Homocystinuria is a disorder of methionine metabolism, leading to an abnormal accumulation of homocysteine and its metabolites (homocystine, homocysteine-cysteine complex, and others) in blood and urine. Normally, these metabolites are not found in appreciable quantities in blood or urine. Homocysteinemia, a separate but related entity, is defined as elevation of homocysteine level in blood. This condition has also been referred to as homocyst(e)inemia to reflect metabolites that may accumulate. A mild elevation of plasma homocysteine may exist without homocystinuria.
The accumulation of homocysteine and its metabolites is caused by disruption of any of the 3 interrelated pathways of methionine metabolism—deficiency in the cystathionine B-synthase (CBS) enzyme, defective methylcobalamin synthesis, or abnormality in methylene tetrahydrofolate reductase (MTHFR).
Clinical syndromes resulting from each of these metabolic abnormalities have been termed homocystinuria I, II, and III. Three different cofactors/vitamins—pyridoxal 5-phosphate, methylcobalamin, and folate—are necessary for the 3 different metabolic paths.
The pathway, starting at methionine, progressing through homocysteine, and onwards to cysteine, is termed the transsulfuration pathway. Conversion of homocysteine back to methionine, catalyzed by MTHFR and methylcobalamin, is termed as the remethylation pathway. A minor amount of remethylation takes place via an alternate route using betaine as the methyl donor.
Homocysteinemia theoretically could be a result of defects at any of these 3 locations. These abnormalities could arise from a genetic predisposition or from genetic predisposition worsened by comorbid conditions and/or nutritional and environmental factors. These conditions and factors may be related to abnormal MTHFR, chronic renal failure, hypothyroidism, malignancies, methotrexate treatment, oral contraceptive use, consumption of animal proteins, and smoking.
An abnormal gene on chromosome 1 has been proposed as the cause of reduction in MTHFR; however, whether this mutation alone can lead to cerebrovascular events or whether it requires additional environmental or nutritional lack of folic acid to cause symptomatic homocysteinemia is unclear.[1]
Increased homocysteine level is associated with a higher risk of strokes. Carotid stenosis appears to have a graded response to increased levels of homocysteine. Increased carotid plaque thickness has been associated with high homocysteine and low B-12 levels. Yoo et al studied both intracranial and extracranial vessels by MR angiography and reported that homocysteine levels were higher in patients with 2- or 3-vessel stenoses than in those with 1-vessel stenosis.[2] In patients with baseline homocysteine level exceeding 9.1 umol/L, supplementation with B vitamins resulted in slowed progression of carotid intimal medial thickness (CIMT).
Several mechanisms have been suggested as the possible cause of accelerated vascular disease. These include (1) endothelial cell damage, (2) smooth muscle cell proliferation, (3) lipid peroxidation, (4) up-regulation of prothrombotic factors (XII and V), and (5) down-regulation of antithrombotic factors or endothelial-derived nitric oxide.
Incidence of homocystinuria is approximately 1 per 100,000.
Reported incidence of homocystinuria varies between 1 in 50,000 and 1 in 200,000.
Homocystinuria is associated with the following physical findings:
Acute stroke diagnosis and treatment requires that certain laboratory studies such as complete blood count, chemistries, prothrombin/activated partial thromboplastin times (PT/aPTT), brain imaging, echocardiography, and vascular studies be done to exclude the usual causes, some of which may be treatable or preventable.
A methionine-restricted diet is sometimes necessary if homocysteine is not controlled adequately by medications.
Homocystinuria: Patients may be divided into pyridoxine-sensitive and pyridoxine-insensitive groups. In the first group, pyridoxine, folic acid, and vitamin B-12 are prescribed. These 3 vitamins, in combination, reduce the homocysteine levels as well as provide clinical benefit. Secondary stroke prevention rests on risk factor reduction. Aspirin, clopidogrel, and aspirin-dipyridamole have been suggested for secondary stroke prophylaxis, but whether other antiplatelet agents or anticoagulation are equally or more effective is not known.
Homocysteinemia: No consensus exists on optimal approaches to the treatment of homocysteinemia.
Clinical Context: Cofactor for cystathionine B-synthase in transsulfuration pathway of methionine metabolism.
Clinical Context: Cofactor/precursor for methylene tetrahydrofolate reductase enzyme.
Clinical Context: Deoxyadenosyl-cobalamin and hydroxocobalamin are active forms of vitamin B-12.
Clinical Context: Promotes conversion of homocysteine to methionine via a minor pathway.
Early diagnosis of homocystinuria along with prophylactic medical and dietary care is a key to better long-term prognosis; it can halt or even reverse some of the complications.