Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released 2.0.0
• Status (Pediatric): Passed (Consensus scoring is Complete)
• GENE/GENE PANEL: CBS
• Condition: Cystathionine Beta-Synthase Deficiency
• Mode(s) of Inheritance: Autosomal Recessive

Actionability Assertion

• CBS ⇔ 0009352 (classic homocystinuria): Moderate Actionability

Actionability Rationale

A small majority of experts supported an assertion of moderate based on the unclear effectiveness of these interventions in an unselected adult-diagnosed population. Treatment would be based on homocysteine level rather than solely on molecular findings thus overtreatment should be avoided.

Final Consensus Scores

Gene Condition Pairs: CBS ⇔ 0009352 (OMIM:236200)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
CBS deficiency-related morbidity and mortality from elevated blood homocysteine levels / Evaluation and management by specialists to achieve and maintain target homocysteine levels	2	3C	3C	2	10CC
Morbidity and mortality from thromboembolism / Prophylactic anti-thrombotic measures when warranted (e.g., pregnancy, immobility)	2	2D	2C	3	9DC

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

Prevalence estimates for homocystinuria due to cystathionine beta-synthase (CBS) deficiency range from 1/1,800 to 1/1,000,000. The prevalence varies widely depending on geographic location and the method of ascertainment. Both newborn screening (NBS) and clinical ascertainment underestimate prevalence because of undetected individuals. A systematic review estimated the birth prevalence worldwide to be between 1/42,000 to 1/109,000 depending on method of ascertainment. [1, 2, 3, 4, 5]

Clinical Features

There are two recognized phenotypic variants of CBS deficiency: pyridoxine-responsive and pyridoxine-unresponsive. Pyridoxine-responsive is typically, but not always, milder with a later age of onset than pyridoxine-unresponsive.
In general, CBS deficiency 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: Individuals may have skeletal abnormalities such as excessive height and limb length. Individuals with CBS deficiency are often tall and slender and are prone to osteoporosis. Symptoms may give the clinical impression of Marfan syndrome. Bone deformities such as pectus excavatum or carinatum, genu valgum, arachnodactyly, pes cavus, dolichostenomelia, and scoliosis can also be present. The facial appearance may be altered by prominence and protrusion of the upper teeth due to overcrowding and the palate is almost always high arched.
•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 common. IQ can range widely from 10 to 138. Seizures, extrapyramidal signs (e.g., dystonia, polymyoclonus, and parkinsonism), psychiatric problems (e.g., depression, personality disorder, psychosis, obsessive-compulsive disorder) and behavioral problems (e.g., aggression and drug or alcohol abuse) may also occur, especially in pyridoxine unresponsive individuals. [1, 3, 4, 5, 6]

Natural History

In general, individuals with CBS deficiency appear normal at birth but have a progressive disease course if untreated. There is a wide range of ages at presentation. Children are more likely to present with developmental delay, ectopia lentis, and skeletal abnormalities. Adults are more likely to be diagnosed following vascular events. Most manifestations, however, can occur at almost any age. 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 12. As puberty nears, long bone overgrowth becomes evident. Roughly half of individuals show signs of osteoporosis by their teens. Psychosis may be a presenting sign in adolescence. Cerebrovascular events typically manifest during young adulthood, though they have been reported earlier. Thromboembolism is the major cause of morbidity and early death. In the largest published series of untreated individuals, 50% of the vascular complications were associated with deep venous thrombosis, 32% stroke, 11% peripheral arterial disease and 4% myocardial infarction. Among pyridoxine-responsive individuals, a vascular event in adolescence or adulthood is often the presenting feature. Pregnancy increases the risk of thromboembolisms, especially in the post-partum period. Some females present for the first time with thromboses during pregnancy or the post-partum period. However, most pregnancies are uncomplicated. Once complications have occurred, they are often irreversible. Without treatment, life expectancy is markedly reduced in pyridoxine-unresponsive individuals. The life expectancy of pyridoxine-responsive individuals is uncertain. In a large series of 629 biochemically and/or clinically diagnosed individuals with CBS deficiency, the chances of not surviving to age 30 was 4% and 23% for pyridoxine-responsive and nonresponsive, respectively. Thromboembolism was the main cause of death (42/59 deaths, 71%). [1, 3, 4, 5]

2. How effective are interventions for preventing harm?

Patient Management

The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet to help clinical decision-making following NBS: https://www.acmg.net/PDFLibrary/Methionine.pdf. [7]

In CBS deficiency the aim of treatment is to prevent all complications (early and late) by controlling the elevated total plasma homocysteine (tHcy) concentrations by using one or a combination of treatments. Individuals are unlikely to develop complications if tHcy is maintained below 120 µmol/L. However, it is recommended to keep the concentration below 100 µmol/L because levels fluctuate, and the complications associated with high levels are so serious. Treatment should be managed by a metabolic dietician. With early life-long adequate treatment, outcomes are generally good, although the very long-term outcomes are not yet known. (Tier 2) [1]

Consultation with and management by a clinical geneticist/medical biochemical geneticist is also recommended. (Tier 4) [3]

To assess pyridoxine responsiveness after infancy, it is recommended to give 10 mg/kg/day pyridoxine up to a maximum of 600 mg/day for 6 weeks; the plasma tHcy concentration should be measured at least twice before treatment and twice on treatment. Protein intake should be normal, folate supplements should be given, and vitamin B12 deficiency should be corrected prior to testing. Individuals who achieve plasma tHcy levels below 50 umol/l on pyridoxine are considered responsive and do not need any other treatment. If the tHcy falls >20% but remains above 50 umol/l, additional treatment should be considered (i.e., diet and/or betaine). If tHcy falls by <20% on pyridoxine, the individual is likely to be unresponsive. Decreases in the tHcy concentration occur after pharmacological doses of pyridoxine in a substantial proportion of individuals with CBS deficiency. (Tier 2) [1]

For long-term treatment, the pyridoxine dose should be the lowest that achieves the biochemical targets (plasma tHcy <50 umol/L). Based on expert opinion, it is recommended to use doses up to 10 mg/kg/day and avoid doses above 500 mg/day. Partially pyridoxine-responsive individuals may need higher doses and additional treatment (betaine and/or diet). There is no evidence that long-term pyridoxine is beneficial if there is no biochemical response in a properly conducted test. (Tier 2) [1]

Dietary treatment should be considered for all individuals with CBS deficiency, including late-diagnosed individuals, unless target tHcy levels are achieved entirely by pyridoxine supplementation. Diet may be used either as a sole treatment or adjunctive therapy along with pyridoxine and/or betaine. Most pyridoxine-unresponsive individuals require a diet very low in natural protein, with supplements of a methionine (Met)-free L-AA mixture. Some partially pyridoxine-responsive individuals benefit from milder protein restriction without Met-free L-AA supplements. In individuals with severe deficiency, additional cystine supplementation may be necessary. Lifelong treatment is required. Problems with adherence can be reduced by starting dietary treatment as young as possible and utilizing the skills of an experienced metabolic dietitian. (Tier 2) [1]

Betaine should be considered as an adjunctive treatment in individuals who cannot achieve target levels of tHcy by other means. Additional treatment with betaine can help individuals who are partially responsive to pyridoxine or who are on dietary treatment but find it difficult to adhere to dietary restrictions and to attain good metabolic control. Betaine treatment alone seldom achieves target tHcy levels in individuals with pyridoxine-unresponsive CBS deficiency. Betaine lowers tHcy levels potentially allowing an increase in Met intake. (Tier 2) [1]

Since most of the studies on the effectiveness of treatments include CBS-deficient individuals who were on diet and/or pyridoxine + betaine, all studies on effectiveness are summarized below.
In a study of 629 individuals with CBS deficiency, pyridoxine unresponsive early-treated individuals who were administered a Met-restricted diet had higher IQs compared to late-treated individuals (early-treated mean IQ of 94 + 4 vs late-treated mean IQ of 57.6 + 1.9; p< .001). In addition, early treated individuals had significantly fewer observed lens dislocations than the number expected. (Tier 2) [1]

In a second study of 23 pyridoxine unresponsive individuals diagnosed at birth those compliant with treatment (n=13) had a full-scale IQ of 105.8 (range 84-120) while the poorly compliant group (n=6) had a mean full-scale IQ of 80.8 (range 40-103). (Tier 2) [1]

In a study of 158 individuals with CBS deficiency (44% pyridoxine responsive, 56% pyridoxine unresponsive; mean age 29.4 years; range 4.5 to 70) there were 2822 patient-years of treatment (pyridoxine and/or dietary Met restriction + betaine), with an average of 17.9 years per individual. Plasma Hcy levels were markedly reduced from pretreatment levels but usually remained moderately elevated. There were 17 vascular events in 12 individuals at a mean age of 42.5 years (range 18 to 67). Without treatment, 112 vascular events would have been expected (relative risk of 0.09; p<0.0001). (Tier 2) [1]

In a study of 32 individuals with CBS deficiency, 17 individuals were pyridoxine-responsive and treated with pyridoxine, folic acid, and vitamin B12. Plasma tHcy levels were consistently <20 umol/L over an average treatment period of 16.6 years. There were two vascular events in this group, compared to 11 expected based on rates among untreated individuals. There was one death at age 30 years, though it is uncertain if this individual was taking her therapy at the time of death. There were 15 pyridoxine-unresponsive individuals treated with pyridoxine, folic acid, vitamin B12 and betaine. Individuals maintained low plasma tHcy levels over an average period of 11 years (mean = 33±17 μmol/L). There were no vascular events in this group during a total of 258 patient years, compared to 10 expected. (Tier 2) [1]

In one study of five pyridoxine unresponsive individuals (age 1 to 19 years) who were unable to attain metabolic control with diet experienced significant reductions in tHcy concentrations when betaine was supplemented. After betaine therapy, tHcy declined (mean 47.4 umol/L; range -21.2 to -104.0 umol/L; p=0.02). Three of five individuals normalized their tHcy concentrations. It was not reported if this translated to improved clinical outcomes. (Tier 3) [3]

All individuals with CBS deficiency should receive adequate folate supplementation. Vitamin B12 should be supplemented (via intramuscular injection) if low. (Tier 2) [1]

Individuals who are poorly controlled or have had a vascular event may warrant additional treatment with anti-platelet drugs or anticoagulants, according to local guidelines. Preventive treatment should be used if there are other risk factors for thromboembolism, such as immobility due to surgery or travel. (Tier 2) [1]

Dehydration and infection increase the risk of venous thrombosis, particularly in children. It is, therefore, important to ensure individuals with CBS deficiency are well hydrated at all times and especially when unwell and during anesthesia and surgery. (Tier 2) [1]

Biochemical control, dietary management, and nutrition should be optimized before elective procedures. Hydration should be maintained with intravenous fluids. Standard anti-thrombotic measures such as elastic stockings, pneumatic leg compression systems and early mobilization should be followed during and immediately after surgery. Low molecular weight heparin is recommended in cases of prolonged immobilization. (Tier 2) [1]

Individuals who have pyridoxine-responsive CBS deficiency should remain on their pyridoxine through pregnancy. Adjuvant therapies may be necessary to maintain adequate energy and protein intake and appropriate Hcy levels. Betaine has been used in pregnancy without adverse effects. All pregnant individuals should receive folate supplementation, along with vitamin B12 if there is evidence of deficiency. Pregnancy, delivery, and the post-partum period pose an additional risk of thrombosis. Anticoagulant therapy in the form of low molecular weight heparin is recommended during the third trimester (and maybe throughout pregnancy) and for at least 6 weeks postpartum. There is some weak evidence that pyridoxine through pregnancy improves outcomes, though this is based on only a few individuals. A large study reported 15 pregnancies in 11 females. Two females (4 pregnancies) received no treatment. Two of the 5 pyridoxine unresponsive and 3 of the 6 pyridoxine responsive individuals were administered anticoagulants. Of the 15 pregnancies, there was only one thrombotic event (superficial venous thrombosis of the leg) in a pyridoxine responsive individual not on any treatment. (Tier 2) [1]

Surveillance

Monitoring of plasma tHcy, Met, folate and vitamin B12 is recommended for all individuals at least annually. The frequency depends on the severity of CBS deficiency, treatment, compliance, age, and clinical condition of the individual. Individuals on dietary treatment require nutritional assessment including blood count, albumin, plasma AA, ferritin, zinc and 25-hydroxyvitamin D at least annually. Selenium and essential fatty acids should be checked if there are concerns about intake. (Tier 2) [1]

Additional monitoring recommendations:
•Growth parameters (e.g., height and weight) at every clinic visit
•Dietary intake analysis at every clinic visit, if on dietary treatment (including late-diagnosed individuals on mild protein restriction)
•Assessment by an ophthalmologist at least annually
•Neurodevelopmental/neurological examination annually
•Regular DEXA scans are recommended every 3-5 years from adolescence unless clinically indicated earlier
•IQ at least every 5 years during childhood
•Lipid profile and cardiovascular risk factor review once in childhood and annually in adulthood
•Clinical psychology or psychiatric assessment, as required (Tier 2) [1]

During pregnancy it is important that dietary management is regularly reviewed with frequent biochemical monitoring, as Met requirements often increase during pregnancy. (Tier 2) [1]

Circumstances to Avoid

Estrogen containing contraceptives should be avoided due to the increased risk of thrombosis. (Tier 2) [1]

Dehydration and immobilization should be avoided to reduce the risk of thromboembolic disease (e.g., surgery, intercurrent illness, prolonged travel). (Tier 2) [1]

Nitrous oxide increases Hcy concentrations and should be avoided as an anesthetic. (Tier 2) [1]

Anesthesia is contra-indicated if the total plasma Hcy level is > 50 umol/L. (Tier 4) [6]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Recessive [3, 5]

Prevalence of Genetic Variants

Over 160 pathogenic variants in the CBS gene are known. Pathogenic variants may not be detected in one of the parental alleles in up to 7-10% of individuals with CBS deficiency. (Tier 3) [1]

Approximately 95-98% of probands with CBS deficiency have a detectable pathogenic variant on sequence analysis. Another ~5% have a pathogenic variant detectable by gene-targeted deletion/duplication analysis. (Tier 3) [3]

One study identified the 25 most common pathogenic variants in CBS through a literature review. In the genetic database gnomAD (including 141,456 unrelated individuals), they found 304 individuals who were heterozygous for any of 20 of the 25 most frequent pathogenic variants yielding a total allele frequency of 1/512. (Tier 5) [8]

Penetrance

At the mildest end of the spectrum, there is a large group of individuals who are extremely sensitive to pyridoxine. It is likely that many of these individuals remain asymptomatic throughout life. Others present as adults with thromboembolism; a few have ectopia lentis but most have no other complications. (Tier 3) [1]

In a large case series of 629 individuals with CBS deficiency (treated and untreated), among the untreated individuals age-related penetrance estimates were reported as:
Ectopia lentis (by age 10): pyridoxine responsive=55%, pyridoxine unresponsive=82%
Vascular event (by age 15): pyridoxine responsive=12%, pyridoxine unresponsive=27%
Spinal osteoporosis (by age 15): pyridoxine responsive=36%, pyridoxine unresponsive=64%
Mortality (by age 30): pyridoxine responsive=4%, pyridoxine unresponsive=23%
Without treatment, almost 90% of pyridoxine unresponsive individuals have learning difficulties. By 12 years of age 85% have dislocated lenses and 20% have seizures. In untreated pyridoxine unresponsive individuals, risk for venous thromboembolic complications may be as high as 50% by 30 years of age. (Tier 3) [1, 5]

Relative Risk

No information on relative risk was found.

Expressivity

There is a wide spectrum of severity, from individuals who are currently asymptomatic to those with severe multi-system disease, with a wide range of ages at presentation and differing rates of disease progression. The phenotype broadly relates to pyridoxine-responsiveness. (Tier 3) [1]

For pathogenic variants commonly present in the homozygous state, there are a few well established genotype-phenotype correlations with good concordance between pyridoxine responsiveness and a milder clinical phenotype. For example, one of the most the common variants, c.833T>C (p.I278T), is pan ethnic, accounts for nearly 24% of all pathogenic variants, and when homozygous leads to a mild pyridoxine-responsive type of CBS deficiency. (Tier 3) [1, 9]

All four, or only one, of the systems (eye, skeletal, vascular, CNS) can be involved. Expressivity is variable for the clinical signs. (Tier 4) [3]

4. What is the Nature of the Intervention?

Nature of Intervention

Pyridoxine usually has no side effects when used in recommended doses. Peripheral neuropathy is the most important adverse effect of pyridoxine. It has been reported in a number of individuals treated with long-term high doses of pyridoxine (>900 mg/day). Withdrawal of pyridoxine has led to improvement of the neuropathy in some individuals. Periods of apnea and unresponsiveness have been reported in a few neonates following large oral doses of pyridoxine. Rhabdomyolysis has also been reported in one infant. [1]

There are very few reported complications with well managed dietary treatment, however the diet is lifelong, complex, and difficult so poor adherence is common, particularly for late teenagers and young adults. The introduction of dietary restriction is extremely difficult in late-diagnosed individuals. Daily Met-free L-AA supplementation should be split into three to four doses throughout the day. Adherence to these supplements can be poor due to their taste. Cystine supplementation can be difficult to administer due to its poor solubility and unpleasant taste. [1, 3]

Generally, betaine is well tolerated and safe. Betaine has been used in pregnancy without adverse effects. Some people dislike the taste and compliance can be poor. Higher doses have been associated with a fishy odor. [1, 3]

Anticoagulation carries the risk of bleeding into an edematous brain, especially if there is hypertension. [1]

5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?

Chance to Escape Clinical Detection

The sensitivity of NBS for detecting newborns with CBS deficiency is not exactly known and 20-50% of pyridoxine unresponsive individuals may be missed. NBS most likely fails to detect the majority of pyridoxine responsive individuals. (Tier 3) [1]

The diagnosis is often missed for individuals at the mildest end of the spectrum. Since pyridoxine is contained in many vitamin supplements as well as in fortified foods and drinks, plasma tHcy concentrations may be normal in pyridoxine-responsive individuals if they are receiving even low doses of pyridoxine in vitamins and food supplements, and therefore can mask diagnosis in these individuals on biochemical testing. (Tier 3) [1]

Individuals with CBS deficiency can present to many different specialists and diagnosis is often delayed. (Tier 3) [1]

The diversity of clinical manifestations observed in CBS deficiency makes diagnosis difficult and often delays it until late childhood or adulthood. (Tier 4) [6]

Date of Search: 04.20.2016 (updated 06.23.2023)

Reference List

1. Morris AA, Kožich V, Santra S, Andria G, Ben-Omran TI, Chakrapani AB, Crushell E, Henderson MJ, Hochuli M, Huemer M, Janssen MC, Maillot F, Mayne PD, McNulty J, Morrison TM, Ogier H, O'Sullivan S, Pavlíková M, de Almeida IT, Terry A, Yap S, Blom HJ, Chapman KA. Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency. J Inherit Metab Dis. (2017) 40(1573-2665):49-74.

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. S. J. Sacharow, J. D. Picker and H. L. Levy. Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency. GeneReviews((R)). (1993) Website: https://www.ncbi.nlm.nih.gov/pubmed/20301697

4. Classic homocystinuria. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=394

5. 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: http://omim.org.

6. De Lonley, P and Bagou G. Classic Homocystinuria. orphanet Emergency. (2023) Website: https://www.orpha.net/data/patho/Pro/en/Emergency_ClassicHomocystinuria-enPro173.pdf

7. ACMG. Newborn Screening ACT Sheet: Homocystinuria. (2023) Website: https://www.acmg.net/PDFLibrary/Methionine.pdf

8. Weber Hoss GR, Sperb-Ludwig F, Schwartz IVD, Blom HJ. Classical homocystinuria: A common inborn error of metabolism? An epidemiological study based on genetic databases. Mol Genet Genomic Med. (2020) 8(2324-9269):e1214.

9. J. D. Picker, H. L. Levy. Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency. 2014. GeneReviews at GeneTests Medical Genetics Information Resource. (2014) Website: http://www.genetests.org