Classic homocystinuria (cystathionine beta-synthase [CBS] deficiency)

Page most recently updated 7 September 2026

This page focuses on the reported psychiatric associations, which may be the initial presenting manifestation, and on other clinical features that may assist the psychiatrist or primary care physician in identifying the underlying diagnosis, considered through the lenses of the diagnostic lenses framework.

Classic homocystinuria (cystathionine beta-synthase [CBS] deficiency) is a rare inherited metabolic disorder. It is inherited in an autosomal recessive manner, with affected individuals having pathogenic variants in both copies of the CBS gene. Absence of a relevant family history does not exclude the diagnosis. The phenotype may resemble Marfan syndrome and Lujan syndrome (formerly Lujan-Fryns syndrome), particularly in its tall, slender habitus, long limbs, and long fingers, but these conditions are genetically distinct. Classic homocystinuria is particularly associated with intellectual and developmental impairment, ectopia lentis, thromboembolic disease, and markedly elevated plasma homocysteine. A distinctive presentation may include the combination of tall, slender habitus, long limbs and fingers, ectopia lentis, and thromboembolic disease.

It can present with psychiatric features such as anxiety, depression, ADHD, sleep disturbance, anger or aggression, and other behavioral manifestations. Psychotic symptoms have also been reported, although they appear to be uncommon. Cognitive impairment, developmental delay, and speech and language difficulties may occur, particularly in individuals with untreated disease. The neuropsychiatric phenotype is variable and may be influenced by the severity and duration of metabolic disease and by treatment status.

From a morphologic lens perspective, other features include (but are not limited to):

  • Long fingers

Other characteristic features include ectopia lentis, severe myopia, osteoporosis, and skeletal abnormalities, including scoliosis, pectus deformities, genu valgum, pes cavus, and an increased tendency to fractures. Thromboembolic disease is particularly important and may involve the cerebral, pulmonary, or peripheral vascular systems. Neurologic manifestations may include seizures/epilepsy, developmental delay, intellectual impairment, dystonia, and other movement abnormalities, as well as neurologic deficits following thromboembolic events. Additional reported features include hypopigmentation of the skin and hair, malar flushing, livedo reticularis, and pancreatitis.

Early diagnosis is important to identify and treat a potentially serious but treatable metabolic disorder, reduce the risk of thromboembolic events, and monitor ocular, skeletal, neurologic, developmental, and psychiatric complications. Treatment may include pyridoxine (vitamin B6) in responsive individuals, a methionine-restricted diet, folate and vitamin B12 supplementation when indicated, and betaine therapy, under the care of a metabolic specialist.

Selected references and further reading — Morphologic lens

Jones KL, Jones MC, del Campo M. Smith's recognizable patterns of human malformation. 8th ed. Philadelphia: Elsevier; 2021.

Reardon W. The bedside dysmorphologist: a guide to identifying and assessing congenital malformations. 2nd ed. Oxford: Oxford University Press; 2016.

Allanson JE, Biesecker LG, Carey JC, Hennekam RCM. Elements of morphology: introduction. Am J Med Genet A. 2009;149A(1):2-5. doi:10.1002/ajmg.a.32601.

Hennekam RCM, Biesecker LG, Allanson JE, Hall JG, Opitz JM, Temple IK, Carey JC; Elements of Morphology Consortium. Elements of morphology: general terms for congenital anomalies. Am J Med Genet A. 2013;161A(11):2726-2733. doi:10.1002/ajmg.a.36249.