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 B₆ responsive, vitamin B₆ nonresponsive, or partial responders to vitamin B₆. The clinical manifestations in those who are vitamin B₆ responsive are typically (but not always) milder than individuals who are vitamin B₆ nonresponsive.

Diagnosis/testing.

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

Management.

Targeted therapies: Vitamin B₆ (pyridoxine) therapy (in those who are vitamin B₆ responsive); methionine-restricted diet; folic acid and vitamin B₁₂ supplementation as needed; betaine therapy.

Treatment of manifestations: 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.

Surveillance: Evaluation with a metabolic specialist and metabolic dietician; routine labs may include plasma total homocysteine and amino acids, folate, and vitamin B₁₂ 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.

Agents/circumstances to avoid: Oral contraceptives in affected females; surgery if possible; dehydration and immobilization; nitrous oxide.

Evaluation of relatives at risk: 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 CBS pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of sibs.

Pregnancy management: Methionine-restricted diet, betaine; vitamin B₆ for those who are vitamin B₆ 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 CBS 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 CBS pathogenic variants identified in the proband (targeted testing for the CBS pathogenic variants identified in the proband cannot be used to rule out the possibility that a parent has biallelic CBS pathogenic variants). If both parents are known to be heterozygous for a CBS 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 CBS pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

HCU-CBS deficiency should be suspected in an infant with an out-of-range newborn screen (NBS) result or a proband with suggestive clinical and laboratory findings and family history.

Note: (1) Individuals with untreated HCU-CBS deficiency usually develop manifestations in the first or second decade of life. (2) A symptomatic individual can have untreated HCU-CBS deficiency due to NBS not performed, false negative NBS result, or caregivers not adherent to recommended treatment after a positive NBS result.

Establishing the Diagnosis

The diagnosis of HCU-CBS deficiency is established in a proband with biallelic pathogenic (or likely pathogenic) variants in CBS identified by molecular genetic testing (see Table 2).

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic CBS variants of uncertain significance (or of one known CBS pathogenic variant and one CBS variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Testing Following Establishment of the Diagnosis

Pyridoxine (vitamin B₆) challenge test. Individuals with HCU-CBS deficiency can be vitamin B₆ responsive or vitamin B₆ nonresponsive, which is important for management. Once the diagnosis of HCU-CBS deficiency is established, a pyridoxine challenge is used to measure vitamin B₆ responsiveness. Genotype may help predict response to vitamin B_6. Most individuals identified by NBS are not vitamin B₆ responsive. There are options for vitamin B₆ challenge testing, which is typically designed to be done prior to other interventions beyond assuring folate and vitamin B₁₂ levels are sufficient. It is at the provider’s discretion if they prefer to start with dietary therapy prior to a vitamin B₆ challenge test, although this may make the results of the vitamin B₆ challenge test more difficult to interpret.

Guidelines from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) suggest classifying individuals with HCU-CBS deficiency into four groups of pyridoxine responsivity: nonresponders, partial, full, and extreme responders [Kožich et al 2021].

In the neonate identified on NBS

• Option 1 [Morris et al 2017]. Infants identified on NBS are unlikely to respond to pyridoxine, so high-dose pyridoxine is recommended for a shorter period. The affected neonate is given 100 mg pyridoxine daily for two weeks; concentrations of plasma total homocysteine and amino acids are measured at baseline and after one and two weeks.
• Option 2 [Ames et al 2020]. The affected neonate is given 10 mg/kg/day pyridoxine for four days, increasing to 20 mg/kg/day for four days if no appreciable change, and then increasing to 40 mg/kg/day as a maximum dose for another four days.

Note: (1) Caution is needed with doses approaching or exceeding 200 mg/day due to the risk of apnea, creatine kinase (CK) elevation, and transaminase elevation. (2) Infants should not receive more than 200-300 mg of pyridoxine. Several infants given daily doses of 200-500 mg pyridoxine developed respiratory failure and required ventilatory support. The respiratory manifestations resolved on withdrawal of pyridoxine. Additional features in these infants included elevated transaminases and elevated CK [Shoji et al 1998, Mudd et al 2001, Ames et al 2020]. (3) Peripheral neuropathy has been seen as an adverse effect of pyridoxine doses exceeding 900 mg/day [Morris et al 2017].

After infancy. For a clinically identified individual, continue a normal diet, provide folate supplement of 5 mg (for children and adults), correct vitamin B₁₂ deficiency if present, and measure plasma total homocysteine and amino acids [Morris et al 2017]. The affected individual is given up to 10 mg/kg/day pyridoxine up to a maximum of 500 mg/day for six weeks. Note: The typical adult dose is 2-5 mg/kg/day [Kožich et al 2021]. The concentrations of plasma total homocysteine and amino acids are measured prior to and during pyridoxine treatment (frequency of measurements are per provider’s discretion).

• Plasma total homocysteine that falls below 50 µmol/L suggests vitamin B₆ responsiveness and the individual may not require treatment other than pyridoxine.
• A ≥20% reduction in plasma total homocysteine but homocysteine remaining >50 µmol/L suggests partial vitamin B₆ responsiveness, and consideration of additional treatment.
• A <20% reduction in plasma total homocysteine suggests the individual is not responsive to pyridoxine.

Clinical Description

Homocystinuria (HCU) due to cystathionine beta-synthase (CBS) deficiency (HCU-CBS deficiency) is characterized by involvement of the eye, skeletal system, vascular system, and central nervous system (CNS). One to all four of the systems can be involved. Expressivity is variable for all 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 [Kožich et al 2021].

Individuals with HCU-CBS deficiency can be vitamin B₆ responsive, vitamin B₆ nonresponsive, or partial responders to vitamin B₆. The clinical manifestations in individuals with HCU-CBS deficiency that is vitamin B₆ responsive are typically (but not always) milder than those with HCU-CBS deficiency that is vitamin B₆ nonresponsive. Vitamin B₆ responsiveness is determined by a pyridoxine challenge test (see Testing Following Establishment of the Diagnosis). Partial responders to vitamin B₆ typically show some reduction in plasma homocysteine concentrations but are unable to maintain concentrations below 50 µmol/L without additional treatments, such as a methionine-restricted diet, betaine, and/or higher doses of pyridoxine.

Eyes. Myopia followed by ectopia lentis typically occurs after age one year. In most untreated individuals, ectopia lentis occurs by age eight years. Ectopia lentis usually occurs earlier in affected individuals who are vitamin B₆ nonresponsive than in those who are vitamin B₆ responsive. Rarely, ectopia lentis occurs in infancy [Mulvihill et al 2001, Rahman et al 2022]. High myopia may be present in the absence of ectopia lentis.

Skeletal system. Affected individuals are often tall and slender with a marfanoid habitus. Such features include dolichostenomelia (tall stature with disproportionately long limbs), arachnodactyly (long, slender fingers), pectus deformity (pectus excavatum or carinatum), kyphosis, and scoliosis [Morris et al 2017].

Individuals with HCU-CBS deficiency are prone to osteoporosis, especially of the vertebrae and long bones. Low bone mineral density is common in children and adults with HCU-CBS deficiency. Osteoporosis may be detected on lateral lumbar spine radiographs but is best assessed by bone density studies. Dual energy x-ray absorptiometry (DXA) scans usually show reduced density in the lumbar spine and hip [Weber et al 2016].

High-arched palate, pes cavus, and genu valgum may also be present.

Vascular system. Thromboembolism is the major cause of morbidity and early death [Yap 2003]; it can affect any vessel. Cerebrovascular accidents have been described in infants, although vascular events typically present in young adults [Yap et al 2001a, Kelly et al 2003].

Among vitamin B₆-responsive individuals, a vascular event in adolescence or adulthood is often the presenting feature of HCU-CBS deficiency [Magner et al 2011, Sarov et al 2014]. Cerebral venous sinus thrombosis has been a presenting sign in childhood [Karaca et al 2014, Saboul et al 2015].

Pregnancy in individuals with HCU-CBS deficiency further increases the risk for thromboembolism, especially in the postpartum period [Novy et al 2010]; most pregnancies, however, are uncomplicated (see Pregnancy Management).

CNS. Developmental delay is often the first clinical manifestation in individuals with HCU-CBS deficiency. Developmental delay and/or learning difficulties were found in 53% of vitamin B₆-nonresponsive individuals, 30% of partial responders, and 17% of vitamin B₆-responsive individuals at diagnosis [Kožich et al 2021]. Speech delay and learning difficulties are most common, but motor skills may be impaired due to hypotonia or following an early thrombotic event. In those with untreated HCU-CBS deficiency, a broad range of IQ is reported (range: 10-138; mean: 64). Generally, IQ is lower in vitamin B₆-nonresponsive individuals compared to vitamin B₆-responsive individuals. However, early diagnosis following NBS and treatment to maintain low homocysteine levels typically results in normal cognition and prevents intellectual disability [Mudd et al 1985, Yap et al 2001b].

Behavioral findings in individuals with HCU-CBS deficiency reported by the European Network and Registry for Homocystinuria and Methylation Defects (E-HOD) included shyness (53%), anxiety (51%), sleep problems (51%), short attention span (51%), distractibility (47%), and hyperactivity (33%) [Kožich et al 2021]. Another study noted psychiatric manifestations occurred at twice the prevalence of the general population including anxiety (32%) and depression (32%); anger, aggression, suicidal thoughts, and hallucinations were less commonly reported manifestations [Almuqbil et al 2019]. More severe psychopathology (e.g., schizophrenia), described historically in individuals with HCU-CBS deficiency, was not identified in more recent studies, likely due to advances in treatment availability [Almuqbil et al 2019].

Seizures occur in 19% of individuals with HCU-CBS deficiency; the incidence of seizures is similar in vitamin B₆-responsive and nonresponsive individuals per registry data [Kožich et al 2021]. According to the first natural history study [Mudd et al 1985], 21% of the late-detected group had seizures but only ~2% (1/55) detected by NBS had seizures. There is little published on seizure types, and it is unclear if most seizures are secondary to thromboembolic events.

Extrapyramidal signs such as dystonia may occur.

Other features include hypopigmentation of the skin and hair, malar flush, and livedo reticularis; four individuals developed pancreatitis [Aljaberi et al 2025].

Genotype-Phenotype Correlations

The presence of the p.Gly307Ser pathogenic variant predicts vitamin B₆ nonresponsiveness, while presence of pathogenic variant p.Ile278Thr usually predicts vitamin B₆ responsiveness. Other pathogenic variants are associated with either vitamin B₆ responsiveness or nonresponsiveness. The p.Ile278Thr pathogenic variant comprises 25% of pathogenic variants globally and has been identified in individuals from most European countries [Kraus et al 1999, Al-Sadeq & Nasrallah 2020].

Nomenclature

"Homocystinuria" was named for excess homocystine in the urine, though now it is primarily detected by increased total homocysteine in plasma. Homocystinuria may be caused by genetically determined deficient activity of cystathionine beta-synthase (CBS), or a variety of genetic problems that ultimately interfere with conversion of homocysteine to methionine (e.g., methylenetetrahydrofolate reductase deficiency and abnormalities of cobalamin transport or metabolism). For details on the latter conditions, see Watkins & Rosenblatt [2014]. (See also Disorders of Intracellular Cobalamin Metabolism.)

Non-genetically determined severe dietary lack of cobalamin (vitamin B₁₂ deficiency) may also cause "homocystinuria" [Mudd et al 2000].

To attain maximum specificity when using the term "homocystinuria," the specific enzyme or gene in question may be added, e.g., "homocystinuria caused by CBS deficiency" [Mudd et al 2000], which has also been called "classic homocystinuria."

Classic homocystinuria as defined in this GeneReview is due to deficiency of cystathionine beta-synthase (CBS), a pyridoxine (vitamin B₆)-dependent enzyme, and in this GeneReview referred to as "HCU-CBS deficiency."

Prevalence

Prevalence is at least 1:200,000-335,000 and is higher in certain populations with founder pathogenic variants [Skovby et al 2010].

• Qatar. Prevalence of HCU-CBS deficiency in Qatar, estimated at >1:3,000 (1:1,800 in a study of newborns), may be the highest in the world. Pathogenic variant p.Arg336Cys is present in 93% of affected individuals in the Qatari population [El-Said et al 2006, Gan-Schreier et al 2010].
• Ireland. Prevalence is reported to be as high as 1:65,000 [Naughten et al 1998]. Pathogenic variant p.Gly307Ser is the leading cause of homocystinuria in Ireland (71% of pathogenic variants). This pathogenic variant has also been detected frequently in affected individuals of "Celtic" origin in the US and Australia, including families of Irish, Scottish, English, French, and Portuguese ancestry. It accounts for 21% of pathogenic variants in the UK and 8% in the US [Moat et al 2004].
• Germany. Molecular genetic testing of an unaffected control population estimated the prevalence of HCU-CBS deficiency at 1:17,800 based on prevalence of a CBS pathogenic variant and calculated from the Hardy-Weinberg equation [Linnebank et al 2001].
• Norway. Molecular genetic testing of newborns using a panel of six CBS pathogenic variants estimated the prevalence of HCU-CBS deficiency at 1:6,400 based on the heterozygosity rate [Refsum et al 2004].
• The pathogenic variant p.Ile278Thr is a vitamin B₆-responsive variant that is pan ethnic; overall, it accounts for nearly 25% of all pathogenic variants, including 29% of the pathogenic variants in the UK and 18% in the US [Moat et al 2004]. In some countries (e.g., Denmark) it may account for the majority of pathogenic variants [Shih et al 1995, Linnebank et al 2001, Skovby et al 2010, Al-Sadeq & Nasrallah 2020].

Evaluations Following Initial Confirmatory Diagnosis

To establish the extent of disease and needs in an individual diagnosed with HCU-CBS deficiency, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

The evaluations summarized in Table 10 are recommended to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations.

Agents/Circumstances to Avoid

Oral contraceptives containing estrogen, which may tend to increase coagulability and represent risk for thromboembolism, should be avoided in females with HCU.

Surgery should also be avoided if possible because the increase in plasma homocysteine concentrations during surgery and especially post surgery elevates the risk for a thromboembolic event.

Avoid dehydration and immobilization to reduce the risk of a thromboembolic event.

Avoid nitrous oxide, which may increase homocysteine concentration.

Evaluation of Relatives at Risk

Prenatal testing of a fetus at risk. If the CBS pathogenic variants in the family are known, prenatal testing of fetuses at risk may be performed via amniocentesis or chorionic villus sampling to facilitate institution of treatment at birth.

Newborn sib. If prenatal testing was not performed, plasma concentrations of total homocysteine and methionine via plasma 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.

Other at-risk sibs. Evaluation of other at-risk sibs of any age is also warranted to allow for early diagnosis and treatment of HCU; evaluations include:

• Molecular genetic testing if the CBS pathogenic variants in the family are known;
• Plasma total homocysteine analysis and plasma amino acid analysis for methionine concentration.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Women with HCU-CBS deficiency 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. The current European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) guidelines recommend injection of low-molecular-weight heparin during the last trimester of pregnancy, throughout the whole pregnancy if there are other risk factors or history of thrombotic event, and the first six weeks post partum while the uterus is involuting [Pierre et al 2006, Morris et al 2017]. Aspirin in low doses has also been given throughout pregnancy.

Vitamin B₆-responsive individuals should continue pyridoxine during pregnancy. Folate supplementation should be administered to all pregnant women, and vitamin B₁₂ in those with vitamin B₁₂ deficiency.

Maternal HCU-CBS deficiency, unlike maternal phenylketonuria (see Phenylalanine Hydroxylase Deficiency), does not appear to have major teratogenic potential requiring additional counseling or, with respect to the fetus, more stringent management [Levy et al 2002, Vilaseca et al 2004]. Nevertheless, treatment with methionine-restricted diet should be continued during pregnancy. Methionine requirements change throughout the pregnancy, so frequent monitoring is indicated [Morris et al 2017]. Betaine may also be continued and appears not to be teratogenic [Yap et al 2001b, Levy et al 2002, Vilaseca et al 2004, Pierre et al 2006].

Therapies Under Investigation

CBS enzyme replacement therapy (pegtibatinase) has published Phase I/II clinical trials and Phase III and extension studies are being conducted. Pegtibatinase was considered to be generally well tolerated. At the highest dose levels there was a 57%-67% reduction in plasma total homocysteine, and one participant was able to increase dietary protein intake [Ficicioglu et al 2025].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Homocystinuria (HCU) due to cystathionine beta-synthase (CBS) deficiency (HCU-CBS deficiency) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are typically heterozygous for a CBS pathogenic variant.
• Because it is possible (though unlikely) that a parent of the proband has biallelic CBS pathogenic variants and HCU-CBS deficiency but has remained undiagnosed, the following evaluations are recommended to allow reliable recurrence risk assessment:
  • Measure plasma homocysteine concentration in each parent;
  • Obtain a detailed medical history; and
  • Consider clinical examination of the parents for features of HCU-CBS deficiency.
  If the parents are consanguineous and/or if features are present in the medical history or on laboratory testing/clinical exam, 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 (see Pregnancy Management).
• If a molecular diagnosis has been established in the proband, targeted analysis can be used to determine if the parents are heterozygous for the CBS pathogenic variants identified in the proband. (Note: Targeted testing for the CBS pathogenic variants identified in the proband cannot be used to rule out the possibility that a parent has biallelic CBS pathogenic variants.) If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity.
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing HCU-CBS deficiency.

Sibs of a proband

• If both parents are known to be heterozygous for a CBS 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.
• If one parent is known to have biallelic CBS pathogenic variants and the other parent is known to be heterozygous for a CBS pathogenic variant, each sib of an affected individual has at conception a 50% chance of being affected and a 50% chance of being an asymptomatic carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing HCU-CBS deficiency.

Offspring of a proband

• Unless an affected individual's reproductive partner also has HCU-CBS deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in CBS and will not be affected.
• If the reproductive partner of the proband is heterozygous for a CBS pathogenic variant, offspring have a 50% chance of being affected and a 50% chance of being carriers.
• If the reproductive partner of the proband also has HCU-CBS deficiency, all offspring will have HCU-CBS deficiency.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a CBS pathogenic variant.

Carrier Detection

Molecular genetic carrier testing for at-risk family members requires prior identification of the CBS pathogenic variants in the family.

Molecular genetic testing is the standard of care for carrier detection. Individuals who are heterozygous for a CBS pathogenic variant have normal fasting plasma total homocysteine concentration. Methionine loading and subsequent testing for elevated total homocysteine was used historically to differentiate carriers from non-carriers but is no longer clinically available. Note: Carriers may have elevated total homocysteine in the presence of folate deficiency [Lu et al 2015].

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk sibs for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with HCU-CBS deficiency, particularly if consanguinity is likely and/or both partners are of the same ancestry. Founder variants have been identified in several populations (see Prevalence). In the Qatari population, the carrier frequency is approximately 1/50 due to the founder variant p.Arg336Cys [El-Said et al 2006, Morris et al 2017, Al-Sadeq & Nasrallah 2020].

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the CBS pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider the use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

CBS encodes cystathionine beta-synthase (CBS), the enzyme that catalyzes the first irreversible step in the transsulfuration pathway in which homocysteine condenses with serine to form cystathionine, a precursor to cysteine. CBS removes excess homocysteine and provides cysteine, a precursor for glutathione (an antioxidant) and other sulfur-containing molecules. The active form of CBS is a homotetramer that contains one heme and one pyridoxal 5'-phosphate (PLP) per each subunit [Kraus et al 1999, Miles & Kraus 2004].

Vitamin B₆ (pyridoxine) response determines the clinical course and will largely inform early-onset multisystemic vs later-onset disease. In individuals who are vitamin B₆ responsive, PLP promotes proper protein conformation and enhances enzymatic efficiency. Administered vitamin B₆ (pyridoxine) will convert to PLP in the body as long as the pyridoxal kinase enzyme is functioning.

CBS deficiency leads to homocysteine and methionine accumulation and low cysteine. Elevated homocysteine is toxic to multiple tissues; it interferes with cross-linkage of sulfhydryl groups (impacting elastin and collagen), causes endothelial dysfunction, and impairs thrombolysis [Lai & Kan 2015, Morris et al 2017].

The most common pathogenic variant types are missense, followed by frameshift and splicing variants [Kožich & Majtan 2024]. Most pathogenic variants affect the active core of CBS. Pathogenic variants may also impair the binding of adenosine derivatives (e.g., AMP, ATP, S-adenosylmethionine), thus interfering with cellular energy [Scott et al 2004].

Mechanism of disease causation. Loss of function

Author Notes

Dr Harvey Levy conducts clinical research in homocystinuria (HCU) and has been the Principal Investigator of the Boston site for the clinical trial of pegtibatinase. He currently serves on the Travere Steering Committee for the Phase III continuation of the pegtibatinase clinical trial.

Dr Stephanie Sacharow is director for the Dr Harvey Levy Program for Phenylketonuria and Related Conditions and was Co-Investigator on the Phase I/II enzyme therapy trial and homocystinuria natural history trial.

Acknowledgments

We would like to acknowledge the European Network and Registry for Homocystinuria and Methylation defects and refer to their guidelines: Guidelines and recommendations - E-HOD - European Network and Registry for Homocystinurias and Methylation Defects.

We would like to acknowledge the HCU Network America for their homocystinuria resources, advocacy, and events.

Author History

Harvey L Levy, MD (2004-present)
Jonathan D Picker, MBChB, PhD; Boston Children's Hospital (2004-2025)
Stephanie J Sacharow, MD (2017-present)

Revision History

• 25 September 2025 (sw) Comprehensive update posted live
• 18 May 2017 (ha) Comprehensive update posted live
• 13 November 2014 (me) Comprehensive update posted live
• 26 April 2011 (me) Comprehensive update posted live
• 29 March 2006 (me) Comprehensive update posted live
• 15 January 2004 (ca) Review posted live
• 2 September 2003 (hl) Original submission

Published Guidelines / Consensus Statements

• Morris AAM, Kožich V, Santra S, Andria G, Ben-Omran TIM, Chakrapani AB, Crushell E, Henderson MJ, Hochuli M, Huemer M, Janssen MCH, Maillot F, Mayne PD, McNulty J, Morrison TM, Ogier H, O’Sullivan S, Pavlíková M, Talvares de Almeida I, Terry A, Yap S, Blom HJ, Chapman KA. Guidelines for the diagnosis and management of cystathionine β-synthase deficiency. J Inherit Metab Dis. 2017;40:49-74. [PubMed]

Literature Cited

• Alcaide P, Krijt J, Ruiz-Sala P, Ješina P, Ugarte M, Kožich V, Merinero B. Enzymatic diagnosis of homocystinuria by determination of cystathionine-ß-synthase activity in plasma using LC-MS/MS. Clin Chim Acta. 2015;438:261–5. [PubMed: 25218699]
• Aljaberi R, Romo L, Cohen RZ, Mellor T, Steffensen M, Ficicioglu C, Hainline B, Gambello MJ, Levy HL, Li H. Pancreatitis is an emerging rare complication of classic homocystinuria: a case series and literature review. Am J Med Genet A. 2025. Epub ahead of print. [PubMed: 40771008]
• Almuqbil MA, Waisbren SE, Levy HL, Picker JD. Revising the psychiatric phenotype of homocystinuria. Genet Med. 2019;21:1827–31. [PubMed: 30643218]
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