Clinical characteristics: 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). All four ‒ or only one ‒ of the systems can be involved; expressivity is variable for all of the clinical signs. It is not unusual for a previously asymptomatic individual to present in adult years with only a thromboembolic event that is often cerebrovascular. Two phenotypic variants are recognized, B6-responsive homocystinuria and B6-non-responsive homocystinuria. B6-responsive homocystinuria is usually milder than the non-responsive variant.
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 (e.g., dystonia), hypopigmentation of the skin and hair, malar flush, livedo reticularis, and pancreatitis.
Diagnosis/testing: The cardinal biochemical features of homocystinuria include markedly increased concentrations of plasma total homocysteine and methionine. The diagnosis can be substantiated by detection of biallelic pathogenic variants in CBS, the gene encoding cystathionine β-synthase.
Management: Treatment of manifestations: Treatment aims to correct the biochemical abnormalities, especially to control the plasma homocysteine concentrations and prevent thrombosis. Complications of homocystinuria should be managed appropriately; e.g., by surgery for ectopia lentis.
Prevention of primary manifestations: Individuals are treated to maintain normal or near-normal plasma total homocysteine concentrations using vitamin B6 (pyridoxine) therapy (if shown to be B6 responsive), a methionine-restricted diet, and folate and vitamin B12 supplementation. Betaine therapy 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.
Surveillance: Affected individuals should be monitored at regular intervals to detect any clinical complications that may develop, for dietary compliance and for measurement of plasma total homocysteine and amino acids.
Agents/circumstances to avoid: Oral contraceptives in affected females. Surgery if possible. If surgery is required, intravenous fluid with 5% dextrose in 0.5 normal saline at 1.5 times maintenance should be given and continued until oral fluids are taken ad lib, with close monitoring to avoid fluid overload.
Evaluation of relatives at risk: Measurement of total homocysteine and amino acids in at-risk sibs immediately after birth ensures reduction of morbidity and mortality by early diagnosis and treatment. If the CBS pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of sibs
Pregnancy management: For women with classic homocystinuria: dietary treatment and betaine, and vitamin B6 for those B6 responsive, with careful biochemical monitoring throughout pregnancy. Prophylactic anticoagulation with low molecular-weight heparin is recommended during the third trimester and post partum to reduce risk of thromboembolism.
Genetic counseling: 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 and prenatal testing for a pregnancy at increased risk are possible if the CBS pathogenic variants have been identified in an affected family member.
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