Classical homocystinuria due to CBS deficiency

Homocystinuria is a rare autosomal recessive inherited metabolic disorder caused by a defect in an enzyme that converts homocysteine to cystathione. Cystathionine beta synthase results in accumulation of homocysteine in the blood and its excretion in urine.

The clinical manifestations of homocystinuria include developmental delay/intellectual disability, ectopia lentis and/or severe myopia, skeletal abnormalities (excessive height and length of the limbs), thromboembolism and severe premature atherosclerosis.

Less marked rises in the plasmatic homocysteine are much more frequent and are present in about 5- 7% of the population. Although it is not associated with the clinical stigmas of homocystinuria, growing evidence suggests that moderate hyperhomocysteinemia is an independent risk factor for vascular atherosclerosis and recurrent venous thromboembolism.

Higher concentration levels of plasmatic homocysteine can occur due to genetic defects in the enzymes implicated in homocysteine metabolism, nutritional deficiencies in vitamin cofactors or with other factors including some chronic and medicinal medical conditions. Some medicines used in hypercholesterolemia such as fibrates and nicotinic acid can elevate homocysteine levels in approximately a 30%; however the clinical significance of this is uncertain. Smoking can also raise the levels of homocysteine and chronic renal insufficiency owing to the decrease in renal elimination and metabolic disorders caused.


This is the most frequent of the methionine metabolisms. Neonatal screening is carried out world-wide with a prevalence of cases between 1 in 200,000 and 1 in 350,000. The disorder appears to be more frequent in New South Wales (Australia) (1 in 60,000) and Ireland. Early treatment of patients identified by screening programs has produced favorable results.

Homocystinuria is an inherited autosomal recessive disorder. The cystathionine beta synthase gene is located on the chromosome 21q22.3 and the majority of the patients are heterozygous for the two different alleles. The heterozygous carriers are usually asymptomatic; thromboembolism and cardiomyopathy are more frequent in this group than in the general population.


Infants with this disorder are normal at the moment of birth. The clinical manifestations during infancy are non-specific and include a failure to grow and gain weight at the expected rate and have developmental delays. By approximately age three, additional, more specific symptoms and findings may become apparent. These may include partial dislocation (subluxation) of the lens of the eyes (ectopia lentis), associated "quivering" (iridodonesis) of the colored region of the eyes (iris), severe nearsightedness (myopia), and other eye (ocular) abnormalities. Progressive mental retardation is frequent although intelligence may be normal in some cases.

Patients with homocystinuria have skeletal problems similar to those of Marfan syndrome: they are generally tall and have long, thin arms and legs and spider-like fingers (arachnodactyly).

In addition, affected individuals may have scoliosis, pectus excavatum or carinatum (chest sinks in or sticks out), genu valgum (knock-knee condition), pes cavus (high arched foot), high-arched palate and crowded teeth. Frequently, these individuals have pale skin, blue eyes and malar flush. Generalized osteoporosis, especially on the spinal column, constitutes the principal X-ray finding.

There are often venous thromboembolic events affecting small and large blood vessels, especially those in the brain, and that can happen at any age. Optic atrophy, paralysis, pulmonary heart disease and severe high blood pressure (owing to renal disease) are among the serious consequences of the thromboembolic events caused by alterations in the vascular walls and an increase in the platelet stickiness secondary to the rise in homocysteine concentration.

The increase in the body fluids in methionine as well as in homocysteine is a diagnostic analytic finding. An analysis of recently excreted urine should be analyzed since to detect the presence of homocysteine since this substance is unstable and tends to disappear when storing the urine. Cysteine concentrations are low or absent in the plasma.


It is possible to carry out a prenatal diagnosis by a cultivated enzymatic analysis of amniotic cells or chorionic villus or by DNA analysis.

Response or no response to pyridoxine (vitamin B6)

Approximately 40% of the patients respond to treatment with elevated doses of vitamin B6 and tend to have lighter manifestations than those who do not respond to B6 treatments. These patients have a somewhat residual enzymatic activity.

The degree of response to vitamin B6 can be different in the different families affected. Some patients do not respond owing to a folate depletion. A patient should not be considered non-responsive to vitamin B6 treatment until folate acid has been added to the therapeutic regimen.

In those individuals that do not respond to vitamin B6 treatment, a restriction of methionine intake, together with the administration of cysteine, is recommended. In some cases of this variant, the addition of betaine eliminates the necessity of a restrictive diet. Betaine reduces the homocysteine concentrations in the body fluids by homocysteine remethylation to methionine which results in a greater rise of plasmatic methionine. This treatment achieves a clinical improvement (avoids vascular events) in patients that are non-responsive to vitamin B6.

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