CBS gene

Also known as: Classic homocystinuria; Homocystinuria with or without response to pyridoxine (B6); Homocystinuria due to cystathione beta-synthase deficiency; CBS deficiency


1. The disease:

Homocystinuria caused by cystathionine β-synthase (CBS) deficiency is characterized by involvement of the eye (ectopia lentis and/or severe myopia), skeletal system (excessive height, long limbs, scolioisis, and pectus excavatum), vascular system (thromboembolism), and CNS (developmental delay/intellectual disability).

2. The Symptoms:

Patients are normal at birth and, if left untreated, the disease course is progressive. Lack of early signs or symptoms does not exclude the diagnosis.

  • Eye anomalies include ectopia lentis (85% of the cases), with high myopia.
  • Skeletal changes include genu valgum and pes cavus, followed by marfanoid habitus, pectus excavatum or carinatum and kyphosis, or scoliosis and osteoporosis.
  • Thromboembolism, affecting both large and small arteries and veins, is the most striking cause of morbidity and mortality.
  • Intellectual disability is described; IQ in individuals with untreated homocystinuria ranges widely, from 10 to 138. In B6-responsive individuals the mean IQ is 79 versus 57 for those who are B6-non-responsive. Clinically significant psychiatric illness is found in 51% of cases. Other features that may occur include: seizures, psychiatric problems, extrapyramidal signs (e.g., dystonia), hypopigmentation of the skin and hair, malar flush, livedo reticularis, and pancreatitis.

3. Actions to take in case of early diagnosis:

  • Infants with a positive genetic test (having 2 pathogenic variants or 2 copies of a single pathogenic variant in the gene CBS) should continue breastfeeding and avoid baby formulas. Early treatment is essential in preventing chronic symptoms.
  • Biochemical correlation is essential for confirming diagnosis with plasma quantitative amino acids and homocysteine levels (Hcy). Biochemical NBS with tandem mass spectrometry can also help (can shows increased methionine).
  • Classic Homocystinuria is a lifelong disease that requires lifetime management and regular follow-up with a metabolic physician and dietician, a part from a multidisciplinary approach to care.
  • When diagnosed in the newborn infant, as ideally it should be, the aim of treatment must be to ensure the development of normal intelligence and prevent the development of other complications.
  • Treatment aims to correct the biochemical abnormalities, especially to control the plasma homocysteine concentrations and prevent thrombosis.
  • To maintain normal or near-normal plasma total homocysteine concentrations, vitamin B6 (pyridoxine) therapy (if shown to be B6 responsive), a methionine-restricted diet, and folate and vitamin B12 supplementation are used.
  • Betaine anhydrous is usually added to the therapeutic regimen; in adolescents and adults, betaine may be the major form of treatment, but it is preferable to remain on life-long metabolic diet.
  • Genetic counseling is highly recommended for family planning and evaluation of at-risk family members such as siblings.

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