Clinical characteristics.

Homocystinuria caused by cystathionine β-synthase (CBS) deficiency is characterized by involvement of the eye (ectopia lentis and/or severe myopia), skeletal system (excessive height, long limbs, scolioisis, and pectus excavatum), vascular system (thromboembolism), and CNS (developmental delay/intellectual disability). 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. Two phenotypic variants are recognized, B₆-responsive homocystinuria and B₆-non-responsive homocystinuria. B₆-responsive homocystinuria is usually milder than the non-responsive variant.

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 B_6-non-responsive. Other features that may occur include: seizures, psychiatric problems, extrapyramidal signs (e.g., dystonia), hypopigmentation of the skin and hair, malar flush, livedo reticularis, and pancreatitis.

Diagnosis/testing.

The cardinal biochemical features of homocystinuria include markedly increased concentrations of plasma total homocysteine and methionine. The diagnosis can be substantiated by detection of biallelic pathogenic variants in CBS, the gene encoding cystathionine β-synthase.

Management.

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

Prevention of primary manifestations: Individuals are treated to maintain normal or near-normal plasma total homocysteine concentrations using vitamin B₆ (pyridoxine) therapy (if shown to be B₆ responsive), a methionine-restricted diet, and folate and vitamin B₁₂ supplementation. Betaine therapy is usually added to the therapeutic regimen; in adolescents and adults, betaine may be the major form of treatment, but it is preferable to remain on life-long metabolic diet.

Surveillance: Affected individuals should be monitored at regular intervals to detect any clinical complications that may develop, for dietary compliance and for measurement of plasma total homocysteine and amino acids.

Agents/circumstances to avoid: Oral contraceptives in affected females. Surgery if possible. If surgery is required, intravenous fluid with 5% dextrose in 0.5 normal saline 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 total homocysteine and amino acids in at-risk sibs immediately after birth ensures reduction of morbidity and mortality 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

Pregnancy management: For women with classic homocystinuria: dietary treatment and betaine, and vitamin B₆ for those B₆ responsive, with careful biochemical monitoring throughout pregnancy. Prophylactic anticoagulation with low molecular-weight heparin is recommended during the third trimester and post partum to reduce risk of thromboembolism.

Genetic counseling.

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 and prenatal testing for a pregnancy at increased risk are possible if the CBS pathogenic variants have been identified in an affected family member.

Suggestive Findings

Homocystinuria caused by CBS deficiency (classic homocystinuria) should be suspected in newborns with an abnormal newborn screen due to increased methionine 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.

Establishing the Diagnosis

The diagnosis of classic homocystinuria is established in a proband by measurement of plasma total homocysteine (tHcy) and amino acids in plasma (see Plasma Homocysteine and Amino Acids) and/or by identification of biallelic pathogenic variants in CBS through molecular genetic testing (see Table 2). Enzyme analysis of cystathionine β-synthase (CBS) activity may be performed if pathogenic variants are not identified.

Testing Following Establishment of the Diagnosis

Pyridoxine (B₆) challenge test. The two phenotypic variants of classic homocystinuria – B₆-responsive and B₆-non-responsive homocystinuria – can 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.

• In the neonate. While continuing a normal diet, plasma is obtained for baseline measurements of total homocysteine and amino acids.
  The affected individual is given 100 mg pyridoxine daily for two consecutive days; concentrations of plasma total homocysteine and amino acids are measured 48 hours after the first dose.
  • A reduction of 30% or more in plasma total homocysteine and/or plasma methionine concentration suggests B₆ responsiveness.
  • If no significant change occurs, 200 mg pyridoxine is given orally for two consecutive days and the plasma total homocysteine and amino acid analysis are repeated after 48 hours on this dose.
  • If still no change has occurred, 300 mg of pyridoxine is given to the neonate. If plasma homocysteine and methionine concentrations are not significantly decreased after the last dose of pyridoxine, it is concluded that the individual is B₆-non-responsive.
• Beyond the neonatal period. For a clinically identified individual, continue a normal diet and provide folate supplement of 5 mg (for children and adults); correct B₁₂ deficiency if present. Obtain plasma for baseline measurements of total homocysteine and amino acids.
  The affected individual is given 100 mg pyridoxine daily for two consecutive days, and the concentrations of plasma total homocysteine and amino acids are again measured 48 hours after the first dose.
  • A reduction of 30% or more in plasma total homocysteine and/or plasma methionine concentration suggests B₆ responsiveness.
  • If no significant change occurs, 200 mg pyridoxine is given orally for two consecutive days and the plasma total homocysteine and amino acid analysis are repeated after 48 hours on this dose.
  • If still no change has occurred, 500 mg of pyridoxine is given orally to a child or adult. If plasma 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: (1) 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]. (2) Peripheral neuropathy has been seen as an adverse effect of pyridoxine doses exceeding 900 mg per day [Morris et al 2017].

Clinical Description

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 a marfanoid habitus.

Individuals with homocystinuria are prone to osteoporosis, especially of the vertebrae and long bones; 50% of individuals show signs of osteoporosis by their teens. Osteoporosis may be detected radiographically by lateral view of the lumbar spine or bone density studies. DXA bone density analysis usually shows reduced density in the lumbar spine and hip [Weber et al 2016].

Scoliosis, high-arched palate, arachnodactyly, 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 2015].

Pregnancy increases the risk for thromboembolism, especially in the postpartum period [Novy et al 2010]; most pregnancies, however, are uncomplicated. See Pregnancy Management.

CNS. Developmental delay is often the first 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 untreated 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 plasma free homocystine <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 2014].

Extrapyramidal signs such as dystonia may occur.

Other features include hypopigmentation of the skin and hair, malar flush, livedo reticularis, and pancreatitis.

Genotype-Phenotype Correlations

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

Nomenclature

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

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

To attain maximum specificity when using the term "homocystinuria," the 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 as defined 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.

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

Evaluations Following Initial Diagnosis

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

• Consultation with a clinical geneticist/medical biochemical geneticist for additional testing and treatment plan
• Pyridoxine (vitamin B₆) challenge prior to initiation of treatment (see Testing Following Establishment of the Diagnosis, Pyridoxine (B₆) challenge test)
• Consultation with a genetic counselor for genetic counseling and recurrence risk counseling

Treatment of Manifestations

Treatment should be managed by a biochemical geneticist and metabolic dietician and aimed at prevention of primary manifestations of homocystinuria. For published management guidelines, see Morris et al [2017].

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 homocysteine concentrations as much as possible, to prevent or at least reduce the complications of homocystinuria [Yap & Naughten 1998], and to prevent further complications such as thrombosis [Morris et al 2017].

The best results have been reported in those individuals identified by newborn screening and treated shortly after birth in whom the plasma free homocystine concentration is maintained below 11 µmol/L (preferably, ≤5 µmol/L) [Yap et al 2001b]. This corresponds to a plasma total homocysteine concentration below 120 µmol/L or, preferably, below 100 µmol/L [Morris et al 2017]. For B₆-responsive individuals, the goal for plasma total homocysteine is below 50 µmol/L [Morris et al 2017].

These goals may need revision when very long-term data becomes available.

Measures used to control total plasma homocysteine concentration include vitamin B₆ (pyridoxine) therapy (if shown to be B₆ responsive), methionine-restricted diet, and folate and vitamin B₁₂ supplementation. Betaine therapy is usually added to the therapeutic regimen; in adolescents and adults betaine may be the major form of treatment but it is preferable to remain on life-long metabolic diet. In those who have already had a vascular event, betaine therapy alone may prevent recurrent events [Lawson-Yuen & Levy 2010].

Details about each aspect of treatment follow.

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 adults receive 500-1000 mg daily).

Dietary treatment. B₆-non-responsive neonates or those only very poorly responsive to pyridoxine 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.

The majority of B₆-responsive individuals also require a methionine-restricted diet for metabolic control.

The diet for homocystinuria is very complex and the skills of an experienced metabolic dietician must be utilized. 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. Breast feeding may be continued in combination with the methionine-free amino acid infant formula [MacDonald et al 2006]. 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 total homocysteine as well as methionine.

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 homocysteine 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 hydroxycobalamin at 1 mg IM per month.

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 total homocysteine concentrations but raises the plasma concentration of methionine.

For children the initial betaine dose is 50 mg/kg twice daily, adjusted according to response (increased weekly by 50 mg/kg increments). For adults the initial dose is 3 g twice daily. The dose and frequency are adjusted according to biochemical response. There is unlikely to be any benefit in exceeding a dose of 150-200 mg/kg/day [Morris et al 2017].

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 were unable to attain metabolic control with 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 diminished significantly over time [Maclean et al 2012].

Surveillance

Affected individuals should be monitored at regular intervals to detect any clinical complications that may develop, to assess dietary compliance, and to measure plasma total homocysteine and methionine concentrations. Infants should be monitored monthly for the first six months of life and bimonthly until age one year, then every three months until age three years. Semiannual monitoring through the remainder of childhood and annual monitoring in adolescence and adulthood are indicated. Complications should be promptly addressed with appropriate therapy.

Plasma total homocysteine and methionine concentrations should be monitored in all persons receiving betaine (see Prevention of Primary Manifestations, Betaine treatment).

Vitamin B₁₂ and folate levels should be monitored.

Regular ophthalmology assessments can identify eye complications such as progressive myopia and ectopia lentis and allow for early treatment and prevention of further complications such as retinal detachment.

DXA scans should be performed every three to five years following adolescence to monitor for osteoporosis [Morris et al 2017].

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 homocysteine concentrations during surgery and especially post-surgery elevates the risk for a thromboembolic event. If surgery is required, intravenous fluids containing 5% dextrose in 0.5 N saline 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 total homocysteine and amino acids should be measured in at-risk sibs as soon as possible after birth so that morbidity and mortality can be reduced by early diagnosis and treatment.

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 [Pierre et al 2006]. 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 [Morris et al 2017]. Betaine may also be continued and appears not to be teratogenic [Yap et al 2001b, Levy et al 2002, Vilaseca et al 2004, Pierre et al 2006].

Therapies Under Investigation

CBS enzyme replacement therapy is currently in development in the preclinical phase [Bublil et al 2016].

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

Mode of Inheritance

Homocystinuria caused by cystathionine β-synthase deficiency (classic homocystinuria) 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 (i.e., carriers of at least one CBS pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing 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 homocysteine and amino acid analysis in both parents. This becomes even more imperative if the mother is 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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing homocystinuria.

Offspring of a proband. Because classic homocystinuria is treatable, affected individuals who have the benefit of effective treatment may be 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. Each sib of the proband's parents is at a 50% risk of being a carrier of a CBS pathogenic variant.

Carrier Detection

Molecular genetic testing. Carrier testing for at-risk family members requires prior identification of both CBS pathogenic variants 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.
• 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, Krupková-Meixnerová 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.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

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

Prenatal Testing and Preimplantation Genetic Testing

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

If the CBS pathogenic variants are unknown, measurement of CBS enzyme activity assayed in cultured amniocytes is theoretically possible. However, identifying a laboratory to perform this testing may be challenging; currently no such testing is available in the US.

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

Published Guidelines / Consensus Statements

• Morris AAM, Kožich V, Santra S, Andria G, Ben-Omran TIM, Chakrapani AB, Crushell E, Henderson MJ, Hochuli M, Huemer M, Janssen MCH, Maillot F, Mayne PD, McNulty J, Morrison TM, Ogier H, O’Sullivan S, Pavlíková M, Talvares de Almeida I, Terry A, Yap S, Blom HJ, Chapman KA. Guidelines for the diagnosis and management of cystathionine β-synthase deficiency. J Inherit Metab Dis. 2017;40:49–74. [PMC free article: PMC5203861] [PubMed: 27778219]

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Author Notes

Authors' website: New England Consortium of Metabolic Programs

Revision History

• 18 May 2017 (ha) Comprehensive update posted live
• 13 November 2014 (me) Comprehensive update posted live
• 26 April 2011 (me) Comprehensive update posted live
• 29 March 2006 (me) Comprehensive update posted live
• 15 August 2005 (cd) Revision: sequence analysis of entire coding region no longer clinically available
• 15 January 2004 (ca) Review posted live
• 2 September 2003 (hl) Original submission