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Homocystinuria (Classic)

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Guidance for primary care clinicians diagnosing and managing children with classic homocystinuria

Homocystinuria is an autosomal recessive 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 2 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. Early treatment with a low methionine diet and/or betaine may help prevent or limit complications.

Other Names

Cystathionine beta-synthase deficiency (CBS deficiency)

Key Points

Classic homocystinuria – vitamin B6 responsive / non-responsive
Classic homocystinuria is an autosomal recessive inherited metabolic disorder caused by deficient activity of the enzyme cystathionine beta-synthase (CBS). CBS, with its cofactor vitamin B6 (pyridoxine), converts homocysteine to cystathione. Defective CBS activity results in the accumulation of the toxic compound homocysteine in blood and urine. Classic homocystinuria can be subcategorized as either vitamin B6 responsive or vitamin B6 non-responsive. As implied, those who are vitamin B6 responsive can be controlled more easily with vitamin B6 supplementation and therefore typically have a more mild clinical course.

Diagnosis
Newborn screening will identify most before symptoms develop, though it still should be considered in adults who were born before it was added to the newborn screen or children born outside of the US. Clinical presentation is nonspecific initially and may include failure to thrive and developmental delay. Evaluation and testing should be done in consultation with a biochemical (metabolic) geneticist.

Treatment goals
Early treatment with vitamin B6 supplementation, a low methionine diet, and/or betaine may help prevent or limit complications (cognitive and behavioral function, len dislocation, skeletal growth, and thromboembolic events).

Role 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.

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

Thromboembolism risk
Thromboembolic episodes can be seen even in children and are the major cause of morbidity and mortality. Risk for thromboembolism increases in adolescence, adulthood, and during and soon after pregnancy. Surgery and anesthesia also pose a significant risk for thrombosis. [Morris: 2017] Oral contraceptives containing estrogen should be avoided due to hypercoagulability.

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

Diagnosis

Presentations

Individuals with classic homocystinuria may present with a wide spectrum of signs and symptoms with varying severity, including onset from childhood to late adulthood.
Features that may be observed include:
  • Asymptomatic infants with a positive newborn screen
  • Failure to thrive
  • Marfanoid habitus (tall thin stature, scoliosis, pectus deformity)
  • Ophthalmologic problems such as severe myopia and ectopia lentis (dislocated lens)
  • Normal intellect to mild disability and psychiatric disturbances
  • Thromboembolic events
  • Malar flush, livedo reticularis
  • Pancreatitis
  • Psychiatric problems (anxiety, depression, OCD)
  • Seizures
  • Osteoporosis

Diagnostic Criteria and Classifications

Diagnosis is typically made after newborn screening identifies an elevated methionine level. Homocystinuria (Classic) provides guidance for primary care clinicians to act on positive newborn screens.
Follow-up biochemical testing is necessary to confirm elevated methionine on plasma amino acids analysis and markedly elevated total plasma homocysteine. A normal homocysteine with highly elevated methionine is not consistent with homocystinuria and requires further evaluation for hypermethioninemia (see Confirmatory Algorithm for Elevated Methionine +/- Elevated Homocysteine (ACMG)).

Diagnostic Testing & Screening

Lab Testing

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. 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.

Genetic Testing

Genetic testing is then performed by the metabolic geneticist to identify the specific disease-causing variants in the CBS gene. 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] Other genes that can cause elevated homocysteine levels may be tested at the same time, though notably, these genes (MTHFR, MTR, MTRR, MMADHC) cause very different metabolic disorders with different clinical presentations and treatment approaches. [Sacharow: 2017]

Testing for 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.

Genetics

Since classic homocystinuria is an autosomal recessive condition, family members may not have a history of this condition. It is caused by variants in the cystathionine beta-synthase (CBS) gene that markedly reduces enzyme activity.
Carriers (people with 1 variant and 1 normal CBS gene) do not have classic homocystinuria.

Incidence & Prevalence

The 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]

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.
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 hypotonia; progressive scoliosis; 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 an 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, high-protein diets (e.g., 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.

Comorbid Conditions

Evaluation for homocystinuria could be considered for those with ophthalmologic problems (e.g., downward dislocation of the lens and myopia), bone abnormalities with marfanoid habitus, pectus excavatum, osteoporosis, mild intellectual disability, and/or psychiatric disturbances.
Patients with homocystinuria are also at increased risk for thromboembolic episodes (e.g., stroke, pulmonary embolism, or DVT) even in childhood. This risk progresses into adulthood with accelerated arteriosclerosis and thrombotic complications, especially during the peripartum period for pregnant women.
In addition to biochemical genetics, all children with suspected homocystinuria should be followed by pediatric ophthalmology to assess for myopia and ectopia lentis (dislocated lens).

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] Thromboembolic episodes are the major cause of morbidity and mortality and can be seen even in children. Homocysteine levels are much easier to manage in those who are vitamin B6 responsive, requiring less intensive treatment and generally having better outcomes than those who are vitamin B6 non-responsive.

Treatment & Management

Overview

Classic homocystinuria treatment goals are to minimize the risk of complications by reducing total homocysteine levels. With treatment, particularly if started in the neonatal period, it is possible to avoid exposure to excess homocysteine levels. Doing so is associated with improved cognitive and behavioral function, avoidance of lens dislocation, normalized skeletal growth, and near-normal risk for thromboembolic events.
This section describes different systems and how the primary care clinician should treat and monitor children who have been diagnosed with homocystinuria. This includes therapies that are considered current standard of care, though new therapies, including enzyme replacement therapy, are being studied in humans and may be more widely available in the near future.

Genetics/Metabolics

Refer to biochemical (metabolic) genetics for collaborative management, which typically includes:
  • Periodic testing of plasma total homocysteine, methionine, and other amino acids to monitor treatment efficacy.
  • Correction of biochemical abnormalities is the main goal of treatment, although normal homocysteine levels are not typically attainable, especially for vitamin B6 non-responsive patients. 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]
  • Not all, but some will be prescribed a protein-restrictive diet to be initiated and followed by a metabolic nutritionist.
  • Supplementation of pyridoxine (vitamin B6) (for those with 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. Non-responsive individuals can be prescribed pyridoxine as well to prevent deficiency, although a lower dose may be used in these cases.
  • Folate (vitamin B9) and cobalamin (vitamin B12) supplementation to optimize homocysteine metabolism (remethylation). Deficiencies in these levels must be prevented as they contribute to increased homocysteine levels.
  • A specialized medical formula. Using a Letter of Medical Necessity for Metabolic Conditions (Nutricia) (PDF Document 248 KB) may be helpful for requesting coverage of amino acid-based medical food and formula.
  • Betaine treatment. 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 and is 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]

Development & Behavior

With treatment, normal IQ is possible. However, due to increased risk of developmental delay and intellectual disability, all children with this condition should have their developmental and educational progress monitored closely and be involved with developmental therapies as needed. Developmental Screening provides information about guidelines, surveillance, and response to positive screens. Developmental - Behavioral Pediatrics (see RI providers [12]) may be helpful when development needs to be assessed or if delays are suspected.

Eyes/Vision

All who have a confirmed diagnosis should be referred to pediatric ophthalmology. Patients may present with severe myopia and ectopia lentis, which may be bilateral or unilateral. Severe myopia needs to be treated early to avoid poor optical cortical development and permanently poor vision, particularly if the vision loss is asymmetric. Ectopic lentis may be more severe in children who are not B6-responsive. Surgery is generally required to remove the lens and replace it.
Advocate for school vision services, which should be provided to those children with severe vision problems.

Nutrition/Growth/Bone

Evaluate for orthopedic issues, including osteoporosis, marfanoid habitus, scoliosis, pectus deformities, and pes cavus. Refer as indicated to Pediatric Orthopedics for musculoskeletal issues, Pediatric Physical Medicine & Rehab (Physiatry) for dystonia or joint mobility problems, or Pediatric Endocrinology for treatment of osteoporosis.

Hematologic

Individuals with homocystinuria are prone to thromboembolism, particularly in adolescence, pregnancy, and postpartum. Thromboembolic episodes can be seen even in children and are the major cause of morbidity and mortality.
Although not usually a problem in infants, parents should understand the 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. It remains controversial whether thromboprophylaxis should be universally recommended. Notably, maternal homocystinuria has not been reported to have adverse effects on the developing fetus during pregnancy.
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]
Oral contraceptives containing estrogen should be avoided due to hypercoagulability.

Other

Be vigilant for pancreatitis, psychiatric problems, and seizures. Refer as needed to Pediatric Gastroenterology, Pediatric Psychiatry, or Pediatric Neurology as needed.

Services and Referrals

Biochemical Genetics (Metabolics) (see RI providers [3])
Children suspected of having classic homocystinuria should be referred to metabolic genetics for evaluation and, ideally, collaborative management. Periodic visits should be scheduled for ongoing care.

Nutrition, Metabolic (see RI providers [13])
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 methionine. The metabolic nutritionist will also assess adequate intake of nutrients.

Developmental - Behavioral Pediatrics (see RI providers [12])
Particularly helpful to optimize development and to evaluate older children with behavioral or learning concerns.

Early Intervention for Children with Disabilities/Delays (see RI providers [13])
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.

Pediatric Ophthalmology (see RI providers [8])
Infants and children should be followed by pediatric ophthalmology at least annually. Severe myopia needs to be treated early to avoid poor optical cortical development and permanent vision loss.

Pediatric Orthopedics (see RI providers [16])
Children with evidence of orthopedic concerns should be evaluated and, if indicated, followed periodically by orthopedics.

As needed:

ICD-10 Coding

E72.11, Homocystinuria
Further coding details can be found at ICD-10 for Homocystinuria (icd10data.com)

Resources

Information & Support

Related Portal Content
Homocystinuria (Classic)
Guidance for primary care clinicians receiving a positive newborn screen result.
Homocystinuria (FAQ)
Answers to questions families often have about caring for their child with homocystinuria.
Formulas for Metabolic Conditions (PDF Document 138 KB)
Formulas by name, age, use, and manufacturer for those with metabolic conditions, including homocystinuria.
Care Notebook
Medical information is in one place with fillable templates to help families and providers. Choose only the pages needed to keep track of the current health care summary, care team, care plan, and health coverage.
Developmental Screening
Guidelines, surveillance, and response to positive screens.
Working with Insurance Companies
Letters of Medical Necessity and appealing funding denials.

For Professionals

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.

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.

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.

For Parents and Patients

Argininemia - Information for Parents (STAR-G)
A fact sheet, written by a genetic counselor and reviewed by genetic specialists, for families who have received a diagnosis of arginase deficiency; Screening, Technology, and Research in Genetics.

Arginase Deficiency (MedlinePlus) Arginase Deficiency Foundation

Tools

RI ACT Sheet for Methionine (Homocystinuria) (ACMG) (PDF Document 139 KB)
Provides recommendations for clinical and laboratory follow-up of the newborn with out-of-range screening results, along with national and local resources for clinicians and families; American College of Medical Genetics.

Confirmatory Algorithm for Elevated Methionine +/- Elevated Homocysteine (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.

Services for Patients & Families in Rhode Island (RI)

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.

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.

Authors & Reviewers

Initial publication: February 2015; last update/revision: September 2022
Current Authors and Reviewers:
Author: Brian J. Shayota, MD, MPH
Reviewer: Nicola Longo, MD, Ph.D.
Authoring history
2021: update: Brian J. Shayota, MD, MPHA
2015: update: Meghan S Candee, MD, MScR
2013: first version: Nicola Longo, MD, Ph.D.A
AAuthor; CAContributing Author; SASenior Author; RReviewer

Page Bibliography

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