Definition: a group of inherited genetic disorders characterized by impaired homocysteine metabolismPasted image 20231111104739.pngPasted image 20240404211022.png

Epidemiology


Etiology

  • Autosomal recessive
  • Cause deficiencies in one or more of the following enzymes
    • Methionine synthase
    • Cystathionine synthase: an enzyme that catalyzes the conversion of homocysteine and serine to cystathionine, using vitamin B6 as a cofactor.
    • Methylenetetrahydrofolate reductase (MTHFR): an enzyme involved in folate metabolism that reduces N5,10-methylenetetrahydrofolate to methyltetrahydrofolate.
  • Impaired affinity of cystathionine synthase for pyridoxal phosphate

Pathophysiology

  • Methionine synthase (homocysteine methyltransferase) deficiency → impaired conversion of homocysteine into methionine
  • Cystathionine synthase deficiency → impaired conversion of homocysteine into cystathionine
  • All forms result in the accumulation of homocysteine.

Clinical features

  • Nonspecific features in infancy: growth faltering, developmental delay
  • Eyes
    • Downward and inward subluxation of the ocular lens (ectopia lentis) after 3 years of age (in Marfan syndrome, the lens usually luxates upwards and outwards)Pasted image 20231111110428.png
    • Myopia and glaucoma later in life
  • Progressive intellectual disability
  • Psychiatric and behavioral disorders
  • Light skin
  • Marfanoid features
    • Tall, thin
    • Pectus deformities (e.g., pectus excavatum)
    • Scoliosis
    • Elongated limbs (↑ arm:height ratio; ↓ upper:lower body segment ratio), arachnodactyly
    • Hyperlaxity of joints and hyperelasticity of the skin

Tip

Marfan syndrome and homocystinuria both present with marfanoid habitus. Distinguishing features include intellectual disability, which is only seen in homocystinuria, and the direction of lens dislocation (downwards in homocystinuria and upwards in Marfan syndrome).


Diagnostics

  • ↑ Homocysteine in urine and serum
  • Urine sodium nitroprusside test: Urine changes color to an intense red in the presence of homocysteine.
  • Serum methionine levels
    • Increased in cystathionine synthase deficiency
    • Decreased in methionine synthase deficiency and methylenetetrahydrofolate reductase deficiency

Treatment

  • Some patients respond to large doses of pyridoxine (vitamin B6).
  • Methionine synthase deficiency: high-methionine diet
  • Cystathionine synthase deficiency
  • Impaired affinity of cystathionine synthase for pyridoxal phosphate: high-cysteine diet
  • MTHFR deficiency: supplementation of folate