Homocystinuria

Dr. Arvind Kumar

Introduction

  1. Homocystinuria is an inborn error of metabolism characterized by excessive accumulation of homocysteine and its metabolites in blood and urine.
  2. It is primarily caused by defects in the methionine metabolism pathway, leading to disruption in the conversion of homocysteine to cystathionine or methionine.
  3. The condition is autosomal recessive and results in multisystem involvement, especially affecting the nervous, skeletal, ocular, and vascular systems.

 

Metabolic Pathway

Under normal physiological conditions:

  • Methionine, an essential amino acid, is converted to S-adenosylmethionine (SAM), a universal methyl donor.

  • After methyl donation, S-adenosylhomocysteine (SAH) is formed and subsequently hydrolyzed to homocysteine.

  • Homocysteine has two metabolic fates:

    1. Remethylation back to methionine (requires vitamin B12 and folate as cofactors).

    2. Transsulfuration to cystathionine (requires vitamin B6 as a cofactor) via the enzyme cystathionine β-synthase (CBS).

 

Pathophysiology

In homocystinuria type I, deficiency of cystathionine β-synthase (CBS) blocks the transsulfuration pathway, resulting in:

  • Accumulation of homocysteine and methionine in plasma.

  • Decreased production of cystathionine and cysteine.

  • Elevated urinary excretion of homocystine (oxidized form of homocysteine).

The high levels of homocysteine promote oxidative stress, endothelial damage, and abnormal collagen cross-linking, which explain the vascular and connective tissue manifestations.

Genetics and Types

Homocystinuria is autosomal recessive and genetically heterogeneous.
The main types are:

Type Enzyme Defect Cofactor Deficiency Vitamin Responsiveness Biochemical Findings
Type I Cystathionine β-Synthase (CBS) deficiency Vitamin B6 (pyridoxine) Pyridoxine-responsive or non-responsive forms ↑ Homocysteine, ↑ Methionine
Type II Defect in methylcobalamin formation Vitamin B12 Responsive to B12 ↑ Homocysteine, ↓ Methionine
Type III Defect in methyltetrahydrofolate reductase (MTHFR) Folate Responsive to folate ↑ Homocysteine, ↓ Methionine

 

Clinical Manifestations

The symptoms usually appear during childhood or adolescence. Key features include:

1. Ocular Manifestations

  • Ectopia lentis (dislocation of the lens) – downward and inward displacement.

  • Severe myopia.

  • Glaucoma or retinal detachment may occur.

2. Skeletal Abnormalities

  • Marfanoid habitus: tall, thin build with long limbs and arachnodactyly.

  • Kyphosis, scoliosis, and osteoporosis.

  • Premature osteoporosis due to defective collagen cross-linking.

3. Neurological Features

  • Developmental delay and intellectual disability.

  • Seizures in severe cases.

  • Behavioral or psychiatric disturbances (anxiety, depression).

4. Vascular Involvement

  • Thromboembolism is the most serious complication.

  • Predisposition to both arterial and venous thrombosis.

  • It can cause stroke, myocardial infarction, or pulmonary embolism at a young age.

 

Diagnosis

1. Biochemical Tests

  • Plasma homocysteine: markedly elevated (>100 µmol/L in CBS deficiency).

  • Plasma methionine: elevated in type I; decreased in remethylation defects.

  • Urine: positive for homocystine on nitroprusside test.

2. Enzyme and Genetic Analysis

  • Direct assay of CBS activity in cultured fibroblasts.

  • Molecular genetic testing for CBS, MTHFR, or cobalamin metabolism genes.

3. Additional Tests

  • Amino acid chromatography for plasma/urine profile.

  • Ophthalmic examination for lens dislocation.

  • Imaging for skeletal and vascular complications.

 

Treatment

The management depends on the underlying enzyme defect and responsiveness to vitamins.

1. Pyridoxine (Vitamin B6) Therapy

  • Given in all newly diagnosed cases to test B6 responsiveness.

  • Doses: 100–500 mg/day.

  • Responsive patients may show dramatic improvement.

2. Dietary Management

  • Low-methionine, cysteine-supplemented diet.

  • Protein restriction to minimise methionine load.

  • Use of methionine-free medical foods containing other essential amino acids.

3. Additional Therapies

  • Betaine (trimethylglycine): enhances remethylation of homocysteine to methionine.

  • Folic acid and Vitamin B12: support the remethylation pathway.

  • Antiplatelet or anticoagulant therapy: to prevent thrombotic events.

 

Prognosis

  • Early diagnosis and proper management can prevent or reverse most symptoms, except intellectual disability if already established.
  • Untreated cases often develop progressive vascular complications leading to premature death.

 

Screening and Prevention

  • Newborn screening using tandem mass spectrometry can detect elevated methionine.

  • Carrier detection and genetic counseling for families with affected children.

  • Prenatal diagnosis via enzyme assay or DNA testing of chorionic villus or amniotic cells.

 

Key Differentials

 

Disorder Key Feature Distinguishing Point
Marfan syndrome Skeletal and ocular abnormalities Normal homocysteine levels
MTHFR deficiency Neurological symptoms Low methionine levels
Vitamin B12 deficiency Megaloblastic anemia Reversible with B12 therapy