Figure 1. Methionine metabolic pathway
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for the most up-to-date Resources information.—ED.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Disease characteristics. Homocystinuria caused by cystathionine β-synthase (CBS) deficiency is characterized by developmental delay/mental retardation, 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 eight years of age. Individuals are often tall and slender with an asthenic habitus ("marfanoid" look) and prone to osteoporosis. Thromboembolism is the major cause of early death and morbidity. IQ in individuals with homocystinuria ranges from 10 to 138. The mean IQ of affected individuals with B6-responsiveness is 79 versus 57 for those who are B6 non responsive. Other features that may occur include seizures, psychiatric problems, extrapyramidal signs such as dystonia, hypopigmentation, pancreatitis, malar flush, and livedo reticularis.
Diagnosis/testing. The cardinal biochemical features of homocystinuria are markedly increased concentrations of plasma homocystine, total homocysteine, and methionine; increased concentration of urine homocystine; and reduced cystathionine β-synthase (CBS) enzyme activity. CBS is the only gene known to be associated with homocystinuria caused by cystathionine β-synthase deficiency. Molecular genetic testing, including targeted mutation analysis for the two common alleles and sequence analysis of the entire coding region, is clinically available.
Management. Complications of homocystinuria should be managed appropriately, e.g., by surgery for ectopia lentis. Treatment aims to correct the biochemical abnormalities, especially to control plasma homocystine concentration and prevent thrombosis. Individuals identified by newborn screening are treated shortly after birth to maintain plasma homocystine concentration below 11 µmol/L. Treatment includes using vitamin B6 (pyridoxine) therapy, protein-restricted and methionine-restricted diets, betaine treatment, and/or folate and vitamin B12 supplementation. Plasma methionine concentrations should be monitored in all persons receiving betaine. Oral contraceptives are avoided in affected females. Surgery is avoided if possible; fluid maintenance and risk of fluid overload are carefully monitored if surgery is required. Measurement of plasma concentrations of amino acids and homocysteine in at-risk sibs immediately after birth ensures reduction of morbidity and mortality by early diagnosis and treatment. Prophylactic anticoagulation during the third trimester of pregnancy and post partum in women with homocystinuria is recommended 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. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Prenatal testing is available for fetuses at increased risk through measurement of CBS enzyme activity assayed in cultured amniocytes but not in chorionic villi, since this tissue has very low activity of the CBS enzyme; measurement of total homocysteine in cell-free amniotic fluid; and molecular genetic testing if both disease-causing alleles of an affected family member have been identified. Carrier testing for at-risk family members may be available once the CBS mutations have been identified in the proband.
Figure 1. Methionine metabolic pathway
Figure 1). The 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 only thromboembolism expressed in early to middle adult years.
The major findings in classic homocystinuria:
Developmental delay/mental retardation
Ectopia lentis (dislocation of the ocular lens) and/or severe myopia
Skeletal abnormalities such as excessive height and length of the limbs
Vascular abnormalities characterized by thromboembolism
Clinical suggestion of Marfan syndrome
Newborn screening diagnosis. Classic homocystinuria can be detected by screening the Guthrie blood spot card for hypermethioninemia by either bacterial assay or tandem mass spectrometry [Chace et al 1996].
Methods used to measure methionine vary among newborn screening programs both within and outside of the US [Peterschmitt et al 1999]. 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.
If the second test confirms hypermethioninemia, quantitative plasma and urine amino acid testing with attention to concentrations of methionine, homocystine, and total homocysteine is performed to confirm or exclude the diagnosis of homocystinuria (Table 1).
It is important to note that the 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 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.
For laboratories offering biochemical testing, see
.
The 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 symmetrical 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 reduction
Total 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. tfHcy is distinguished from tHcy, which includes the Hcy that was formerly protein bound.
The cardinal biochemical features of classic homocystinuria are 1) markedly increased concentrations of plasma homocystine, total homocysteine, homocysteine-cysteine mixed disulfide, and methionine and 2) increased concentration of urine homocystine (Table 1).
| Analyte | Specimen | Expected Findings | ||
|---|---|---|---|---|
| Neonate with Homocystinuria | Untreated Older Individual with Homocystinuria | Control | ||
| Homocystine | Plasma 1 | 10-100 µmol/L (0.1-1.3 mg/dL) | >100 µmol/L (>3 mg/dL) | <1 µmol/L (<0.03 mg/dL) |
| Total homocysteine (tHcy) | Plasma 1 | 50-100 µmol/L | >100 µmol/L | <15 µmol/L |
| Methionine | Plasma | 200-1500 µmol/L (3-23 mg/dL) | >50 µmol/L (>0.7 mg/dL) | 10-40 µmol/L (0.2-0.6 mg/dL) |
| Homocystine | Urine 2 | Detectable | Detectable | Undetectable |
1. 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 [Uhlendorf et al 1973, Fowler et al 1978] 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 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 in a child or adult but no more than 300 mg in an infant. If plasma homocystine 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 have developed respiratory failure that require ventilatory support. The respiratory symptoms resolved on withdrawal of pyridoxine [Shoji et al 1998; Mudd, Levy et al 2001].
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, as 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.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. CBS is the only gene known to be associated with homocystinuria caused by cystathionine β-synthase deficiency.
Most of the mutations found in individuals with CBS deficiency are missense mutations and the vast majority are private mutations. Seventy-one missense mutations have been found to date. There are only four known nonsense mutations and the remainder are various deletions, insertions, and splicing mutations [Kraus et al 1999]. Most individuals globally are compound heterozygotes with private mutations.
Molecular genetic testing: Clinical uses
Molecular genetic testing: Clinical methods
Targeted mutation analysis. The two most common CBS mutations, I278T and G307S, are found in exon 8.
The I278T mutation is panethnic; overall, it accounts for nearly 25% of all disease-causing alleles. I278T accounts for 29% of the mutant alleles in affected individuals examined in the UK and 18% in the US [Moat et al 2004]. In some countries, e.g., the Netherlands, it accounts for more than half of the affected alleles [Kluijtmans et al 1999].
The G307S mutation is the leading cause of homocystinuria in Ireland (71% of affected alleles) [Gallagher et al 1995]. 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. G307S 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 Georgia (US) found homozygosity in four and heterozygosity in the remaining eight [Kruger et al 2003].
Table 2 summarizes molecular genetic testing for this disorder.
| Test Methods | Mutations Detected | Mutation Detection Rate 1 | Test Availability |
|---|---|---|---|
| Targeted mutation analysis | CBS I278T allele | US: 18% 2 UK: 29% 3 | Clinical
|
| CBS G307S allele | Ireland: >70% 4 UK: 21% 3 US: 8% 3 | ||
| Sequence analysis | CBS sequence alterations | >95% 5 |
1. % of mutant alleles
2. Kraus et al 1999
3. Moat et al 2004
4. Gallagher et al 1995
5. Kruger et al 2003, De Lucca & Casique 2004
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
The diagnosis of classic homocystinuria is established by amino acid analysis of plasma and urine, as well as determination of 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
No other phenotypes are associated with mutations in CBS.
Homocystinuria is characterized by involvement of the eye, skeletal system, vascular system, and CNS [Mudd et al 1985]. 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].
Eyes. Myopia followed by ectopia lentis typically occurs after one year of age. In the majority of untreated individuals, ectopia lentis occurs by eight years of age [Burke et al 1989]. Ectopia lentis usually occurs earlier in affected individuals who are B6-non-responsive than in those who are B6-responsive [Mudd et al 1985]. Rarely, ectopia lentis occurs in infancy [Mulvihill et al 2001].
Skeletal system. Affected individuals are often tall and slender with an asthenic habitus ("marfanoid" look).
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 frequent.
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, Boers et al 2001; 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 [Mudd et al 1985].
Seizures occur in 21% of untreated individuals.
Many individuals have psychiatric problems including personality disorder, anxiety, depression, obsessive-compulsive behavior, and psychotic episodes [Abbott et al 1987].
Extrapyramidal signs such as dystonia may occur.
Other features include hypopigmentation, pancreatitis, malar flush, and livedo reticularis.
The presence of a single G307S allele almost always predicts B6 non-responsiveness, while presence of an I278T allele usually predicts B6 responsiveness [Kraus et al 1999, Gaustadnes et al 2002, Kruger et al 2003]. Other mutant alleles are associated with B6 responsiveness or non-responsiveness [Kraus et al 1999].
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 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 Rosenblatt & Fenton 2001).
Non-genetically determined severe dietary lack of cobalamin (vitamin B12 deficiency) has also been said to 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 is at present undetermined; both newborn screening and clinical ascertainment underestimate prevalence because of undetected cases. Prevalence has been reported as 1:200,000 to 1:335,000 [Mudd et al 1995].
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 mutations estimated the prevalence of classic homocystinuria to be approximately 1:6400, based on the heterozygosity rate [Refsum et al 2004].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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.
Figure 2. Pathway demonstrating disorders in the biochemical differential diagnosis for homocystinuria
Figure 2 and Table 3) and can be secondary to other disorders or to nutritional aberrations:
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, Cerone et al 2001], 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 [Levy et al 1969] or methionine-enriched infant formula [Mudd et al 2003].
| Type of Defect | Disorder | Plasma Concentration | ||
|---|---|---|---|---|
| Homocystine | Total Homocysteine | Methionine | ||
| Methionine transmethylation | MAT I/III 1 deficiency | 0 | ↑ (normal, slight) | ![[up double arrow]](corehtml/pmc/pmcents/x21D1.gif) |
| GNMT 2 deficiency | ||||
| S-adenosylhomocysteine hydrolase deficiency | ||||
| Transsulfuration | Homocystinuria | | | |
| Remethylation | MTHFR deficiency | | | ![[down double arrow]](corehtml/pmc/pmcents/x21D3.gif)
(rarely normal) |
| Cobalamin defects | ||||
1. Methionine adenosyltransferase I/III
2. Glycine N-methyltransferase
All affected individuals, whether clinically diagnosed or identified by newborn screening, should be challenged with pyridoxine (vitamin B6) before treatment is begun (see Testing).
Complications should be managed appropriately, e.g., surgery for ectopia lentis [Neely & Plager 2001].
The principles of treatment are to correct the biochemical abnormalities, especially to control the elevated plasma homocystine concentration as much as possible and to prevent, or at least reduce, the complications of homocystinuria [Yap & Naughten 1998] or to prevent further complications such as thrombosis. 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, no higher than 5 µmol/L) [Yap, Rushe et al 2001]. 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 benefit, 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, Boers et al 2001; Lawson-Yuen & Levy, in press]. In converting homocysteine to methionine, betaine lowers the plasma-free homocysteine 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; however, 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 concentration. 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 hydroxocobalamin at 1 mg IM per month.
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 methionine concentrations should be monitored in all persons receiving betaine.
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, as 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 represents a cardiovascular risk as a result of fluid overload, basic fluid maintenance may be administered with careful clinical observation.
Plasma concentrations of amino acids and 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.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
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 [Wilcken & Wilcken 1997; Yap, Rushe et al 2001; Levy et al 2002; Gissen et al 2003; Vilaseca et al 2004].
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Homocystinuria caused by cystathionine β-synthase deficiency is inherited in an autosomal recessive manner.
Parents of a proband
The unaffected parents of an affected individual are obligate heterozygotes and therefore carry at least one disease-causing CBS allele.
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 individuals have an increased risk of 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 disease-causing mutation in the CBS gene.
Each offspring of a proband whose partner is a carrier has a 50% chance of being affected and a 50% chance of being a carrier.
Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.
Carrier testing for at-risk family members may be available once the CBS mutations have been identified in the proband (see Determination of carrier status).
Biochemical testing is not a reliable method of carrier identification.
Maternal homocystinuria. 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]. 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.
DNA banking. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.
Biochemical testing
Prenatal testing is available for fetuses at increased risk through measurement of CBS enzyme activity assayed in cultured amniocytes obtained by amniocentesis usually performed at about 15-18 weeks' gestation [Fowler & Jakobs 1998], but not in chorionic villi since this tissue has very low CBS enzyme activity [Fowler et al 1989].
Measurement of total homocysteine in cell-free amniotic fluid is also possible [Rabier et al 1996].
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Molecular genetic testing. No laboratories offering molecular genetic testing for prenatal diagnosis of homocystinuria caused by cystathionine β-synthase deficiency are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutations have been identified in an affected family member in a research or clinical laboratory. For laboratories offering custom prenatal testing, see
.
Requests for prenatal testing for conditions such as homocystinuria caused by cystathionine β-synthase deficiency that 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, careful discussion of these issues is appropriate.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified in an affected family member in a research or clinical laboratory. For laboratories offering PGD, see
.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| CBS | 21q22.3 | Cystathionine beta-synthase |
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
| 236200 | HOMOCYSTINURIA |
| Gene Symbol | Locus Specific | Entrez Gene | HGMD |
|---|---|---|---|
| CBS | CBS | 875 (MIM No. 236200) | CBS |
For a description of the genomic databases listed, click here.
Normal allelic variants: The CBS gene has 23 exons, is 25-30 kbp long and, depending on the tissue, is expressed as alternatively spliced mRNA isoforms with size varying from 2.5 to 3.7 kbp as well as SNPs, STR/VNTR, and ins/del.
Pathologic allelic variants: At least 130 CBS mutations have been described as causing homocystinuria [www.uchsc.edu/sm/cbs/cbsdata/cbsmain.htm; Kraus et al 1999; Mudd, Levy et al 2001; 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].
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].
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
National Library of Medicine Genetics Home Reference
Homocystinuria
Association for Neuro-Metabolic Disorders (ANMD)
PO Box 0202/L3220
1500 Medical Center Drive
Ann Arbor, MI 48109-0202
Phone: 313-763-4697
Fax: 313-764-7502
Canadian Society For Metabolic Disease
PO Box 64606
1942 Como Lake Avenue
Coquitlam, British Columbia, Canada V3J 7V7
Phone: 604-464-1017
Children Living with Inherited Metabolic Diseases (CLIMB)
Climb Building
176 Nantwich Road
Crewe CW2 6BG
United Kingdom
Phone: (+44) 0870 7700 326
Fax: (+44) 0870 7700 327
Email: steve@climb.org.uk
www.climb.org.uk
National Coalition for PKU and Allied Disorders
PO Box 1244
Mansfield, MA 02048
Phone: 877-996-2723
Fax: 508-337-4577
Email: Coalition4pkuad@aol.com
www.pku-allieddisorders.org
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
Authors’ Web site: New England Consortium of Metabolic Programs
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
