Homocystinuria

Disorder of Metabolism

Homocystinuria is inherited disorder of the metabolism of the amino acid methionine due to a deficiency of - cystathionine beta synthase or methionine synthase

These are a series of inborn errors of metabolism that are characterized by

increased homocysteine levels in blood and urine.

These are autosomal recessive disorders and are seen in 1 in 200,000 births.

Normal homocysteine level in blood is 5–15 micromol/L. It can rise to 50-100

times the normal level in diseases. Moderate increase is seen in aged people,

vitamin B12 or B6 deficiency, smokers and alcoholics and also in

hypothyroidism.

Elevated homocysteine levels in blood is associated with increased risk of

coronary artery disease through increased oxidant stress, impaired endothelial

function, and induction of thrombosis.

Causes of homocystinuria

1. Cystathionine beta synthase deficiency (defective CBS gene)

2. Deficient N 5 ,N 10 -Methyl THFA reductase (defective MTHFR gene)

3. Cobalamin (B12) deficiency.

Clinical manifestations

1. Mental Retardation

2. Charlie Chaplin gait - Bilateral extorsion of the tibia .

3. Involvement in the eye: Ectopia Lentis (Subluxation of lens) and severe Myopia are seen.

4. Increased platelet adhesiveness and increased risk of intravascular

thrombosis due to activation of Hagemann’s factor (clotting factor XII).

Diagnosis

Cyanide-Nitroprusside test is positive in urine. Urinary homocysteine exceeds

300 mg/24 hours.

Treatment

Diet low in methionine and vitamin B6 therapy along with folate and B12

supplements. Betaine therapy is usually added to the therapeutic regimen.

Important Points

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• Homocystinuria - disorder of the metabolism of the amino acid methionine

Which enzyme deficiency causes Homocystinuria?

Deficiency of cystathionine beta synthase or methionine synthase

Which Vitamin deficiency can cause symptoms of homocysteinuria?

Symptoms of homocystinuria can also be caused by a deficiency of vitamins B6, B12, or folate

How the Ectopia Lentis of homocystinuria differs from Ectopia lentis of Marfan syndrome?

Ectopia lentis –

Ectopia lentis

Marfan syndrome	Ectopia lentis- Upward dislocation
Homocystinuria	Ectopia lentis- Downward dislocation

What is the cause of homocystinuria?

Homocystinuria is caused by the deficiency of :

Deficiency of Enzymes-

1. Cystathionine beta synthase

2. Methionine synthase

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Deficiency of Vitamins-

1. Folic acid

2. Vitamin B12

3. Pyridoxine (vitamin B6)

What are the types of homocystinuria?

Homocystinuria type-I-

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Due to the deficiency of cystathionine ß synthase, Most common inborn error of methionine metabolism.

homocystinuria type-II -

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Homocystinuria due to defect in methylcobalamin formation, Characterized by the triad of megaloblastic anemia, Homocystinuria and hypomethionemia.

Homocystinuria type-III-

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Deficiency of the enzyme methyltetrahydrofolate reductase Characterized by homocystinemia,homocystinuria, Low-low normal levels of methionine

Homocystinuria type-I

Due to the deficiency of cystathionine ß synthase, Most common inborn error of methionine metabolism.

Homocystinuria type-II

Homocystinuria due to defect in methylcobalamin formation, Characterized by the triad of megaloblastic anemia, Homocystinuria and hypomethionemia.

Homocystinuria type-III

Deficiency of the enzyme methyltetrahydrofolate reductase. Characterized by homocystinemia and homocystinuria, Low-low normal levels of methionine