Homocystinuria (HCU) is an inherited disorder of the metabolism of the amino acid methionine due to a deficiency of cystathionine beta synthase or methionine synthase. It is an inherited autosomal recessive trait, which means a child needs to inherit a copy of the defective gene from both parents to be affected. Symptoms of homocystinuria can also be caused by a deficiency of vitamins B<sub>6</sub>, B<sub>12</sub>, or folate.

  • Flush across the cheeks
  • Musculoskeletal
  • Tall, thin build resembling Marfanoid habitus or subluxation of lens
  • Myopia (nearsightedness)
  • Glaucoma
  • Optic atrophy
  • Retinal detachment
  • Cataracts
  • Vascular disease
  • Homocysteine binds to the endothelium of the blood vessels and activate signaling pathways leading to the release of pro-inflammatory molecules. This may cause the following :
  • Extensive atheroma formation at a young age which affects many arteries but not the coronary arteries
  • Intravascular thrombosis

Cause

It is usually caused by the deficiency of the enzyme cystathionine beta synthase, Additionally, organic acid analysis or quantitative determination of methylmalonic acid should help to exclude cobalamin (vitamin B<sub>12</sub>) defects and vitamin B<sub>12</sub> deficiency giving a differential diagnosis.

The laboratory analysis of homocysteine itself is complicated because most homocysteine (possibly above 85%) is bound to other thiol amino acids and proteins in the form of disulphides (e.g., cysteine in cystine-homocysteine, homocysteine in homocysteine-homocysteine) via disulfide bonds. Since as an equilibrium process the proportion of free homocysteine is variable a true value of total homocysteine (free + bound) is useful for confirming diagnosis and particularly for monitoring of treatment efficacy. To this end it is prudent to perform total homocyst(e)ine analysis in which all disulphide bonds are subject to reduction prior to analysis, traditionally by HPLC after derivatisation with a fluorescent agent, thus giving a true reflection of the quantity of homocysteine in a plasma sample.

Treatment

No specific cure has been discovered for homocystinuria; however, many people are treated using high doses of vitamin B<sub>6</sub> (also known as pyridoxine). Slightly less than 50% respond to this treatment and need to take supplemental vitamin B<sub>6</sub> for the rest of their lives. Those who do not respond usually respond to supplementation with folic acid and trimethylglycine (betaine).

Prognosis

The life expectancy of patients with homocystinuria is reduced only if untreated. It is known that before the age of 30, almost one quarter of patients die as a result of thrombotic complications (e.g., heart attack).

Society and culture

One theory suggests that Akhenaten, a pharaoh of the eighteenth dynasty of Egypt, may have had homocystinuria.

See also

  • Cystinuria
  • DNA methylation
  • Hyperhomocysteinemia

References

Further reading

  • GeneReview/NIH/UW entry on Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency