria

1. In the USA, 1:150,000 cases may show homocystinuria.
2. This is an autosomal recessive disease.
   1. Homocystinuria is inherited in families as an autosomal recessive trait. This means the child must inherit the non-working gene from both parents to be seriously affected.
3. This is a disorder of methionine metabolism which leads to:
   1. Accumulation of homocysteine and its metabolites in the blood and urine.
   2. Normally these are not found in the blood and the urine.
4. This may be seen in patients with cobalamin and folate deficiency.
5. This group of disorders is characterized by excessive excretion of homocysteine in the urine.
6. Basically, there is a deficiency of the cystathionine beta-synthase enzyme deficiency.
   1.  This is a metabolic disorder resulting from a deficiency in the cystathionine beta-synthase enzyme responsible for methionine and homocysteine metabolism.
   2. In this case, methionine is measured.
   3. Homocysteine normally does not accumulate in the plasma because it is unstable and, when present in excess, undergoes oxidation to homocystine.

7. The concentration of homocystine in the urine is not detectable, but decreased homocysteine conversion to cystathionine by cystathionine beta-synthase enzyme or back to methionine leads to homocystinuria.
8. There is an excess of homocysteine and methionine in the blood.
   1. There is the presence of homocysteine and methionine in the urine.

Clinical presentation of Homocystinuria

1. Clinical presentation may be nonspecific, and there is failure to thrive and development is delayed.
2. Diagnosis is usually delayed up to 3 years of age if the newborn screening is not done.
3. Untreated patients are associated with:
   1. Dislocated lenses, myopia, glaucoma, retinal detachment, and degeneration.
   2.  Optic atrophy and cataract may develop later on.
4. Muscle weakness.
5. Osteoporosis is quite common.
6. Arterial and venous thrombosis.
   1. Delay in the development of infants.
   2. Hypercoagulability.
7. Mental retardation is seen in >50% of the cases.
   1. These neurological symptoms include seizures, abnormal EEG, and psychiatric abnormalities.
8. Thromboembolic attacks are common.
9. A special dietary supplement may help to prevent this complication.
10. Other symptoms seen are :
    1. Chest deformities (pectus carinatum, pectus excavatum)
    2. Flushing across the cheeks.
    3. High arches of the feet.
    4. Intellectual disability.
    5. Knock knees.
    6. Long limbs.
    7. Mental disorders.
    8. Nearsightedness.
    9. Spidery fingers (arachnodactyly).
    10. Tall, thin build.

Diagnosis of Homocystinuria

1. The amino acid screen of blood and urine.
2. Methionine is tested in the urine.
3. Genetic testing.
4. Liver biopsy and enzyme assay.
5. Skeletal x-ray.
6. Skin biopsy with a fibroblast culture.
7. Standard ophthalmic exam.
8. A urine test on cyanide/nitroprusside shows cherry red color.

Normal of Homocystinuria

• Random urine samples are negative.
• Methionine level = 1.0 to 2.0 mg/dL (67 to 134 µmol/L).

Treatment for Homocystinuria

1. No specific treatment.
2. Dietary restriction of the methionine.
3. The patients are given high doses of Vit. B6.
4. 50% may respond and will need it. B6 for the rest of the life.
5. In unresponsive patients, given a low sulfur diet, especially low methionine.
6. A low dose of folic acid and a supplement of cystine may help.
7. Betaine is used to reduce the concentration of homocysteine, promoting the conversion of homocysteine back to methionine.
8. A low-protein diet is recommended.
   1. Life expectancy is reduced if not treated.

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