DiagnosisClassic homocystinuria discussed in this GeneReview is caused by deficiency of cystathionine β-synthase (CBS), a pyridoxine (vitamin B₆)-dependent enzyme. Because homocysteine is at the branch point between transsulfuration and methionine remethylation in the methionine metabolic cycle, a block at CBS limits transsulfuration and results in both increased homocysteine and increased methionine, the latter caused by enhanced remethylation (Figure 1).FigureFigure 1. Methionine metabolic pathway Clinical DiagnosisThe diagnosis of homocystinuria caused by CBS deficiency is suspected in individuals with findings that range from multiple organ disease beginning in infancy or early childhood to thromboembolism only, expressed in early to middle adult years.The major findings in classic homocystinuria:Developmental delay / intellectual disabilityEctopia lentis (dislocation of the ocular lens) and/or severe myopiaSkeletal abnormalities such as excessive height and length of the limbsVascular abnormalities characterized by thromboembolismClinical suggestion of Marfan syndrome although often joint flexibility is decreased in homocystinuriaNewborn screening diagnosis. Classic homocystinuria can be detected in some (but not all) affected individuals by screening the newborn ‘Guthrie’ blood spot specimen for hypermethioninemia. Increasingly the method used to measure methionine is tandem mass spectrometry (MS/MS). See National Newborn Screening Status Report (pdf).If the initial screening test result exceeds the cut-off level of methionine, follow-up testing is required. This may be a repeat dried blood specimen submitted to the newborn screening program or quantitative plasma amino acid analysis and analysis of plasma total homocysteine as recommended in the methionine and of the American College of Medical Genetics (www.acmg.net). The choice between the dried blood specimen and the plasma analyses is based on the recommendation of the screening program which usually depends on the degree of the methionine increase in the initial screen.If the selection above is a second test sent to the newborn screening program and if the result confirms hypermethioninemia, quantitative plasma amino acid testing with attention to concentrations of methionine, homocystine, and homocysteine-cysteine mixed disulfide as well as a specific plasma total homocysteine analysis are performed to confirm or exclude the diagnosis of homocystinuria (Table 1).
Note: at least one newborn screening program performs second-tier testing for homocysteine on all newborn specimens with elevated methionine in order to reduce the frequency of false-positive results [Matern et al 2007]. It is important to note that newborn screening is for methionine and not for homocystine or homocysteine. Thus, other causes of elevated total homocysteine, such as disorders of remethylation (e.g., methylenetetrahydrofolate reductase deficiency and the cobalamin defects [see Differential Diagnosis]) are not detected because the methionine level in these disorders is reduced (or normal).Virtually all infants with homocystinuria detected by newborn screening programs have had pyridoxine (vitamin B₆) non-responsive homocystinuria. It is likely that infants who are pyridoxine responsive do not have increased methionine during the first two to three days of life, when the newborn screening specimen is obtained.TestingThe terms used to describe the sulfur amino acids are confusing because homocysteine, the thiol within the methionine metabolic pathway (Figure 1) with its free sulfur, readily combines with other thiols (such as another homocysteine or cysteine) to form a disulfide; it is primarily the disulfides that are measured in the standard amino acid analysis. For clarity, Mudd et al [2000] have proposed the following terminology to describe the sulfur amino acid metabolites that are important in homocystinuria and related disorders:Homocysteine (HcyH). A thiol compound:
Homocystine (Hcy-Hcy). A symmetric disulfide:
Homocysteine-cysteine mixed disulfide (Hcy-Cys). An asymmetric disulfide:
Total homocysteine (tHcy). All of the Hcy that is present, including that which is bound to protein, most of which is liberated from disulfide bonding by a specific analysis that requires prior reductionTotal free homocysteine (tfHcy). A measurement sometimes used in following individuals with homocystinuria, calculated by assigning two Hcy's to the amount of free homocystine (Hcy-Hcy), one Hcy to the amount of homocysteine-cysteine mixed disulfide (Hcy-Cys), and adding the amounts. Total free Hcy is distinguished from tHcy, which includes the Hcy that was formerly protein bound.The cardinal biochemical features of classic homocystinuria are:Markedly increased concentrations of plasma homocystine, total homocysteine, homocysteine-cysteine mixed disulfide, and methionineIncreased concentration of urine homocystine (Table 1).Table 1. Biochemical Testing to Establish the Diagnosis of HomocystinuriaView in own windowAnalyteSpecimenExpected FindingsNeonate with HomocystinuriaUntreated Older Individual with HomocystinuriaControlHomocystinePlasma ¹ 10-100 µmol/L
(0.1-1.3 mg/dL)>100 µmol/L
(>3 mg/dL)(<0.03 mg/dL)Total homocysteine (tHcy)Plasma ¹ 50-100 µmol/L>100 µmol/LMethioninePlasma200-1500 µmol/L
(3-23 mg/dL)>50 µmol/L
(>0.7 mg/dL)10-40 µmol/L
(0.2-0.6 mg/dL)HomocystineUrine ² DetectableDetectableUndetectable1. Without deproteinizing the plasma or serum specimen before transportation to compensate for the instability of thiol compounds in blood, homocystine and the free homocysteine-cysteine mixed disulfide may become undetectable after only one day of sample storage. Rapid deproteinization preserves the disulfides as free analytes for at least seven days in storage at -20°C. Alternatively, plasma tHcy measurement is a more effective method for assuring accurate diagnosis of homocystinuria. After a week of storage without deproteinization, virtually all tHcy can still be recovered by a method of preparation that includes a reducing agent such as dithiothreitol [Smith et al 1998].2. Urine homocystine is quite stable owing to the relatively small amount of protein in urine (e.g., bound thiols such as cysteine).Cystathionine β-synthase (CBS) enzyme activity. CBS enzyme activity is measured in cultured skin fibroblasts. The enzyme activity in individuals with homocystinuria ranges from 0 to 1.8 U/mg protein as compared to control activity of 3.7-60 U/mg protein. Enzyme activity may be higher in pyridoxine-responsive individuals than in those who are non-responsive [Chen et al 2006] but cannot reliably distinguish responders from non-responders.Pyridoxine (B6) challenge test. The two phenotypic variants of classic homocystinuria are B₆-responsive and B₆-non-responsive homocystinuria. B₆-responsive homocystinuria is typically, but not always, milder than the non-responsive variant. Vitamin B₆ responsiveness is determined by a pyridoxine challenge.While continuing a normal diet, plasma is obtained for baseline measurements of amino acids, the affected individual is given 100 mg pyridoxine orally, and the concentrations of plasma amino acids are again measured 24 hours later. A reduction of 30% or more in plasma homocystine or homocysteine and/or plasma methionine concentration suggests B₆ responsiveness.If no significant change occurs, 200 mg pyridoxine is given orally and the amino acid analysis repeated in 24 hours.If still no change has occurred, 500 mg of pyridoxine is given orally to a child or adult but no more than 300 mg to an infant. If plasma homocystine or homocysteine and methionine concentrations are not significantly decreased after the last dose of pyridoxine, it is concluded that the individual is B₆-non-responsive.
Note: Infants should not receive more than 300 mg of pyridoxine. Several infants given daily doses of 500 mg pyridoxine developed respiratory failure and required ventilatory support. The respiratory symptoms resolved upon withdrawal of pyridoxine [Shoji et al 1998, Mudd et al 2001b].Determination of carrier status. A single biochemical test cannot distinguish heterozygotes for CBS deficiency from controls.Heterozygotes for CBS deficiency have normal fasting plasma total homocysteine concentration but may have elevated urinary homocystine.Plasma total homocysteine concentration response after methionine loading (100 mg methionine/kg [671 µmol/kg]) is abnormal in 73% of heterozygotes with pyridoxine non-responsive homocystinuria and 33% of heterozygotes with pyridoxine-responsive homocystinuria [Guttormsen et al 2001].
Note: Caution should be exercised in performing a methionine loading test because adverse reactions have been reported [Cottington et al 2002, Krupkova-Meixnerova et al 2002].Molecular genetic testing may replace metabolite testing for determination of carrier status in families in which CBS mutations are known.Molecular Genetic TestingGene. CBS is the only gene in which mutations are known to result in homocystinuria caused by cystathionine β-synthase deficiency.Of the 153 mutations currently identified, 67% in individuals with CBS deficiency are missense mutations, the vast majority of which are private mutations. Among the other mutations, only five are nonsense mutations and the remainder are various deletions, insertions, and splicing mutations (see CBS mutation database for the database of current mutations). Most individuals worldwide are compound heterozygotes with private mutations.Clinical testingTargeted mutation analysis. The two most common CBS mutations, p.Ile278Thr and p.Gly307Ser, are found in exon 8:The p.Ile278Thr mutation is pan ethnic; overall, it accounts for nearly 25% of all disease-causing alleles, including 29% of the mutant alleles 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 disease-causing alleles [Skovby et al 2010].The p.Gly307Ser mutation is the leading cause of homocystinuria in Ireland (71% of disease-causing alleles). It has also been detected frequently in US and Australian affected individuals of 'Celtic' origin, including families with Irish, Scottish, English, French, and Portuguese ancestry. p.Gly307Ser accounts for 21% of mutant alleles in the UK and 8% in the US [Moat et al 2004].Sequence analysis. Direct sequencing of the entire coding region of CBS in 36 affected individuals from 28 unrelated Australian families detected homozygous or compound heterozygous mutations in 26 families. In the remaining two families, only one mutant allele was found [Gaustadnes et al 2002]. Sequencing of the CBS coding region in seven Venezuelan persons detected homozygosity in six and heterozygosity in one [De Lucca & Casique 2004]. A similar study among 12 affected individuals in the state of Georgia (US) found homozygosity in four and heterozygosity in the remaining eight [Kruger et al 2003].Duplication/deletion testing. Nine individuals with deletions or duplications involving 25 or more nucleotides have been reported to date [Kraus Lab / CBS mutation database]. Table 2. Summary of Molecular Genetic Testing Used in Homocystinuria Caused by Cystathionine Beta-Synthase DeficiencyView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityCBSTargeted mutation analysisp.Ile278Thr alleleUS: 18% 2UK: 29% 3Clinical p.Gly307Ser alleleIreland: >70% 4UK: 21% 3US: 8% 3Sequence analysisSequence variants 5>95% 6Duplication / deletion testing 7Exonic, multiexonic, and whole gene deletionsUnknown 81. The ability of the test method used to detect a mutation that is present in the indicated gene2. Kraus et al [1999]3. Moat et al [2004]4. Gallagher et al [1995]5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.6. Kruger et al [2003], De Lucca & Casique [2004]7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.8. Microarray deletion/duplication testing is only performed when no or only one mutation is found by sequencing, thus frequency determination is not valid.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a probandTo establish the diagnosis of classic homocystinuria:Measure amino acids in plasma and urine;Determine plasma homocysteine concentration in the absence of pyridoxine supplementation (including a multivitamin) for two weeks.The diagnosis can also be confirmed by:Measurement of CBS enzyme activity in cultured fibroblasts;Molecular genetic testing of CBS.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other phenotypes are associated with mutations in CBS.}

Natural HistoryHomocystinuria is characterized by involvement of the eye, skeletal system, vascular system, and CNS. All four, or only one, of the systems can be involved. Expressivity is variable for all of the clinical signs. It is not unusual for a previously asymptomatic individual to present in adult years with only a thromboembolic event that is often cerebrovascular [Yap 2003, Skovby et al 2010].Eyes. Myopia followed by ectopia lentis typically occurs after age one year. In the majority of untreated individuals, ectopia lentis occurs by age eight years. Ectopia lentis usually occurs earlier in affected individuals who are B₆ non-responsive than in those who are B₆ responsive. Rarely, ectopia lentis occurs in infancy [Mulvihill et al 2001].Skeletal system. Affected individuals are often tall and slender with an asthenic (‘marfanoid’) habitus.
Individuals with homocystinuria are prone to osteoporosis, especially of the vertebrae and long bones. Fifty percent of individuals show signs of osteoporosis by their teens. Osteoporosis is most efficiently detected radiographically by lateral view of the lumbar spine.
Scoliosis, high-arched palate, pes cavus, pectus excavatum or pectus carinatum, and genu valgum are also frequently seen.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 problems typically appear in young adults [Yap et al 2001a, Kelly et al 2003].
Pregnancy increases the risk for thromboembolism, especially in the post-partum period; most pregnancies, however, are uncomplicated.CNS. Developmental delay is often the first abnormal sign in individuals with homocystinuria. IQ in individuals with homocystinuria ranges from 10 to 138. B₆-responsive individuals are more likely than individuals with B₆-non-responsive homocystinuria to be cognitively intact or only mildly affected; the mean IQ of individuals with B₆ responsiveness is 79 versus 57 for those who are B₆ non-responsive. B₆-non-responsive individuals who were identified on newborn screening, received early treatment, and had good compliance (maintenance of free homocysteine <11 μmol/L) had a mean IQ of 105 [Yap et al 2001b].
Seizures occur in 21% of untreated individuals.
Many individuals have psychiatric problems including personality disorder, anxiety, depression, obsessive-compulsive behavior, and psychotic episodes.
Extrapyramidal signs such as dystonia may occur.Other features include hypopigmentation, pancreatitis, malar flush, and livedo reticularis.

Differential DiagnosisThe clinical condition that most closely mimics classic homocystinuria is Marfan syndrome, which shares the features of long thin body habitus, arachnodactyly, and predisposition for ectopia lentis and myopia. Although ectopia lentis can also occur early in sulfite oxidase deficiency, this condition is clinically distinct from homocystinuria. Individuals with sulfite oxidase deficiency and Marfan syndrome have normal concentrations of plasma homocystine, total homocysteine, and methionine.Increased concentrations of homocystine/homocysteine or methionine also occur in biochemical genetic disorders that generally fall into two groups (see Figure 2 and Table 3) and can be secondary to other disorders or to nutritional aberrations:FigureFigure 2. Pathway demonstrating disorders in the biochemical differential diagnosis for homocystinuria Defects of methionine, S-adenosylmethionine, or S-adenosylhomocysteine metabolism, which typically have increased methionine concentration but undetectable homocystine and normal or only slightly increased total homocysteine concentration. Included in this category are several hypermethioninemic disorders such as methionine adenosyltransferase I/III deficiency [Stabler et al 2002], glycine N-methyltransferase deficiency [Mudd et al 2001a], and S-adenosylhomocysteine hydrolase deficiency [Baric et al 2004].Methionine remethylation defects, which typically have increased plasma homocystine and total homocysteine but low methionine concentrations. Because newborn screening is based on the detection of methionine (not homocystine or homocysteine), disorders of remethylation (e.g., methylenetetrahydrofolate reductase deficiency and the cobalamin defects) are not detected because plasma methionine concentration in these disorders is reduced (or normal). These disorders are folate or vitamin B₁₂ dependent.Secondary hypermethioninemia with no detectable plasma homocystine and normal or only mildly increased total homocysteine, which occurs in liver disease associated with tyrosinemia type I [Grompe 2001] or galactosemia and in cases of excessive methionine intake from high-protein diet or methionine-enriched infant formula [Mudd et al 2003].Table 3. Biochemical Aspects of Disorders Affecting Methionine MetabolismView in own windowType of DefectDisorderPlasma ConcentrationHomocystineTotal HomocysteineMethionineMethionine transmethylationMAT I/III deficiency ^{10↑
(normal, slight)↑↑GNMT deficiency 2S-adenosylhomocysteine hydrolase deficiencyTranssulfurationHomocystinuria↑↑↑↑↑↑RemethylationMTHFR deficiency↑↑↑↑↓↓
(rarely normal)Cobalamin defects1. MAT = methionine adenosyltransferase2. GNMT = glycine N-methyltransferaseNote to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).}

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in all individuals diagnosed with homocystinuria caused by cystathionine beta synthase deficiency, a pyridoxine (vitamin B₆) challenge should be conducted before treatment is begun (see Testing, Pyridoxine (B6) challenge test).Treatment of ManifestationsComplications should be managed appropriately, e.g., surgery for ectopia lentis [Neely & Plager 2001].Prevention of Primary ManifestationsThe principles of treatment are to correct the biochemical abnormalities, especially to control the elevated plasma homocystine and homocysteine concentrations as much as possible and to prevent or at least reduce the complications of homocystinuria [Yap & Naughten 1998] and to prevent further complications such as thrombosis. In those who have already had a vascular event, betaine therapy alone may prevent recurrent events [Lawson-Yuen & Levy 2010].The best results occur in those individuals identified by newborn screening and treated shortly after birth in whom the plasma homocystine concentration is maintained below 11 µmol/L (preferably, ≤5 µmol/L) [Yap et al 2001b]. It is not yet known to what extent plasma total homocysteine concentrations need to be controlled for optimal outcome.The following are measures used to control plasma homocystine concentration:Vitamin B6 (pyridoxine) therapy. In those who are shown to be B₆ responsive, treatment with pyridoxine in a dose of approximately 200 mg/day or the lowest dose that produces the maximum biochemical benefit (i.e., lowest plasma homocysteine and methionine concentrations), as determined by measurement of total homocysteine and amino acid levels, should be given.
Pyridoxine may also be included in treatment despite evidence of B₆ non-responsiveness, typically in doses of 100-200 mg daily, although some dosing of adults at 500-1000 mg daily occurs.Dietary treatment. The majority of B₆-responsive individuals also require a protein-restricted diet for metabolic control.
B₆-non-responsive neonates require a methionine-restricted diet with frequent metabolic monitoring. This diet should be continued indefinitely. Dietary treatment should be considered for clinically diagnosed individuals but often is not tolerated if begun in mid-childhood or later.
Dietary treatment reduces methionine intake by restricting natural protein intake. However, to prevent protein malnutrition, a methionine-free amino acid formula supplying the other amino acids (as well as cysteine which may be an essential amino acid in CBS deficiency) is provided. The amount of methionine required is calculated by a metabolic dietician and supplied in natural food and special low-protein foods and monitored on the basis of plasma concentrations of homocystine and total homocysteine as well as methionine.Betaine treatment. Treatment with betaine provides an alternate remethylation pathway to convert excess homocysteine to methionine (see Figure 1) and may help to prevent complications, particularly thrombosis [Yap et al 2001a, Lawson-Yuen & Levy 2010 ]. By converting homocysteine to methionine, betaine lowers plasma homocystine and total homocysteine concentrations but raises the plasma concentration of methionine. Betaine is typically provided orally at 6-9 g/day in two divided doses; the optimal dosing has not been determined [Schwahn et al 2003].
Betaine 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. Individuals who are pyridoxine non-responsive who could not attain metabolic control on diet substantially reduced their plasma homocysteine concentrations when betaine was supplemented [Singh et al 2004].
Side effects of betaine are few. (1) Some affected individuals develop a detectable body odor, resulting in reduced compliance. (2) The increase in methionine produced by betaine is usually harmless; however, cerebral edema has occurred when hypermethioninemia is extreme (>1000 µmol/L) [Yaghmai et al 2002, Devlin et al 2004, Tada et al 2004, Braverman et al 2005]. Eliminating betaine resulted in rapid reduction of the hypermethioninemia and resolution of the cerebral edema.Folate and vitamin B12 supplementation. Folate and vitamin B₁₂ optimize the conversion of homocysteine to methionine by methionine synthase, thus helping to decrease the plasma homocystine and homocysteine concentrations. When the red blood cell folate concentration and serum B₁₂ concentration are reduced, folic acid is given orally at 5 mg per day; and vitamin B₁₂ is given as hydroxycobalamin at 1 mg IM per month.SurveillanceAffected individuals should be monitored at regular intervals to detect any of the clinical complications that may develop. Appropriate therapy for the complications should be given as soon as possible.Plasma methionine concentrations should be monitored in all persons receiving betaine.Agents/Circumstances to AvoidOral contraceptives, which may tend to increase coagulability and represent risk for thromboembolism, should be avoided in females with homocystinuria.Surgery should also be avoided, if possible, because the increase in plasma homocystine and homocysteine concentrations during surgery and especially post-surgery represents 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 fluids can be taken orally. If 1.5 times maintenance fluids represent a cardiovascular risk as a result of fluid overload, basic fluid maintenance may be administered with careful clinical observation.Evaluation of Relatives at RiskPlasma concentrations of amino acids and total homocysteine should be measured in all sibs at risk as soon as possible after birth so that morbidity and mortality can be reduced by early diagnosis and treatment.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management Because women with homocystinuria may have greater-than-average risk for thromboembolism, especially post partum, prophylactic anticoagulation during the third trimester of pregnancy and post partum is recommended. The usual regimen is injection of low molecular weight heparin during the last two weeks of pregnancy and the first six weeks post partum [Gissen et al 2003]. Aspirin in low doses has also been given throughout pregnancy.Maternal homocystinuria, 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 pyridoxine or methionine-restricted diet or both should be continued during pregnancy. Betaine may also be continued and appears not to be teratogenic [Yap et al 2001b, Levy et al 2002, Gissen et al 2003, Vilaseca et al 2004, Pierre et al 2006].Therapies Under InvestigationA clinical trial, ‘Oxidative Stress Markers in Inherited Homocystinuria and the Impact of Taurine,’ was begun at The Children’s Hospital, Denver in January of 2010. See ClinicalTrials.gov.Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCBS21q22​.3Cystathionine beta-synthaseCBS homepage - Mendelian genesCBSData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency (View All in OMIM) View in own window 236200HOMOCYSTINURIA DUE TO CYSTATHIONINE BETA-SYNTHASE DEFICIENCY 613381CYSTATHIONINE BETA-SYNTHASE; CBSNormal allelic variants. CBS has 23 exons, is 25-30 kb long, and, depending on the tissue, is expressed as alternatively spliced mRNA isoforms with size varying from 2.5 to 3.7 kbp. There are multiple types of normal allelic variants in this gene.Pathologic allelic variants. At least 130 CBS mutations have been described as causing homocystinuria [CBS Mutation Database, Kraus et al 1999, Mudd et al 2001b, Moat et al 2004]. Most mutations are private; they comprise missense and nonsense mutations, deletions, insertions, and splicing mutations [Urreizti et al 2003, Linnebank et al 2004, Miles & Kraus 2004, Moat et al 2004].Table 4. Selected CBS Pathologic Allelic Variants View in own windowDNA Nucleotide ChangeProtein Amino Acid Change Reference Sequence c.833T>Cp.Ile278ThrNM_000071​.2
NP_000062​.1c.919G>Ap.Gly307SerSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). Normal gene product. The primary gene splice form encodes a subunit of 63 kd. The active form of the enzyme is a homotetramer that contains one heme and one pyridoxal 5'-phosphate per each subunit [Kraus et al 1999, Miles & Kraus 2004].Abnormal gene product. Most mutations affect the active core of cystathionine β-synthase. Mutations may also impair the binding of adenosine derivatives (e.g., AMP, ATP, S-adenosylmethionine), thus interfering with cellular energy [Scott et al 2004].