Homocystinuria caused by cystathionine -synthase (CBS) deficiency is characterized by developmental delay/intellectual disability, ectopia lentis and/or severe myopia, skeletal abnormalities (excessive height and length of the limbs), and thromboembolism. Expressivity is variable for all of the clinical signs. Two phenotypic variants are recognized, B6-responsive homocystinuria and B6-non-responsive homocystinuria. B6-responsive homocystinuria is typically, but not always, milder than the non-responsive variant. In the majority of untreated affected individuals, ectopia lentis occurs by age eight years. Individuals are often tall and slender with an asthenic ( marfanoid ) habitus and are prone to osteoporosis. Thromboembolism is the major cause of early death and morbidity. 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. Other features that may occur include: seizures, psychiatric problems, extrapyramidal signs such as dystonia, hypopigmentation, malar flush, livedo reticularis, and pancreatitis.
The cardinal biochemical features of homocystinuria are: markedly increased concentrations of plasma homocystine, total homocysteine, homocysteine-cysteine mixed disulfide, and methionine; increased concentration of urine homocystine; and reduced cystathionine -synthase (CBS) enzyme activity. Molecular genetic testing of CBS, the gene in which mutations result in homocystinuria caused by cystathionine -synthase deficiency, is clinically available.
Homocystinuria is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members is possible once the CBS mutations have been identified in the family. Prenatal testing is possible for fetuses at increased risk through measurement of CBS enzyme activity assayed in cultured amniocytes (but not in chorionic villi because this tissue has very low activity of the CBS enzyme); measurement of total homocysteine in cell-free amniotic fluid; and molecular genetic testing if both disease-causing alleles of an affected family member have been identified.