All four causes of homocystinuria are inherited in an autosomal recessive fashion.
There are four forms of homocystinuria. They include cystathionine synthase deficiency, decreased affinity of cystathionine synthase for pyridoxal phosphate, methionine synthase deficiency, and methylenetetrahydrofolate reductase (MTHFR) deficiency.
Cystathionine synthase is an enzyme that catalyzes the reaction homocysteine to cystathionine. This enzyme uses the cofactor pyridoxal phosphate. A deficiency in this enzyme can cause accumulation of homocysteine in the blood and urine.
Homocystinuria can be caused by a decreased affinity of cystathionine synthase for vitamin B6 (in the form of pyridoxal phosphate) which is an essential cofactor in the reaction. Due to the decreased affinity, cystathionine synthase is unable to catalyze the reaction, leading to buildup of homocysteine in the blood and urine.
Methionine synthase, also called homocysteine methyltransferase, is responsible for regeneration of methionine from homocysteine. A deficiency of methionine synthase can cause a buildup of homocysteine in the blood and urine.
MTHFR is an enzyme in the folate cycle which catalyzes the conversion of 5,10-methylenetetrahydrofolate (THF) to 5-methyl THF. This is then used for pyrimidine synthesis. The folate cycle depends on homocysteine metabolism to function. MTHFR deficiency therefore leads to a build up on homocysteine, or homocystinuria.
Marfanoid habitus is used to describe a constellation of physical findings including tall stature, long limbs, spider like fingers, and hyperlaxity of joints. Associated conditions include Marfan syndrome, MEN2B, homocystinuria, and spontaneous pneumothorax.
Kyphosis is a condition of extreme curvature of the upper back. This pathologic curving of the spine can be seen in homocystinuria.
Eye anomalies are common in homocystinuria, especially lens subluxation. Lens subluxation in homocystinuria is characterized by an inferiorly displaced or malpositioned lens in the eyes. Contrast this with Marfan's syndrome, where there is superior lens subluxation.
Intellectual disability is characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors. It is common is individuals with homocystinuria.
An especially important cause of morbidity and mortality is vascular disease including atherosclerosis. Patients exhibit extensive atheroma formation at a young age. Almost one fourth of patients die before the age of 30 as a result of thrombotic complications.
While homocystinuria generally describes patients with a genetic disorder leading to elevated homocysteine levels, otherwise normal patients could also have elevated levels in certain circumstances. For example, people with low dietary intake of folate, vitamin B6 or B12 can have increased levels of homocysteine. Though these patients don't have the genetic enzyme deficiencies described in classical homocystinuria, they may still be at elevated risk for atherosclerosis.
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