Classical homocystinuria due to CBS deficiency

Homocysteine is an intermediate amino acid formed by the conversion of methionine to cysteine. Alterations in the genes involved in its metabolism can lead to the accumulation of homocysteine which is detrimental to our organism. Classical homocystinuria due to CBS deficiency is the most frequent congenital alteration of methionine metabolism and affects the CBS gene that codes for the enzyme cystathionine beta-synthase. Alterations in CBS can lead to increased homocysteine concentration in body fluids, known as homocystinuria or hyperhomocysteinemia, which can trigger a series of vascular and neurological complications ranging from mild to severe depending on how affected the enzyme activity is.

The worldwide prevalence of homocystinuria is estimated to range from 1 case per 200,000 population to 1 case per 350,000 population. However, it is most common in New South Wales, Australia (1/60,000), Ireland (1/65,000), Germany (1/17,800) and Qatar (1/1,800).

Infants with homocystinuria are normal at birth and symptoms, which appear during infancy, are nonspecific and include growth and developmental delay. The diagnosis is usually made after the third year of life, when bilateral lens subluxation or displacement occurs. Other symptoms such as astigmatism, glaucoma, staphyloma, cataracts, retinal detachment and optic atrophy appear later. Progressive mental retardation is common, although cases with normal intelligence have been reported.

Approximately 50% of patients have skeletal abnormalities reminiscent of Marfan syndrome (tall and thin, with elongated limbs), and other features such as long, curved fingers, scoliosis and joint laxity. Thromboembolic episodes are frequent.

Half of the patients usually respond to treatment with high doses of pyridoxine (vitamin B6) and have milder symptoms than those who do not respond to treatment. The response will depend on the effect of the mutation on the enzymatic activity of CBS or cystathionine beta-synthase.

In people with homocystinuria who do not respond to vitamin B6, restriction of dietary methionine intake is recommended, together with the administration of cysteine. In some cases, the addition of betaine obviates the need for a restrictive diet. This treatment achieves clinical improvement (avoidance of vascular episodes) in patients insensitive to vitamin B6.