Homocystenuria

Definition

• Homocystinuria is a group of autosomal recessive disorders of sulfur amino acid metabolism characterized by the accumulation of homocysteine (Hcy) in blood and urine.
• Classic Homocystinuria: Due to deficiency of Cystathionine $\beta$-Synthase (CBS).
• Other Forms: Defects in homocysteine remethylation (e.g., MTHFR deficiency, Cobalamin defects).

Etiology and Pathophysiology

1. Classic Homocystinuria (CBS Deficiency)

• Enzyme: Cystathionine $\beta$-Synthase (Requires Vitamin B6/Pyridoxine as cofactor).
• Pathway: Transsulfuration pathway (Methionine $\to$ Homocysteine $\to$ Cystathionine $\to$ Cysteine).
• Biochemical Defect: Block in conversion of Homocysteine to Cystathionine.
• Consequences:
  • Accumulation of Homocysteine and Methionine.
  • Deficiency of Cysteine (becomes essential).
  • Toxicity: Elevated Hcy causes endothelial injury (thrombosis), interferes with collagen/elastin cross-linking (fibrillin-1 inhibition), and acts as an NMDA receptor agonist (neurotoxicity).

2. Remethylation Defects

• Enzymes: Methylene Tetrahydrofolate Reductase (MTHFR) or Methionine Synthase.
• Biochemistry: Failure to convert Homocysteine back to Methionine.
• Profile: High Homocysteine but Low Methionine.

Clinical Features (Classic CBS Deficiency)

Multisystem involvement affecting Eyes, Skeleton, CNS, and Vascular system. Patients usually appear normal at birth.

1. Ocular (Key Feature)

• Ectopia Lentis (Lens Dislocation):
  • Occurs in >85% of untreated patients.
  • Direction: Typically Downwards and Inwards (Inferonasal).
  • Onset: Usually by 3–4 years; almost all by 10 years.
• Other: Severe Myopia, glaucoma, retinal detachment.

2. Skeletal (Marfanoid Habitus)

• Appearance: Tall stature, long limbs (dolichostenomelia), arachnodactyly (long fingers).
• Deformities: Pectus carinatum or excavatum, genu valgum, high-arched palate.
• Bone Density: Severe Osteoporosis (distinct from Marfan syndrome) leading to pathological fractures and vertebral collapse ("codfish vertebrae").

3. Vascular (Major Cause of Morbidity/Mortality)

• Thromboembolism: Can affect any vessel (arterial or venous) at any age.
• Manifestations: Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), Stroke (CVA) in young children, Myocardial Infarction.
• Trigger: Surgery, dehydration, or immobilization can precipitate fatal thrombosis.

4. Central Nervous System

• Intellectual Disability: Common (IQ 30–75) but variable; B6-responsive patients often have normal IQ.
• Psychiatric: Anxiety, depression, obsessive-compulsive behavior.
• Seizures: Occur in ~20% of patients.

5. Cutaneous

• Malar Flush: Flushing of cheeks (distinctive).
• Thin, fair skin and fair hair (hypopigmentation).

Investigations

1. Screening

• Cyanide-Nitroprusside Test: Urine turns deep red/magenta (detects sulfhydryl groups).
  • False Negatives: Low protein intake.
  • False Positives: Cystinuria.
• Newborn Screening (NBS): Detects elevated Methionine.
  • Limitation: May miss B6-responsive forms or remethylation defects (where Methionine is low).

2. Confirmatory Tests

• Plasma Amino Acids:
  • Classic: Elevated Methionine, Elevated Homocysteine, Low Cysteine.
  • Remethylation Defect: Low Methionine, Elevated Homocysteine.
• Plasma Total Homocysteine (tHcy): Markedly elevated (>100 µmol/L; Normal <15).
• Enzyme Assay: CBS activity in cultured fibroblasts or liver biopsy.
• Genetics: CBS gene mutation analysis.

3. Pyridoxine (B6) Challenge Test

• Purpose: To determine B6 responsiveness (prognostic factor).
• Method: Give 100–500 mg Vitamin B6 daily.
• Response: Significant drop in plasma Hcy and Methionine implies B6-Responsive Homocystinuria (milder phenotype).

Management

1. B6-Responsive Patients (~50%)

• Vitamin B6 (Pyridoxine): High dose (200–500 mg/day).
• Goal: Maintain plasma Hcy <50 µmol/L.
• Supplementation: Folate and Vitamin B12 (optimize remethylation).

2. B6-Non-Responsive Patients

• Dietary Restriction:
  • Low Methionine Diet: Restrict animal protein (meat, dairy, eggs).
  • Medical Formula: Methionine-free amino acid mixture containing Cysteine.
• Betaine (Trimethylglycine):
  • Mechanism: Donates methyl group to Homocysteine to form Methionine (alternate remethylation pathway independent of folate).
  • Indication: First-line adjunct in non-responsive cases.
  • Risk: Can excessively raise Methionine levels (monitor for cerebral edema risk if Met >1000 µmol/L).

3. General Measures

• Anticoagulation: Not routine prophylactically, but aggressive hydration is mandatory during surgery or illness.
• Eye Care: Regular ophthalmology follow-up; surgery for dislocated lenses.
• Bone Health: Calcium, Vitamin D, exercise to manage osteoporosis.

Prognosis

• Untreated: Poor life expectancy due to vascular events (50% mortality by age 20-30).
• Treated:
  • B6-Responsive: Excellent prognosis; normal IQ and lifespan if treated early.
  • Non-Responsive: Good outcome if diet/Betaine started in neonates. Late treatment prevents further thrombosis but does not reverse ID or lens dislocation.