Homocystinuria due to Cystathionine Beta-Synthase Deficiency

CLINICAL CHARACTERISTICS

Homocystinuria (HCU) due to cystathionine beta-synthase (CBS) deficiency (HCU-CBS deficiency) is characterized by involvement of four major systems: the eye (ectopia lentis and/or severe myopia), skeletal system (excessive height, long limbs, osteoporosis, scoliosis, arachnodactyly, pes cavus, pectus excavatum or carinatum, and genu valgum), vascular system (thromboembolism), and central nervous system (developmental delay, intellectual disability, seizures, psychiatric and behavioral manifestations, and dystonia). In a symptomatic individual, one to all four of the systems can be involved; expressivity is variable for all the clinical manifestations. It is not unusual for a previously asymptomatic individual to present in adulthood or earlier with only a thromboembolic event that is often cerebrovascular. Other features that may occur include hypopigmentation of the skin and hair, malar flush, livedo reticularis, and pancreatitis. Thromboembolism is the major cause of early death and morbidity. Individuals with HCU-CBS deficiency can be vitamin B responsive, vitamin B nonresponsive, or partial responders to vitamin B. The clinical manifestations in those who are vitamin B responsive are typically (but not always) milder than individuals who are vitamin B nonresponsive.

DIAGNOSIS/TESTING: The diagnosis of HCU-CBS deficiency is established in a proband with biallelic pathogenic variants in identified by molecular genetic testing.

MANAGEMENT

Vitamin B (pyridoxine) therapy (in those who are vitamin B responsive); methionine-restricted diet; folic acid and vitamin B supplementation as needed; betaine therapy. Management of methionine-restricted diet and other targeted therapies per metabolic and dietary specialist to control the plasma homocysteine concentration and prevent thrombosis; treatment of ocular manifestations per ophthalmologist; management of scoliosis and kyphosis per orthopedist; treatment of pectus deformity as needed; management of low bone density per metabolic bone specialist; treatment of acute vascular event per vascular specialist; education regarding risk and manifestations of thrombosis; developmental and educational support; standard treatments of seizures per experienced neurologist; support in transition to adult care. Evaluation with a metabolic specialist and metabolic dietician; routine labs may include plasma total homocysteine and amino acids, folate, and vitamin B with frequency per metabolic specialist, and additional labs in those on a methionine-restricted diet; ophthalmology evaluation to evaluate for myopia and ectopia lentis at least annually; assess for long bone overgrowth and deformity, genu valgum, pes cavus, pectus deformity, kyphosis, scoliosis, and frequency of fractures at each visit; radiographs for scoliosis as needed; bone density scan every three to five years from adolescence and more frequently in those with frequent fractures and/or vitamin D deficiency; lipid profile once in childhood and annually in adulthood; monitor developmental and educational progress at each visit; neuropsychological testing and behavioral assessment as needed; assess for seizures, movement disorders, response to treatment, and for any new central nervous system manifestations at each visit or as needed; assess growth, quality of life, and social work and family needs at each visit. Oral contraceptives in affected females; surgery if possible; dehydration and immobilization; nitrous oxide. Plasma concentrations of total homocysteine and amino acids should be measured in at-risk sibs as soon as possible after birth so that morbidity and mortality can be reduced by early diagnosis and treatment. Evaluation of other at-risk sibs of any age is also warranted to allow for early diagnosis and treatment of homocystinuria. If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of sibs. Methionine-restricted diet, betaine; vitamin B for those who are vitamin B responsive. 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

HCU-CBS deficiency is inherited in an autosomal recessive manner. Because it is possible (though unlikely) that a parent of the proband has biallelic pathogenic variants and HCU-CBS deficiency but has remained undiagnosed, it is appropriate to measure plasma homocysteine concentration in each parent, obtain a detailed medical history, and consider clinical examination of the parents. If the parents are consanguineous and/or if suggestive features are present, further biochemical testing (typically plasma amino acid analysis) and/or genetic testing of the parent(s) is recommended. Evaluation of the mother becomes even more imperative if the mother is considering future pregnancies, as affected women are at increased risk for thromboembolic events during pregnancy. If a molecular diagnosis has been established in the proband, targeted analysis can be used to determine if the parents are heterozygous for the pathogenic variants identified in the proband (targeted testing for the pathogenic variants identified in the proband cannot be used to rule out the possibility that a parent has biallelic pathogenic variants). If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception 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. Once the pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members and prenatal/preimplantation genetic testing are possible.