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Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency

Synonyms: Homocystinuria, Cystathionine Beta-Synthase Deficiency

, MBChB, PhD and , MD.

Author Information
, MBChB, PhD
Assistant Professor in Pediatrics, Division Genetics and Genomics and Division of Psychiatry
Boston Children's Hospital
Boston, Massachusetts
, MD
Professor of Pediatrics, Division of Genetics and Genomics
Boston Children's Hospital
Boston, Massachusetts

Initial Posting: ; Last Update: November 13, 2014.

Summary

Disease characteristics. Homocystinuria caused by cystathionine β-synthase (CBS) deficiency is characterized by developmental delay/intellectual disability, ectopia lentis and/or severe myopia, skeletal abnormalities (excessive height and length of the limbs), and thromboembolism. Expressivity is variable for all of the clinical signs. Two phenotypic variants are recognized, B6-responsive homocystinuria and B6-non-responsive homocystinuria. B6-responsive homocystinuria is typically, but not always, milder than the non-responsive variant. In the majority of untreated affected individuals, ectopia lentis occurs by age eight years. Individuals are often tall and slender with an asthenic (‘marfanoid’) habitus and are prone to osteoporosis. Thromboembolism is the major cause of early death and morbidity. IQ in individuals with untreated homocystinuria ranges widely, from 10 to 138. In B6-responsive individuals the mean IQ is 79 versus 57 for those who are B6 non-responsive. Other features that may occur include: seizures, psychiatric problems, extrapyramidal signs (e.g., dystonia), hypopigmentation, malar flush, livedo reticularis, and pancreatitis.

Diagnosis/testing. The cardinal biochemical features of homocystinuria are: markedly increased concentrations of plasma homocystine, total homocysteine, homocysteine-cysteine mixed disulfide, and methionine; increased concentration of urine homocystine; and reduced cystathionine β-synthase (CBS) enzyme activity. The diagnosis can be substantiated by detection of biallelic pathogenic variants in CBS, the gene encoding cystathionine β-synthase.

Management. Treatment of manifestations: Complications of homocystinuria should be managed appropriately; e.g., by surgery for ectopia lentis. Treatment aims to correct the biochemical abnormalities, especially to control the plasma homocystine and homocysteine concentrations and prevent thrombosis.

Prevention of primary manifestations: Neonates identified by newborn screening are treated to maintain normal or near-normal plasma total homocysteine concentrations using: protein-restricted and methionine-restricted diets; possibly betaine treatment; and/or folate and vitamin B12 supplementation. Those responsive to B6 (pyridoxine) receive pyridoxine therapy. In later childhood and beyond, treatment is aimed at maintaining the plasma homocystine concentration below 11 μmol/L and the plasma total homocysteine concentration as close to normal as possible. Betaine therapy is a major treatment in adolescents and adults.

Surveillance: Plasma total homocysteine and methionine concentrations should be monitored in all persons receiving betaine.

Agents/circumstances to avoid: Oral contraceptives in affected females. Surgery if possible. If surgery is required, fluid at 1.5 times maintenance should be given and continued until oral fluids are taken ad lib, with close monitoring to avoid fluid overload.

Evaluation of relatives at risk: Measurement of plasma concentrations of amino acids and total homocysteine in at-risk sibs immediately after birth ensures reduction of morbidity and mortality by early diagnosis and treatment.

Pregnancy management: For women with homocystinuria: Prophylactic anticoagulation with low molecular-weight heparin is recommended during the third trimester and post partum to reduce risk of thromboembolism.

Genetic counseling. Homocystinuria is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has 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. Carrier testing for at-risk family members is possible if the CBS pathogenic variants in an affected family member have been identified. Prenatal testing is possible for fetuses at increased risk through measurement of CBS enzyme activity assayed in cultured amniocytes (but not in chorionic villi because this tissue has very low activity of the CBS enzyme) or measurement of total homocysteine in cell-free amniotic fluid or molecular genetic testing if both pathogenic allelic variants in an affected family member have been identified.

Diagnosis

Classic 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).

Figure 1

Figure

Figure 1. Methionine metabolic pathway

Suggestive Findings

The diagnosis of homocystinuria caused by CBS deficiency is suspected in newborns with an abnormal newborn screen and individuals with clinical findings that range from multiple organ disease beginning in infancy or early childhood to thromboembolism only, expressed in early to middle adult years.

Newborn Screening

Classic homocystinuria can be detected in some (not all) affected individuals by screening the newborn 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: (1) a repeat dried blood specimen submitted to the newborn screening program or (2) quantitative plasma amino acid analysis and analysis of plasma total homocysteine as recommended in the methionine Image ACMGACT.jpg and Image ACMGalg.jpg of the American College of Medical Genetics. Note: 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 (1) above is selected (i.e., 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: (a) 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]. (b) 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). (c) Virtually all infants with homocystinuria detected by newborn screening programs have had pyridoxine (vitamin B6) non-responsive homocystinuria (see Natural History). It is likely that infants who are pyridoxine responsive rarely have increased methionine during the first two to three days of life, when the newborn screening specimen is obtained.

Clinical Findings

The major clinical findings in classic homocystinuria:

  • Developmental delay / intellectual disability
  • Ectopia lentis (dislocation of the ocular lens) and/or severe myopia
  • Skeletal abnormalities such as excessive height and limb length
  • Vascular abnormalities characterized by thromboembolism
  • Clinical suggestion of Marfan syndrome (although often joint flexibility is decreased in homocystinuria)

Establishing the Diagnosis

The diagnosis of classic homocystinuria in a proband can be established by (1) measurement of amino acids in plasma and urine, (2) assay of cystathionine β-synthase (CBS) enzyme activity, or (3) molecular genetic testing of CBS.

(1) Plasma and urine amino acids. Note: Plasma homocysteine concentration must be determined in the absence of pyridoxine supplementation (including a multivitamin) for two weeks.

The cardinal biochemical features, summarized in Table 1, are:

  • Markedly increased concentrations of plasma homocystine, total homocysteine, homocysteine-cysteine mixed disulfide, and methionine
  • Increased concentration of urine homocystine

Table 1. Cardinal Biochemical Findings that Establish the Diagnosis of Homocystinuria

AnalyteSpecimenExpected Findings
Neonate with
Homocystinuria
Untreated Older Individual with HomocystinuriaControl
Homocystine 1Plasma 2 10-45 µmol/L
(0-1.2 mg/dL)
>100 µmol/L
(>3 mg/dL)
Undetectable
Total homocysteine 1 (tHcy)Plasma 250-100 µmol/L>100 µmol/L<15 µmol/L
MethioninePlasma200-1500 µmol/L
(3-23 mg/dL)
>50 µmol/L
(>0.7 mg/dL)
10-40 µmol/L
(0.2-0.6 mg/dL)
HomocystineUrine 3DetectableDetectableUndetectable

1. Click here for terms used to describe sulfur amino acids.

2. 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].

3. Urine homocystine is quite stable owing to the relatively small amount of protein in urine (e.g., bound thiols such as cysteine).

(2) Measurement of cystathionine β-synthase (CBS) enzyme activity in cultured 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.

Note: 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.

(3) Molecular genetic testing of CBS (encoding cystathionine β-synthase). See Table 2. Identification of biallelic CBS pathogenic variants substantiates the diagnosis. Most individuals worldwide are compound heterozygotes for novel pathogenic variants.

Table 2. Summary of Molecular Genetic Testing Used in Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
CBSTargeted mutation analysis 2See footnote 3
Sequence analysis 4>95% 5
Deletion/duplication analysis6See footnote 7

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants.

2. Pathogenic variants included in a panel may vary by laboratory.

3. The two most common CBS pathogenic variants, p.Ile278Thr and p.Gly307Ser, are found in exon 8. See Molecular Genetics for details.

4. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Sequence analysis of the entire coding region of CBS detected: (a) biallelic pathogenic variants in 26 of 28 unrelated Australian families and one pathogenic variant in the remaining two families [Gaustadnes et al 2002]; (b) biallelic pathogenic variants in six of seven Venezuelans and one pathogenic variant in the other [De Lucca & Casique 2004]; (c) biallelic pathogenic variants in four of 12 affected individuals in the state of Georgia (US) and one pathogenic variant in the remaining eight [Kruger et al 2003, De Lucca & Casique [2004], Karaca et al [2014].

6. Testing that identifies exonic or whole-gene deletions/duplications not 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.

7. Nine individuals with deletions or duplications involving 25 or more nucleotides have been reported to date [Kraus Lab / CBS Mutation Database].

Testing Following Establishment of the Diagnosis

Pyridoxine (B6) challenge test. The two phenotypic variants of classic homocystinuria – B6-responsive and B6-non-responsive homocystinuria – have differing natural history and management. Once the diagnosis of homocystinuria caused by deficiency of cystathionine β synthase (CBS) is established, a pyridoxine challenge to measure vitamin B6-responsiveness is used to determine which phenotype is present.

  • 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 on withdrawal of pyridoxine [Shoji et al 1998, Mudd et al 2001].

Clinical Description

Natural History

Homocystinuria 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].

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 test (see Testing Following Establishment of the Diagnosis).

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].

High myopia may be present in the absence of ectopia lentis.

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].

Among B6-responsive individuals, a vascular event in adolescence or adulthood is often the presenting feature of homocystinuria [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 2014].

Pregnancy increases the risk for thromboembolism, especially in the post-partum period [Novy et al 2010]; 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. Psychosis may be a presenting sign in adolescence [Hidalgo Mazzei et al 2013].

Extrapyramidal signs such as dystonia may occur.

Other features include hypopigmentation, pancreatitis, malar flush, and livedo reticularis.

Genotype-Phenotype Correlations

The presence of a single p.Gly307Ser allele almost always predicts B6 non-responsiveness, while presence of a p.Ile278Thr allele predicts B6 responsiveness [Gaustadnes et al 2002, Kruger et al 2003, Skovby et al 2010]. Other mutant alleles are associated with B6 responsiveness or non-responsiveness [Kraus et al 1999].

Nomenclature

Excess homocystine in the urine (‘homocystinuria’ in the narrowest sense of the word) may be caused by genetically determined deficient activity of cystathionine β-synthase (CBS), or a variety of genetic problems that ultimately interfere with tetrahydrofolate-dependent or methylcobalamin-dependent 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 particular defect 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 discussed in this GeneReview is caused by deficiency of cystathionine β-synthase (CBS), a pyridoxine (vitamin B6)-dependent enzyme.

Prevalence

Prevalence is at present undetermined; both newborn screening and clinical ascertainment underestimate prevalence because of undetected cases [Skovby et al 2010]. Prevalence has been reported as 1:200,000 to 1:335,000.

  • In Qatar the prevalence may be the highest in the world and has been reported as 1:1800 [Gan-Schreier et al 2010].
  • In Ireland, the prevalence is reported to be as high as 1:65,000 [Naughten et al 1998].
  • In Germany, molecular genetic screening of a normal population estimated classic homocystinuria to be as prevalent as 1:17,800 [Linnebank et al 2001].
  • In Norway, molecular genetic screening of newborns employing a panel of six pathogenic variants estimated the prevalence of classic homocystinuria to be approximately 1:6400, based on the heterozygosity rate [Refsum et al 2004].

Differential Diagnosis

The 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:

Figure 2

Figure

Figure 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, glycine N-methyltransferase deficiency and S-adenosylhomocysteine hydrolase deficiency [Mudd 2011].
  • 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 Metabolism

Type of DefectDisorderPlasma Concentration
HomocystineTotal HomocysteineMethionine
Methionine transmethylationMAT I/III deficiency 10
(normal, slight)
↑↑
GNMT deficiency 2
S-adenosylhomocysteine hydrolase deficiency
TranssulfurationHomocystinuria↑↑↑↑↑↑
RemethylationMTHFR deficiency↑↑↑↑↓↓
(rarely normal)
Cobalamin defects

1. MAT = methionine adenosyltransferase

2. GNMT = glycine N-methyltransferase

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in all individuals diagnosed with homocystinuria caused by cystathionine beta synthase deficiency, the following are recommended:

Treatment of Manifestations

Complications should be managed appropriately (e.g., surgery for ectopia lentis) [Neely & Plager 2001].

Prevention of Primary Manifestations

The 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 measures are used to control total plasma homocysteine 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.

Note: In a murine model for homocystinuria the effect of betaine treatment was diminished significantly over time [Maclean et al 2012].

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.

Surveillance

Affected 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 total homocysteine and methionine concentrations should be monitored in all persons receiving betaine.

Agents/Circumstances to Avoid

Oral 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 fluids at 1.5 times maintenance represent a cardiovascular risk as a result of fluid overload, basic fluid maintenance may be administered with careful clinical observation.

Evaluation of Relatives at Risk

Plasma 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.

If the CBS pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of sibs.

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

Pregnancy Management

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. 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 Investigation

A clinical trial, ‘Oxidative Stress Markers in Inherited Homocystinuria and the Impact of Taurine,’ was begun at The Children’s Hospital, Denver in August of 2010 and is still recruiting participants. See ClinicalTrials.gov.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Homocystinuria caused by cystathionine β-synthase deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The unaffected parents of an affected individual are obligate heterozygotes and therefore carry at least one CBS pathogenic variant.
  • Heterozygotes (carriers) are asymptomatic and never develop homocystinuria.
  • Because it is possible (though unlikely) that a parent has classic homocystinuria but has remained asymptomatic, it is appropriate to obtain a detailed medical history and perform an examination as well as plasma and urine amino acid analysis in both parents. This becomes even more imperative should the mother be considering future pregnancies, as affected women are at increased risk for thromboembolic events during pregnancy.

Sibs of a proband

  • At conception, each sib of an affected individual has 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 an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. Because classic homocystinuria is treatable, affected individuals who have the benefit of effective treatment are physically and intellectually normal and can reproduce.

  • The offspring of an individual with classic homocystinuria have at least one CBS pathogenic variant.
  • The offspring of a proband whose partner is a carrier have a 50% chance of being affected and a 50% chance of being carriers.
  • All offspring of a proband whose partner also has classic homocystinuria will have classic homocystinuria.

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

Carrier Detection

Molecular genetic testing. Carrier testing for at-risk family members is possible if both CBS pathogenic variants have been identified in the family.

Biochemical genetic testing. 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].

Related Genetic Counseling Issues

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

Maternal homocystinuria, unlike maternal phenylketonuria, 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, Pierre et al 2006]. Nevertheless, treatment to control plasma homocystine and homocysteine concentrations should be continued during pregnancy.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Biochemical testing

  • Prenatal testing for pregnancies at increased risk is possible through measurement of CBS enzyme activity assayed in cultured amniocytes obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation [Fowler & Jakobs 1998], but not in chorionic villi because this tissue has very low CBS enzyme activity.
  • Measurement of total homocysteine in cell-free amniotic fluid is also possible.

Molecular genetic testing. If the CBS pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

Requests for prenatal testing for conditions which (like homocystinuria caused by cystathionine β-synthase deficiency) have effective treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the CBS pathogenic variants have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Homocystinuria: Genetic Fact Sheet for Parents
    Screening, Technology And Research in Genetics (STAR-G)
  • National Library of Medicine Genetics Home Reference
  • National Organization for Rare Disorders (NORD)
  • Association for Neuro-Metabolic Disorders (ANMD)
    5223 Brookfield Lane
    Sylvania OH 43560-1809
    Phone: 419-885-1809; 419-885-1497
    Email: volk4olks@aol.com
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    Climb Building
    176 Nantwich Road
    Crewe CW2 6BG
    United Kingdom
    Phone: 0800-652-3181 (toll free); 0845-241-2172
    Fax: 0845-241-2174
    Email: info.svcs@climb.org.uk

Molecular Genetics

Information 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 Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
CBS21q22​.3Cystathionine beta-synthaseCBS databaseCBS

Data 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)

236200HOMOCYSTINURIA DUE TO CYSTATHIONINE BETA-SYNTHASE DEFICIENCY
613381CYSTATHIONINE BETA-SYNTHASE; CBS

Gene structure. CBS has 23 exons, is 25-30 kb in length, and, depending on the tissue, is expressed as alternatively spliced mRNA isoforms with size varying from 2.5 to 3.7 kbp. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. At least 164 CBS pathogenic variants have been described as causing homocystinuria (see CBS Mutation Database). Most pathogenic variants are private; they comprise missense and nonsense variants, deletions, insertions, and splicing variants [Urreizti et al 2003, Linnebank et al 2004, Miles & Kraus 2004, Moat et al 2004].

Of the 164 pathogenic variants currently identified, 67% in individuals with CBS deficiency are missense variants, the vast majority of which are private. Among the other pathogenic variants, only five are nonsense variants and the remainder are various deletions, insertions, and splicing variants (see CBS Mutation Database for a database of current mutations).

The two most common CBS pathogenic variants, p.Ile278Thr and p.Gly307Ser, are found in exon 8.

  • p.Ile278Thr is pan ethnic; overall, it accounts for nearly 25% of all pathogenic variants, including 29% of the variant 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 pathogenic variants [Skovby et al 2010].
  • p.Gly307Ser is the leading cause of homocystinuria in Ireland (71% of pathogenic variants). It has also been detected frequently in US and Australian affected individuals of 'Celtic' origin, 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].

Table 4. Selected CBS Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
c.833T>Cp.Ile278ThrNM_000071​.2
NP_000062​.1
c.919G>Ap.Gly307Ser

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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 pathogenic variants affect the active core of cystathionine β-synthase. 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].

References

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Suggested Reading

  1. Sahai I, Marsden D. Newborn screening. Crit Rev Clin Lab Sci. 2009;46:55–82. [PubMed: 19255915]

Chapter Notes

Author Notes

Authors’ Web site: New England Consortium of Metabolic Programs

Revision History

  • 13 November 2014 (me) Comprehensive update posted live
  • 26 April 2011 (me) Comprehensive update posted live
  • 29 March 2006 (me) Comprehensive update posted to live Web site
  • 15 August 2005 (cd) Revision: sequence analysis of entire coding region no longer clinically available
  • 15 January 2004 (ca) Review posted to live Web site
  • 2 September 2003 (hl) Original submission
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