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The prevalence of the disease varies widely depending on ethnicity and the method of ascertainment, from 1/300,000 in historical clinical descriptions, to 1/1800 in Qatar (highest prevalence in the world), and an estimated 1/17,800 in Germany by molecular genetic screening of a normal population.

Patients exhibit a spectrum of progressively appearing clinical manifestations, ranging from asymptomatic to severe, with one or multiple organ systems involved. Symptoms essentially affect four types of organ: eyes (ectopia lentis), skeletal system (high stature, marfanoid morphotype, skeletal deformations, osteoporosis), vascular system (arterial or veinous thromboembolism), and CNS (developmental delay, autism spectrum disorders, psychiatric disorders). The phenotype and severity of the disease are essentially defined by the degree of response to vitamin B6, the cofactor of the CBS enzyme.

The disease is caused by mutations in the CBS gene (21q22.3) leading to the accumulation of homocysteine and methionine, which are toxic for the endothelium, and causes neurocognitive impairment. Cysteine deficiency probably plays a role in connective tissue abnormalities, including lens dislocation.

The diagnosis is suspected in patients with increased plasma concentrations of total homocysteine (Hcyt) and methionine (Met), and confirmed by the identification of biallelic pathogenic variants in the CBS gene.

The spectrum of differential diagnosis is broad. Clinically, severe forms of CBS deficiency share certain clinical features with Marfan syndrome (FBN1 gene), and lens dislocations are associated with a number of malformative syndromes. The differential diagnoses of hyperhomocysteinemia include some acquired pathologies such as severe chronic renal failure, vitamin B12 or folate deficiency (which can be caused by certain treatments such as methotrexate, metformin, nitrous oxide) and inborn errors of vitamin B12 or folate metabolism.

Prenatal testing is possible if mutations have been identified in the index case.

The disease is autosomal recessive. At conception, each sib of heterozygous parents has a 25% risk of being affected.

There are currently three recognized modalities of treatment. For patients who are pyridoxine responsive, treatment includes pyridoxine only in pharmacological doses (maximum 500 mg/day) in combination with folic acid and vitamin B12 supplements if necessary. In pyridoxine nonresponsive individuals, the recommended treatment is a strict methionine-restricted diet in combination with pyridoxine in partial responders. Betaine anhydrous is a methyl donor that can be used as an adjunct to the diet.

The consequences of untreated, or partially treated, CBS deficiency include thromboembolic events, intellectual disability, ocular and skeletal manifestations. Untreated CBS patients showed that the risk of complications increases with age. The prognosis of patients treated from the neonatal period is good, with virtually complete prevention of all abnormalities. In late-treated patients, therapy aims at preventing thromboembolic events and further escalation of the complications.