The MONDO definition describes homocystinuria as autosomal recessive and as arising from abnormalities in methionine metabolism associated with deficiency of cystathionine synthase, resulting in accumulation of homocysteine. The packet does not certify a specific gene list for this disease entry, so no individual genes are named here. According to expert review, homocystinuria due to cystathionine beta-synthase deficiency is inherited in an autosomal recessive manner, and the parents of an affected individual are typically heterozygous carriers of a pathogenic variant.

The cause described here applies to the cystathionine beta-synthase deficiency form covered by the review; remethylation disorders are described there as distinct conditions.

According to expert review, homocystinuria due to cystathionine beta-synthase deficiency may be suspected from characteristic clinical findings or from an out-of-range newborn screening result. Newborn screening is primarily based on dried blood spots collected between 24 and 72 hours after birth, with methionine concentration typically quantified by tandem mass spectrometry. In the United States most newborn screening laboratories set their own cutoffs for out-of-range results, and actual state programs vary.

After an elevated methionine result, the review describes further evaluation by a repeat dried blood specimen followed by plasma total homocysteine and plasma amino acid analysis, or by direct quantitative plasma amino acid analysis together with plasma total homocysteine. Because newborn screening detects methionine rather than homocysteine, disorders of remethylation, in which methionine is reduced or normal, may not be detected. Virtually all infants detected by newborn screening are described as vitamin B6 nonresponsive.

Vitamin B6 responsiveness is described as determined by a pyridoxine challenge test. The review lists Marfan syndrome as the condition that most closely mimics this disorder, sharing a tall thin habitus, arachnodactyly, and predisposition to ectopia lentis and myopia.

According to expert review, the goal of targeted therapy in homocystinuria due to cystathionine beta-synthase deficiency is to reduce plasma homocysteine concentration and reduce the risk of complications such as thrombosis. Measures described include vitamin B6 therapy in individuals shown to be vitamin B6 responsive, a methionine-restricted diet, and folate and vitamin B12 supplementation. Betaine therapy is described as usually added to the regimen; in adolescents and adults it may be the major form of treatment, though the review describes a life-long methionine-restricted diet as preferable alongside it. In individuals who have already had a vascular event, betaine therapy alone is described as possibly preventing recurrent events.

The packet lists one current FDA-approved product for homocystinuria, Cystadane (betaine), approved through a new drug application reviewed by CDER and first approved in 1996, with an active market status. Several other products carry FDA orphan drug designations for homocystinuria, including an mRNA-based therapy, an engineered bacterial probiotic, enzyme-based therapies, and taurine. An orphan designation is not an approval and does not by itself indicate that a product is in development.

The review also describes post-diagnosis evaluations and ongoing surveillance spanning metabolic and nutritional laboratory measures, eye examinations, skeletal assessment, cardiovascular risk factors, development, and neurobehavioral features, with timing set by treating specialists.

The packet does not certify a natural history field for this disease entry. According to expert review of the cystathionine beta-synthase deficiency form, thromboembolism is the major cause of morbidity and early death and can affect any vessel. Expressivity is variable for all clinical manifestations, and manifestations in vitamin B6-responsive individuals are typically, but not always, milder than in vitamin B6-nonresponsive individuals. The review also notes that previously asymptomatic individuals can first present in adulthood or earlier with only a thromboembolic event. Outcomes for any individual are not predicted by this descriptive summary.

Several certified active clinical trial records are present for this condition, with sponsors including an industry developer of an enzyme therapy and academic groups studying supplementation, quality of life, and expanded newborn screening. Active clinical trials for this condition are listed on ClinicalTrials.gov.