Homocystinuria is a genetic disorder (autosomal recessive) in which the body cannot process amino acids, caused by mutations in the CBS, MTHFR, MTR, and MTRR genes.
Usually, the CBS gene mutation is the cause of homocystinuria. The CBS gene is responsible for the formation of cystathionine beta-synthase, which is responsible for the processing of methionine. Other amino acids, including homocysteine, also are produced via this pathway. This prevents the appropriate utilization of homocysteine, and it, along with other potentially toxic substances, accumulates in the blood.
The other gene mutations (MTHFR, MTR, and MTRR) also lead to homocysteine accumulation, because the enzymes made by these genes are necessary to convert homocysteine back to methionine. This is most commonly caused by an absence of cystathionine beta-synthase (1 in 200,000-335,000 worldwide have this form of homocystinuria). This form results in dislocation of the eye lens, an increased risk of abnormal blood clots, and skeletal abnormalities. Sometimes people with this form of homocystinuria also have issues with development and learning.
Less common forms of homocystinuria result in intellectual disability, seizures, problems with movement, and megaloblastic anemia. People with one mutated copy of the CBS gene and one normal copy do not have homocystinuria, but they are at increased risk for vitamin B12 and folate deficiencies.
Mental retardation is a serious consequence of the disease. Other symptoms include:
·High foot arches
·A tall/thin build
No treatment for homocystinuria exists. The goal of therapy is to treat the acidosis and reverse catabolism. A high-calorie, low-protein diet is recommended. Hydroxycobalamin intramuscular injections (1 milligram [mg] every 1-3 days in responsive individuals) often are given. High doses of vitamin B6 help, at most, slightly less than half of all patients.
Responders will need to take vitamin B6 supplements for the duration of their life, and those who do not respond need to eat a low-methionine diet that is supplemented with L-cysteine, which becomes an essential amino acid in homocysteinemia. All patients with homocysteinemia should receive treatment with pyridoxine at 25-100 mg/day for 4 weeks before the methionine-restricted diet is prescribed. Older children and adults should receive 1 gram/day to test for responsiveness. If plasma metabolic equivalent (MET) and homocysteine levels are reduced, the dosage is decreased until the minimum requirement to meet biochemical response is found. It is necessary to stop vitamin B6 administration if it is not helpful, because it can lead to rhabdomyolysis and peripheral neuropathy.
A normal dose folic-acid supplement also is regularly prescribed for people with low plasma levels. Choline is sometimes supplemented, depending on the primary defect. Gastrostomy tube placement for feeding is frequently necessary.
A high-protein diet is prescribed, at least initially, because requirements increase when L-amino acids supply the majority of protein equivalent. It is very important that people with homocystinuria do not fast for longer than overnight without a dextrose-containing IV. Most people with homocystinuria are prescribed trimethylglycine, which blunts plasma homocysteine response to meals.
Blood and urine screening, genetic testing, liver biopsy, liver enzyme assay, skeletal X-ray, skin biopsy with a fibroblast culture, and ophthalmic exams are common tests. MET concentration ≥1 mg/deciliter (dL) by bacterial inhibition assay or positive urine nitroprusside-cyanide test requires differential diagnosis.
Progression of homocystinuria
The progression of homocystinuria is variable. Some people have much more severe symptoms and a faster disease progression than others.
References and recommended readings
Acosta PB, Yannicelli S. Ross Metabolic Formula System Nutrition Support Protocols. 4th ed. Columbus, OH: Abbott Laboratories; 2001:137-151.
Adams D, Venditti CP. Disorders of intracellular cobalamin metabolism. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=cblAccessed October 31, 2010.
MedlinePlus. Homocystinuria. Available at: http://www.nlm.nih.gov/medlineplus/ency/article/001199.htmAccessed October 31, 2010.
US National Library of Medicine. Homocystinuria. Available at: http://ghr.nlm.nih.gov/condition/homocystinuriaAccessed October 31, 2010.
Review Date 1/11