Homocystinuria

Overview

Homocystinuria is an autosomal recessive inherited metabolic disorder caused by a defect in an enzyme (cystathionine beta-synthase) that converts homocysteine to cystathione. Cystathionine beta-synthase deficiency results in the accumulation of homocysteine in the blood and its excretion in urine. There are two main variants of homocystinuria: one is responsive to vitamin B6 (pyridoxine), the cofactor of cystathionine beta-synthase; the other does not respond to vitamin B6 and usually has more pronounced symptoms. Clinical presentation is nonspecific initially and may include failure to thrive and developmental delay. Patients can present in childhood or adolescence with ophthalmologic problems such as downward dislocation of the lens and myopia, skeletal abnormalities like scoliosis and pectus deformities, marfanoid habitus, intellectual disability, and psychiatric disturbances. Thromboembolic episodes can be seen even in children and are the major cause of morbidity and mortality. Early treatment with a low methionine diet and/or betaine may help prevent or limit complications.

Other Names & Coding

Classic homocystinuria
Cystathionine beta-synthase deficiency (CBS deficiency)
ICD-10 coding

E72.11, homocystinuria

Further coding details can be found at ICD-10 for Homocystinuria (icd10data.com).

Prevalence

Prevalence is reported to be 1:200,000 to 300,000, but this is likely an underestimate since some patients with more mild disease can be missed by newborn screening. [Shinawi: 2007]

Genetics

Homocystinuria is an autosomal recessive genetic condition caused by mutations in the cystathionine beta-synthase (CBS) gene that markedly reduces enzyme activity. Carriers (people who have 1 mutated and 1 normal CBS gene) do not have homocystinuria but they are more likely than people without a CBS mutation to have deficiencies of vitamin B12 and folate acid.

The other much more rare types of homocystinuria are also autosomal recessive, but caused by defects in the remethylation of homocysteine to methionine (involving mutations of the MTHFR, MTR, MTRR, or MMADHC genes); they will be missed by most newborn screening programs.

Prognosis

Infants identified by newborn screening and treated to correct the biochemical abnormalities appear to have fewer manifestations of the condition, including decreased incidence of intellectual disability and thromboembolic events. [Yap: 2000] [Morris: 2017]

Practice Guidelines

Morris AA, Kožich V, Santra S, Andria G, Ben-Omran TI, Chakrapani AB, Crushell E, Henderson MJ, Hochuli M, Huemer M, Janssen MC, Maillot F, Mayne PD, McNulty J, Morrison TM, Ogier H, O'Sullivan S, Pavlíková M, de Almeida IT, Terry A, Yap S, Blom HJ, Chapman KA.
Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency.
J Inherit Metab Dis. 2017;40(1):49-74. PubMed abstract / Full Text

Roles of the Medical Home

In addition to providing routine pediatric preventive and acute care, the medical home collaborates with the metabolic geneticist, supports the family and patient in maintaining the recommended dietary restrictions, and monitors for signs of complications.

Clinical Assessment

Pearls & Alerts for Assessment

False negative newborn screening

Newborn metabolic screening for homocystinuria can miss children with the milder B6-responsive variant of homocystinuria, especially if a second newborn screening is not performed.

Abdominal pain

Severe, sudden abdominal pain may be a sign of pancreatitis, which occurs more frequently in children with homocystinuria than in typical children.

Screening

For the Condition

The Portal's page on Homocystinuria provides newborn screening information.

Of Family Members

The parents of an affected individual have a risk recurrence of 25% for all additional children they have together. Siblings of children with this condition should be screened with plasma amino acids and total plasma homocysteine to determine if they may be affected. If the disease-producing mutation in the family has been identified, genetic testing can be performed to make the diagnosis as well.

For Complications

Children should be screened periodically for developmental issues. The Portal's page on Developmental Screening provides information about guidelines, surveillance, and response to positive screens.

Presentations

Individuals with homocystinuria may present with a wide spectrum of signs and symptoms depending on age of presentation and the organ system(s) involved. Features that may be observed include:
  • Asymptomatic infants with a positive newborn screen
  • Long fingers and toes with marfanoid habitus
  • Severe myopia and ectopia lentis (dislocated lens)
  • Developmental delay/intellectual disability
  • Thromboembolic events
  • Malar flush
  • Livedo reticularis
  • Pancreatitis
  • Psychiatric problems
  • Seizures
  • Dystonia
  • High-arched palate
  • Pectus excavatum or carinatum
  • Scoliosis
  • Infants with newborn stroke (extremely rare) [Cardo: 2000]

Diagnostic Criteria

Recently, diagnosis is typically made after newborn screening identifies an elevated methionine level. Follow-up biochemical testing is necessary to confirm elevated methionine on plasma amino acids analysis and markedly elevated total plasma homocysteine. The metabolic geneticist can then perform genetic testing to identify the specific disease-causing variants in CBS.

Clinical Classification

Genetic testing can determine if a single p.Gly307Ser variant is presenting to predict vitamin B6 non-responsiveness, versus the p.Ile278Thr allele predicting vitamin B6 responsiveness. [Gaustadnes: 2002]

Differential Diagnosis

Marfan syndrome: Patients with homocystinuria can have a similar physical appearance as individuals with Marfan syndrome (long limbs, pectus deformity, and dislocated lenses). Individuals with homocystinuria usually do not have the joint laxity or the cardiac manifestations associated with Marfan syndrome, and the lens dislocation is usually downward, not upward, as in Marfan syndrome. Individuals with Marfan syndrome do not have the same biochemical findings, though with increased levels of serum homocysteine and methionine.

Ehlers-Danlos syndrome (EDS) type 6A (kyphoscoliotic type) is a generalized connective tissue disorder characterized by friable, hyperextensible skin, thin scars, and easy bruising; generalized joint laxity; severe muscle hypotonia at birth; progressive scoliosis, present at birth or within the first year of life; and scleral fragility and increased risk of rupture of the globe. Some patients have a striking marfanoid habitus, which with the scleral fragility, might clinically resemble homocystinuria. Patients with EDS type 6A have normal plasma amino acids but abnormal ratio of urinary pyridinium crosslinks.

S-adenosylhomocysteine hydrolase deficiency, glycine N-methyltransferase deficiency, methionine adenosyltransferase (MAT) deficiency, and adenosine kinase deficiency are rare disorders in which methionine is increased and homocysteine is either normal or mildly increased. Genetic testing may be necessary to differentiate.

Liver disease, diets high in protein (such as with goat milk), low birth weight, and prematurity are associated with elevated methionine levels at birth.

Defects of remethylation such as 5, 10-methylene-tetrahydrofolate reductase deficiency, methionine synthase (cblG), methionine synthase reductase (cblE) deficiency, 5-methyl-tetrahydrofolate-homocysteine-methyltransferase deficiency, vitamin B12 deficiency, and disorders of cobalamin metabolism (cblC, cblD, and cblF) can result in elevated homocysteine as well, but with low methionine levels.

History & Examination

Current & Past Medical History

Individuals may present with a tall, slender habitus and developmental delay/intellectual disability. Young adults may present with lens dislocation or thromboembolic events.

Family History

Since homocystinuria is an autosomal recessive condition, family members may not have a history of this condition.

Pregnancy/Perinatal History

Usually normal

Developmental & Educational Progress

Developmental delays and intellectual disability are common if treatment is not initiated early.

Physical Exam

Infants with classic homocystinuria usually present normally. Later in life, the abnormalities listed below may be seen:

General

Tall thin habitus with long fingers and toes

Growth Parameters

Tall for family height

Skin

Areas of hypopigmentation, malar flush, livedo reticularis

HEENT/Oral

High-arched palate

Chest

Pectus carinatum or excavatum

Extremities/Musculoskeletal

Decreased range of motion at joints, osteoporosis, scoliosis, pectus excavatum or carinatum, genu valgum, pes cavus may be noted.

Neurologic Exam

Developmental delay/intellectual disability, dystonia - seizures may occur in untreated individuals

Testing

Laboratory Testing

Periodic testing of methionine and total homocysteine are measured to make the diagnosis and monitor treatment at the discretion of the metabolic geneticist.

Genetic Testing

Homocystinuria is generally inherited in an autosomal recessive pattern. Focused genetic testing can be performed to look for the genetic mutations known to cause homocystinuria. These include CBS (most common), MTHFR, MTR, MTRR, and MMADHC. [Sacharow: 2017]

Other Testing

Serum levels of homocysteine and methionine are measured periodically to guide therapy.

Specialty Collaborations & Other Services

Genetic Testing and Counseling (see NM providers [64])

Children suspected of having homocystinuria should be referred to metabolic genetics for evaluation and, ideally, collaborative management.

Developmental - Behavioral Pediatrics (see NM providers [2])

Developmental pediatricians may be helpful when development needs to be assessed or if delays are suspected.

Pediatric Ophthalmology (see NM providers [9])

Infants and children should be followed by pediatric ophthalmology. Severe myopia needs to be treated early to avoid poor optical cortical development and permanently poor vision, particularly if the vision loss is asymmetric.

Treatment & Management

Overview

Homocystinuria treatment goals are to minimize the risk of complication by reducing homocysteine levels. This can be accomplished with vitamin B6 supplementation (for those found to be responsive), a methionine-restricted diet, folate and vitamin B12 supplementation, and betaine treatment. It remains controversial whether thromboprophylaxis should be universally recommended.

Pearls & Alerts for Treatment & Management

Additional testing after diagnosis

A pyridoxine (B6) challenge test is performed immediately after the diagnosis and prior to initiation of dietary therapy. The test involves introducing pyridoxine in small, incremental amounts and measuring the effect on plasma baseline measurements. This will determine whether the patient is responsive to vitamin B6. This can be determined with DNA testing as well.

Thromboembolism risk

Individuals with homocystinuria are prone to thromboembolism, particularly in adolescence, pregnancy, and the postpartum period. Although not usually a problem in infants, parents should understand signs and symptoms of thromboembolic events and when to contact medical services. In addition to cerebrovascular events, pulmonary emboli and myocardial infarctions can occur. Low molecular weight heparin is recommended for pregnant women with homocystinuria and individuals who have experienced thromboembolic events.

Precautions when planning surgery

Surgery and anesthesia also pose a significant risk for thrombosis; ideally, metabolic control should be optimized prior to any scheduled procedure. Additionally, good hydration, leg compression systems, and early mobilization are important methods that should be utilized to reduce the risk of thrombosis. [Morris: 2017]

Avoid oral contraceptive with estrogen

Oral contraceptives containing estrogen should be avoided due to hypercoagulability.

Systems

Endocrine/Metabolism

Correction of biochemical abnormalities is the main goal of treatment, although normal homocysteine levels are not typically attainable. Maintaining total homocysteine levels to <50 μmol/L is the goal for most, with levels >100 μmol/L being associated with a significantly increased risk for thrombosis. [Yap: 2001] [Morris: 2017]

Upon diagnosis, all individuals are started on a protein-reduced, methionine-restricted diet that needs to be continued and monitored throughout life. Because the required protein restriction also reduces intake of other essential amino acids, a specialized medical formula is necessary. Plasma concentrations of homocystine, total homocysteine, methionine, and other amino acids are monitored. Intake of protein is adjusted as necessary. Folic acid and vitamin B12 are also added to optimize the metabolism (remethylation) of methionine. Without their administration, patients become deficient in these vitamins, which further increases levels of homocysteine.

Pyridoxine (vitamin B6) is a cofactor of cystathionine beta-synthase and can act as a chaperone to stabilize certain missense mutations. Some patients with homocystinuria respond with a dramatic decrease in homocysteine levels when given pharmacological doses of pyridoxine (vitamin B6 responsive homocystinuria). The dose of pyridoxine is about 100 mg/day in infants for at least 2 weeks to determine responsiveness. If responsive, the dose is then increased as the patient grows older. Nonresponsive individuals can be prescribed pyridoxine as well to prevent deficiency, although a lower dose is necessary in these cases.

Betaine can be used in patients with homocystinuria that have been difficult to manage by other means. The usual dose starts at 100 mg/kg/day divided in 2 doses. Betaine favors the remethylation of homocysteine to methionine, resulting in reduced homocysteine but increased methionine levels. Cerebral edema is a rare complication that has been seen in patients receiving betaine, thought to be related to extremely high levels of methionine in the blood. [Yaghmai: 2002] Total plasma homocysteine will remain elevated even with optimal treatment; maintaining the level of total plasma homocysteine to less than 40 micromolar would be optimal.

Letter of Medical Necessity for Metabolic Conditions (Nutricia) (PDF Document 248 KB), created by a medical nutrition company, may be helpful for requesting coverage of amino acid-based medical food and formula.

Specialty Collaborations & Other Services

Pediatric Genetics (see NM providers [4])

Children who are suspected of having homocystinuria should be referred to metabolic genetics for evaluation and, ideally, collaborative management. Periodic visits should be scheduled for ongoing care.

Nutrition, Metabolic (see NM providers [15])

The diet for homocystinuria should be initiated and followed by a metabolic nutritionist who can make the necessary adjustments to achieve optimum levels of homocysteine and metabolites in the blood. The metabolic nutritionist will also assess adequate intake of nutrients.

Development (general)

All children with this condition should have their developmental and educational progress monitored closely and be involved with developmental therapies as needed. It is not clear if treatment will prevent all manifestations of this condition in the B6 responsive and B6 nonresponsive phenotypes, although there is evidence that it might. [Yap: 2001]

Specialty Collaborations & Other Services

Developmental - Behavioral Pediatrics (see NM providers [2])

Particularly helpful to optimize development and to evaluate older children with behavioral or learning concerns.

Early Intervention for Children with Disabilities/Delays (see NM providers [156])

Children younger than 3 should receive early intervention services and school-aged individuals should have a 504 plan or IEP in place in their school.

Eyes/Vision

Children ages 1 to 25 years with this condition may present with severe myopia and ectopia lentis, which may be bilateral or unilateral. This problem may be more severe in children who are not B6-responsive. Surgery is generally required to remove the lens and replace it. School vision services should be provided to those children with severe myopia.

Specialty Collaborations & Other Services

Pediatric Ophthalmology (see NM providers [9])

Infants and children should be followed by pediatric ophthalmology annually. Severe myopia needs to be treated early to avoid poor optical cortical development and permanently poor vision, particularly if the vision loss is asymmetric.

Vision Screening (see NM providers [186])

Provides eye care services and education to families

Nutrition/Growth/Bone

Orthopedic issues include osteoporosis, marfanoid habitus, scoliosis, pectus carinatum, pectus excavatum, and pes cavus. Monitor for obesity; when diet is poorly executed, it can lead to eating too many calories from fatty, processed foods. Diagnosis and management information for Obesity in Children can be found on the Portal.

Specialty Collaborations & Other Services

Pediatric Orthopedics (see NM providers [13])

Children with evidence of orthopedic concerns should be evaluated and, if indicated, followed periodically by orthopedics.

Issues Related to Homocystinuria

No Related Issues were found for this diagnosis.

Ask the Specialist

In which patients should I begin to consider evaluation for homocystinuria?

Evaluation could be considered for those with ophthalmologic problems (e.g., downward dislocation of the lens and myopia), bone abnormalities with marfanoid habitus or pectus excavatum, osteoporosis, intellectual disability, and/or psychiatric disturbances. Patients with homocystinuria are also at increased risk for thromboembolic episodes (e.g., stroke, pulmonary embolism, or DVT).

If I suspect homocystinuria, which specialist should I first refer my patient to?

This will depend on the clinical symptoms that are prompting an evaluation, but referral could include an ophthalmologist, general geneticist, or metabolic geneticist.

What should I tell my patient's family about homocystinuria?

Many families would want to know why you suspect this diagnosis and that it is a rare disorder caused by an enzyme defect, which causes increased homocysteine in blood and urine. They will need to understand that treatment is available with diet modifications and vitamin supplementation, important for reducing potentially serious complications.

Resources for Clinicians

On the Web

Homocystinuria (GeneReviews)
Detailed information addressing clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular pathogenesis; from the University of Washington and the National Library of Medicine.

Homocystinuria - Information for Professionals (STAR-G)
Contains a structured list of information about homocystinuria; Screening, Technology, and Research in Genetics.

Helpful Articles

PubMed search for homocystinuria and neonatal screening, last 5 years.

Gan-Schreier H, Kebbewar M, Fang-Hoffmann J, Wilrich J, Abdoh G, Ben-Omran T, Shahbek N, Bener A, Al Rifai H, Al Khal AL, Lindner M, Zschocke J, Hoffmann GF.
Newborn population screening for classic homocystinuria by determination of total homocysteine from Guthrie cards.
J Pediatr. 2010;156(3):427-32. PubMed abstract
A study that reports on reliable method for newborn screening for cystathionine beta-synthase deficiency, reaching a sensitivity of up to 100%, even if samples were taken within the first 3 days of life.

Clinical Tools

Care Processes & Protocols

ACT Sheet for Homocystinuria (ACMG)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

Confirmatory Algorithms for Homocystinuria (ACMG)
An algorithm of the basic steps involved in determining the final diagnosis of an infant with a positive newborn screen; American College of Medical Genetics.

Letters of Medical Necessity

Letter of Medical Necessity for Metabolic Conditions (Nutricia) (PDF Document 248 KB)
Two-page downloadable form for requesting coverage of amino acid-based medical food and formula from a medical nutrition company.

Questionnaires/Diaries/Data Tools

Care Notebook (UDOH) (PDF Document 467 KB)
A Word document that can be edited by families to track a child's care, health, and other information. Contains 10 pages from different states; Utah Department of Health.

Toolkits

Boston Children's Hospital Transition Toolkit (NECMP)
Includes health readiness assessments, metabolic conditions basics, and a transition plan for youth with metabolic conditions; New England Consortium of Metabolic Programs.

Resources for Patients & Families

Information on the Web

Homocystinuria - Information for Parents (STAR-G)
A fact sheet, written by a genetic counselor and reviewed by metabolic and genetic specialists, for families who have received an initial diagnosis of this newborn disorder; Screening, Technology and Research in Genetics.

Homocystinuria (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources; from the National Library of Medicine.

Parent Information Sheet Homocystinuria - Confirmed Diagnosis (NHS) (PDF Document 336 KB)
Information for parents for when the results of the newborn blood spot screening are positive; National Institute for Health Research (UK).

Homocystinuria: A Guide for Parents of Babies Recently Screened for Homocystinuria (NECMP)
Information about homocystinuria for patients, including inheritance, diagnosis, maintaining a healthy diet, treatment, and testing of other children; from the New England Consortium of Metabolic Programs.

Services for Patients & Families in New Mexico (NM)

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Authors & Reviewers

Initial publication: February 2015; last update/revision: April 2021
Current Authors and Reviewers:
Author: Brian J. Shayota, MD, MPH
Reviewer: Peer review pending
Authoring history
2015: update: Meghan Candee, MDR
2013: first version: Nicola Longo, MD, Ph.D.A
AAuthor; CAContributing Author; SASenior Author; RReviewer

Bibliography

Cardo Jalón E, Pineda Marfà M, Artuch Iriberri R, Vilaseca Buscà MA, Campistol Plana J.
Proposed protocol for the study of cerebrovascular disease in childhood.
An Esp Pediatr. 2000;52(5):435-42. PubMed abstract

Gan-Schreier H, Kebbewar M, Fang-Hoffmann J, Wilrich J, Abdoh G, Ben-Omran T, Shahbek N, Bener A, Al Rifai H, Al Khal AL, Lindner M, Zschocke J, Hoffmann GF.
Newborn population screening for classic homocystinuria by determination of total homocysteine from Guthrie cards.
J Pediatr. 2010;156(3):427-32. PubMed abstract
A study that reports on reliable method for newborn screening for cystathionine beta-synthase deficiency, reaching a sensitivity of up to 100%, even if samples were taken within the first 3 days of life.

Gaustadnes M, Wilcken B, Oliveriusova J, McGill J, Fletcher J, Kraus JP, Wilcken DE.
The molecular basis of cystathionine beta-synthase deficiency in Australian patients: genotype-phenotype correlations and response to treatment.
Hum Mutat. 2002;20(2):117-26. PubMed abstract

Morris AA, Kožich V, Santra S, Andria G, Ben-Omran TI, Chakrapani AB, Crushell E, Henderson MJ, Hochuli M, Huemer M, Janssen MC, Maillot F, Mayne PD, McNulty J, Morrison TM, Ogier H, O'Sullivan S, Pavlíková M, de Almeida IT, Terry A, Yap S, Blom HJ, Chapman KA.
Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency.
J Inherit Metab Dis. 2017;40(1):49-74. PubMed abstract / Full Text

Sacharow SJ, Picker JD, Levy HL.
Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency.
GeneReviews. 2017. PubMed abstract / Full Text

Shinawi M.
Hyperhomocysteinemia and cobalamin disorders.
Mol Genet Metab. 2007;90(2):113-21. PubMed abstract

Yaghmai R, Kashani AH, Geraghty MT, Okoh J, Pomper M, Tangerman A, Wagner C, Stabler SP, Allen RH, Mudd SH, Braverman N.
Progressive cerebral edema associated with high methionine levels and betaine therapy in a patient with cystathionine beta-synthase (CBS) deficiency.
Am J Med Genet. 2002;108(1):57-63. PubMed abstract

Yap S, Naughten ER, Wilcken B, Wilcken DE, Boers GH.
Vascular complications of severe hyperhomocysteinemia in patients with homocystinuria due to cystathionine beta-synthase deficiency: effects of homocysteine-lowering therapy.
Semin Thromb Hemost. 2000;26(3):335-40. PubMed abstract

Yap S, Rushe H, Howard PM, Naughten ER.
The intellectual abilities of early-treated individuals with pyridoxine-nonresponsive homocystinuria due to cystathionine beta-synthase deficiency.
J Inherit Metab Dis. 2001;24(4):437-47. PubMed abstract