Adult Summary Report Secondary Findings in Adult Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening A Current Version Rule-Out Dashboard Release History Status (Adult): Passed (Consensus scoring is Complete) Curation Status (Adult): Released

Condition: Homocystinuria due to Cystathionine Beta-Synthase Deficiency
Mode(s) of Inheritance: Autosomal Recessive
Actionability Assertion
Gene Disease Pairs(s)
Final Assertion
CBS0009352 (classic homocystinuria)
Assertion Pending
Actionability Rationale
This report was generated prior to the implementation of the process for making actionability assertions. An actionability assertion will be made, but may take time due to the substantial backlog of topics that need assertions.
Final Consensus Scoresa
Outcome / Intervention Pair
Nature of the
Gene Disease Pairs: CBS 0009352 (OMIM:236200)
Pyridoxine Responsive: Thromboembolism / Dietary modifications (includes pyridoxine, methionine-restriction, betaine, folate, and B12 supplements)
Pyridoxine Responsive: Thromboembolism / Prophylactic anti-coagulation in pregnancy
Pyridoxine Responsive: Systemic manifestations (includes CNS disease, skeletal findings, and ocular findings) / Dietary modifications (includes pyridoxine, methionine-restriction, betaine, folate, and B12 supplements)
Pyridoxine Non-Responsive: Thromboembolism / Dietary modifications (includes pyridoxine, methionine-restriction, betaine, folate, and B12 supplements)
Pyridoxine Non-Responsive: Thromboembolism / Prophylactic anti-coagulation in pregnancy
Pyridoxine Non-Responsive: Systemic manifestations (includes CNS disease, skeletal findings, and ocular findings / Dietary modifications (includes pyridoxine, methionine-restriction, betaine, folate, and B12 supplements)

Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
Prevalence estimates for homocystinuria due to cystathionine beta-synthase (CBS) deficiency range from 1/200,000 to 1/344,000. However, these estimates are based on newborn screening and clinical ascertainment and are likely underestimates due to undetected cases. A recent systematic review estimated of the prevalence as about 1/120,000 worldwide.
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Clinical Features
(Signs / symptoms)
Homocystinuria due to CBS deficiency is a disorder of methionine metabolism. There are two recognized phenotypic variants: B₆-responsive and B₆-non-responsive. B₆-responsive is typically, but not always, milder with a later age of onset than B₆-non-responsive. In general, homocystinuria is characterized by involvement of four systems:
• Ocular system: Ectopia lentis is a hallmark feature. Severe myopia may also be present either in the presence or absence of ectopia lentis.
• Skeletal system: Patients may have skeletal abnormalities such as excessive height and limb length. Affected individuals are often tall and slender with a 'marfanoid' habitus, and are prone to osteoporosis.
• Vascular system: The cardinal vascular sign is thromboembolism which can affect both small and large arteries and veins.
• Central nervous system (CNS): Intellectual disability/developmental delay is the most common CNS manifestation. Though IQ can range widely from 10 to 138. Seizures, extrapyramidal signs (e.g., dystonia) and psychiatric problems (e.g, depression, obsessive-compulsive disorder) may also occur.
Some patients have been reported to have a milder form of homocystinuria, which is characterized by an increased risk for thrombotic events in young adulthood, but without the other ocular, skeletal, or nervous system manifestations.
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Natural History
(Important subgroups & survival / recovery)
In general, patients appear normal at birth but have a progressive disease course if untreated. Clinical features typically manifest in the first or second decade of life. Intellectual disability may be the first recognizable sign and may present as developmental delay after the first to second year of life. Myopia typically occurs after age one with the majority of untreated individuals developing ectopia lentis by age 8. Roughly half of patients show signs of osteoporosis by their teens. Cerebrovascular events typically manifest during young adulthood, though they have been reported earlier. Thromboembolism is the major cause of early death and morbidity. Among B₆-responsive individuals, a vascular event in adolescence or adulthood is often the presenting feature. Pregnancy often increases the risk of thromboembolisms, especially in the post-partum period. However, most pregnancies are uncomplicated.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet to help clinical decision-making following newborn screening:
To establish the extent of disease and needs in all individuals diagnosed with homocystinuria caused by CBS deficiency, the following are recommended:
• Pyridoxine (vitamin B₆) challenge prior to treatment to determine B₆-responsiveness
• Medical genetics consultation. (Tier 4)
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In B₆-responsive patients, treatment with pyridoxine should be given. Pyridoxine may also be included in treatment despite evidence of B₆-non-responsiveness. For those that are responsive to pyridoxine, it remains debatable as to whether pyridoxine alone or in combination with other measures provides the optimal biochemical control. (Tier 4)
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Dietary modifications:
• B₆-non-responsive and most B₆-responsive patients require a methionine-restricted diet which should be continued indefinitely. Dietary treatment reduces methionine intake by restricting natural protein intake. To prevent protein malnutrition, a methionine-free amino acid formula supplying the other amino acids including cysteine is provided. This diet is often not tolerated if begun in mid-childhood or later. This diet has been shown to normalize plasma homocysteine levels and prevent clinical manifestations when initiated neonatally. When initiated in late detected cases in whom clinical disease may already be present, no reversal of abnormalities present have been noted, but further progression of complications seems to be halted or ameliorated. In a study of 629 patients, B₆-nonresponsive patients identified neonatally who were administered a methionine-restricted diet had higher IQs and retarded rate of lens dislocation compared to late-detected B₆-nonresponsive patients who were not administered a methionine-restricted diet. Further, patients with both neonatal and late-detected patients had lower rates of thrombotic events then expected without treatment. In a second study, B₆-nonresposive patients diagnosed at birth and compliant with treatment had a full-scale IQ of 105.8 (range 84-120) while the poorly compliant group had a mean full-scale IQ of 80.8 (range 40-103). (Tier 4)
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• Betaine, which converts homocysteine to methionine, may be added to the treatment regimen in individuals poorly compliant with dietary treatment or may become the major treatment modality in those intolerant of the diet. Betaine supplementation has been shown to substantially reduce homocysteine concentrations when among 5 B₆-non-responsive individuals who could not attain metabolic control on diet. (Tier 3)
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• Supplementation with folate and vitamin B₁₂ is recommended to optimize the conversion of homocysteine to methionine by methionine synthase, thus helping to decrease homocysteine concentrations. (Tier 1)
• In a study of 32 patients receiving treatment with pyridoxine, folic acid, and vitamin B₁₂: 17 B₆-reponsive patients maintained plasma total free homocysteine levels <20μmol/L over an average treatment period of 16.6 years, while 15 B₆-non-responsive (who also received betaine) maintained low plasma total free homocysteine levels over an average period of 11 years (mean = 33±17 μmol/L). There were 2 vascular events in B₆-reponsive group, compared to 11 expected based on rates among untreated patients. There were no vascular events in the B₆-non-responsive group, compared to 10 expected. (Tier 3)
• A study of 5 patients with good control of plasma homocysteine through pyridoxine, diet, betaine, and folic acid reported that all patients had bone mineral densities within the normal range with no significant change in skeletal morphology. (Tier 5)
Because women with homocystinuria may be at greater than average risk for thromboembolism, especially post-partum, prophylactic anticoagulation during the third trimester of pregnancy and post-partum is recommended. Maternal homocystinuria does not have a major teratogenic potential. However, treatment with pyridoxine and/or methionine-restricted diet should be continued during pregnancy. Betaine may also be continued. The exact the risk of a thromboembolism event during pregnancy and post-partum is unclear, as the evidence of fatal and near-fatal thromboembolic events in untreated women is limited to single case studies. The evidence for the effectiveness of anticoagulants is also limited. The largest study to date reported 15 pregnancies in 11 women, where 2 of the 5 pyridoxine non-responsive and 3 of the 6 pyridoxine responsive cases were administered anticoagulants. Of the 15 pregnancies, there was only one thrombotic event (superficial thrombophlebitis of the leg) in a pyridoxine responsive case not administered anticoagulants. The remaining evidence includes case studies of women treated with dietary modification (including protein-restriction, pyridoxine, vitamin B12, and betaine) and anticoagulants during pregnancy reported good maternal and fetal outcomes However, additional case studies report thrombotic events even after anticoagulant therapy. (Tier 3)
Affected individuals should be monitored at regular intervals to detect any clinical complications to allow appropriate therapy to be given as soon as possible (Tier 4)
Plasma total homocysteine and methionine concentrations should be monitored in all persons receiving betaine. (Tier 4)
Circumstances to Avoid
Oral contraceptives, which may tend to increase coagulability and increase the risk for thromboembolism, should be avoided in females with homocystinuria. (Tier 4)
Surgery should be avoided, if possible, due to the increase in homocysteine concentrations during surgery and post-surgery which increases the risk for a thromboembolic event. If surgery is required, intravenous fluids at 1.5 times maintenance should be administered before, during, and after surgery until oral fluids are taken, with close monitoring to avoid fluid overload. (Tier 4)
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Recessive
Prevalence of Genetic Variants
Most individuals worldwide are compound heterozygotes for novel pathogenic variants of CBS. No overall estimate of CBS mutation prevalence was found, though this estimate would be expected to be similar to the prevalence of homocystinuria due to CBS deficiency (estimates range from 1/120,000 to 1/344,000). (Tier 3)
(Include any high risk racial or ethnic subgroups)
Among untreated homocystinuria patients, age-related penetrance estimates are:
Ectopia lentis (by age 10): B₆-responsive=55%, B₆-nonresponsive=82%
Vascular event (by age 15): B₆-responsive=12%, B₆-nonresponsive=27%
Spinal osteoporosis (by age 15): B₆-responsive=36%, B₆-nonresponsive=64%
Mortality (by age 30): B₆-responsive=4%, B₆-nonresponsive=23%
In addition, 51% of patients will have clinically significant psychiatric disorders, and 21% will have seizures if untreated. (Tier 3)
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Relative Risk
(Include any high risk racial or ethnic subgroups)
No information on relative risk was found.
The clinical picture is extremely heterogeneous with clinical findings ranging from multiple organ disease to individuals with no overt clinical involvement. (Tier 4)
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4. What is the Nature of the Intervention?
Nature of Intervention
Pyridoxine usually has no side effects when used in recommended doses. Sensory neuropathy and ataxia has been reported in some adults with misuse of megadoses, though symptoms improved with withdrawal of pyridoxine.
Betaine has few side effects, and the increase in methionine produced is usually harmless. Some individuals develop a detectable body odor resulting in reduced compliance. Cerebral edema has occurred with extreme hypermethioninemia, resolved with discontinuation of betaine.
A methionine-restricted diet may be burdensome, especially if begun in mid-childhood or later.
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5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Most cases of B₆-non-responsive homocystinuria due to CBS deficiency are identified by newborn screening. However, milder B₆-responsive cases are preferentially missed given they rarely have elevated levels of methionine during the first two to three days of life. (Tier 3)
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Gene Disease Associations
Disease Associations
OMIM Identifier
Primary MONDO Identifier
Additional MONDO Identifiers
Reference List
1. JD Picker, HL Levy. Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency. 2004 Jan 15 [Updated 2014 Nov 13]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from:
2. Moorthie S, Cameron L, Sagoo GS, Bonham JR, Burton H. Systematic review and meta-analysis to estimate the birth prevalence of five inherited metabolic diseases. J Inherit Metab Dis. (2014) 37(6):889-98.
3. Yap S. Homocystinuria due to cystathionine beta-synthase deficiency. (2005) Accessed: 2016-02-09. Website:
4. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. HOMOCYSTINURIA DUE TO CYSTATHIONINE BETA-SYNTHASE DEFICIENCY. MIM: 236200: 2016 Aug 03. World Wide Web URL:
5. Wilcken DE, Wilcken B. The natural history of vascular disease in homocystinuria and the effects of treatment. J Inherit Metab Dis. (1997) 20(2):295-300.
6. Lim JS, Lee DH. Changes in bone mineral density and body composition of children with well-controlled homocystinuria caused by CBS deficiency. Osteoporos Int. (2013) 24(9):2535-8.
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