The typical form of this aminoaciduria is inherited as an autosomal recessive trait and simulates Marfan disease. Tall, slender habitus; great length of limbs, sometimes scoliosis and arachnodactyly (long, spidery fingers and toes); thin and rather weak muscles; knock-knees; highly arched feet; and kyphosis are the typical skeletal features. Sparse, blond, brittle hair; malar flush; and livedo reticularis are common dermal manifestations, and a dislocation of one or both lenses (usually downward, in contrast to Marfan syndrome) may occur, imparting a tremulous appearance to the irides (iridodonesis). The only neurologic abnormality is mental retardation, usually of mild degree, which sets this syndrome apart from Marfan disease, in which intellect is unimpaired. Several mutations in CBS, the gene that codes for cystathionine beta-synthase is most often implicated but other mutations that affect the conversion of methionine to cysteine to or, less often, homocystine to methionine.
Blood vessel changes of thickening and fibrosis of the coronary, cerebral, and renal arteries tend to appear later in the illness. An abnormality of platelets favoring clot formation and thrombosis of cerebral arteries has been observed. Some patients have died of coronary occlusions during adolescence, and a myocardial lesion may be the source of emboli to cerebral arteries.
Homocysteine is elevated in the blood and CSF, and homocystine in the urine. This is because of an inherited cystathionine synthase deficiency that results in an inadequacy of cystathionine formation, a substance essential to many tissues including the brain. This may be the explanation of the developmental delay. Plasma methionine levels are also elevated. The infarcts in the brain are clearly related to thrombotic and embolic arterial occlusions. The administration of large doses (50 to 500 mg) of pyridoxine (a cystathionine synthase coenzyme), folate 5 mg daily and cobalamin (vitamin B12) 1,000 µg daily, reduces the excretion of homocystine. If vascular lesions have occurred, anticoagulants probably prevent further occlusions.
Homocysteinemia and homocystinuria may also be expressions of 5,10-methylenetetrahydrofolate reductase deficiency. Again, the clinical manifestations consist of multiple cerebrovascular lesions, dementia, epilepsy, and polyneuropathy. The last is believed to be caused by a coincidental folic acid deficiency, but in some cases it may have been caused by chronic phenytoin administration (Nishimura et al).
Much milder elevations of serum homocystine have been recognized as contributing to the risk of coronary disease and stroke in otherwise normal individuals.
Fabry Disease (Anderson-Fabry Disease, GLA Mutation) (See Also Chaps. 33 and 43)
This disease, also known as angiokeratoma corporis diffusum, is inherited as an X-linked recessive trait. It occurs in complete form in males and in incomplete form in female carriers. The primary deficit is in the enzyme alpha-galactosidase A, the result of which is the accumulation of ceramide trihexoside in endothelial, perithelial, and smooth muscle cells of blood vessels as well as in renal tubular and glomerular cells and other viscera and in nerve cells in many parts of the nervous system (hypothalamic and amygdaloid nuclei, substantia nigra, reticular and other nuclei of the brainstem, anterior and intermediolateral horns of the spinal cord, sympathetic and dorsal root ganglia).