Homocystinuria, Diagnosis and Treatment

What sample is needed for Homocystinuria?

1. This test is done on the urine sample.
2. Methionine can be estimated using serum as well.

What are the Indications for Homocystinuria?

• To diagnose the complications due to homocystinuria.

How will you define Homocystinuria?

• It is an autosomal recessive inherited disorder.
• It results from the enzyme cystathionine-beta-synthetase deficiency, which catalyzes cystathionine formation from homocystine and serine.
• It is characterized by increased plasma concentration of methionine, free homocysteine, and cysteine-homocysteine disulfide together with low cystine.
• Homocysteine is an amino acid, where homocystine is a dimer of two homocysteine molecules joined together.

How will you discuss the pathophysiology of Homocystinuria?

1. In the USA, 1:150,000 cases may show homocystinuria.
2. This is an autosomal recessive inherited disorder.
   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 or 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 metabolic disorder results from a deficiency in the cystathionine beta-synthase enzyme, which is 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.

Homocysteine metabolism

What is the clinical presentation of Homocystinuria?

1. Clinical presentation may be nonspecific, with failure to thrive and delayed development.
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 cataracts 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.

How will you diagnose 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 a cherry red color.

What are the normal values of Homocystinuria?

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

What are the differences between homocysteinemia and homocystinuria?

How will you treat 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 cystine supplement may help.
7. Betaine reduces the homocysteine concentration, promoting homocysteine conversion back to methionine.
8. A low-protein diet is recommended.
   1. Life expectancy is reduced if not treated.

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