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Homocystinuria

Overview

Homocystinuria is an autosomal recessive inherited metabolic disorder caused by a defect in an enzyme (that converts homocysteine to cystathione. Cystathionine beta synthase results in 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 than the first variant. 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, bone abnormalities with marfanoid habitus and pectus excavatum, osteoporosis, intellectual disability, and psychiatric disturbances. Thromboembolic episodes can be seen even in children and are a major cause of morbidity and mortality. Early treatment with a low methionine diet and/or betaine may prevent or limit complications. [American: 2012]

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.

Prevalence

Prevalence is reported to be 1 in 300,000, but this is likely an underestimate since some patients with B6-responsive forms can be missed by newborn screening. [Shinawi: 2007]

Genetics

Homocystinuria is caused by mutations in the cystathionine beta synthase (CBS) gene that abolish or markedly reduce enzyme activity. Carriers (people who have one mutated and one normal CBS gene) will not have homocystinuria, but are more likely than people without a CBS mutation to have deficiencies of vitamin B12 and folate acid. Other 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]

Practice Guidelines

There are no published practice guidelines for the evaluation or treatment of homocystinuria.

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 diet, 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 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

Children from the same father and mother as the affected infant have a 1 in 4 chance of having homocystinuria. [New: 2010] Siblings of children with this condition should be screened with plasma amino acids and total plasma homocysteine. If the disease-producing mutation in the family has been identified, carrier testing can be performed.

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
  • Joint abnormalities
  • Malar flush
  • Livedo reticularis
  • Pancreatitis
  • Psychiatric problems
  • Seizures
  • Dystonia
  • High-arched palate
  • Pectus excavatum or carinatum
  • Scoliosis
  • Pes cavus
  • Infants with newborn stroke (extremely rare) [Cardo: 2000]

Diagnostic Criteria

Diagnosis is made by clinical suspicion with confirmation by metabolic testing showing elevated methionine in plasma amino acids and presence of free homocystine, markedly elevated total plasma homocysteine. The metabolic geneticist will test affected individuals to determine which variant is present.

Clinical Classification

Variants of homocystinuria are usually indistinguishable at birth, but only one type will show markedly decreased homocysteine following initiation of B6 therapy.

Differential Diagnosis

Marfan syndrome: Patients with homocystinuria can have the appearance of 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 increased levels of serum homocysteine and methionine.

Ehlers-Danlos syndrome 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 EDS6A 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.

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 with low methionine.

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

Monitor closely

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

Testing

Sensory Testing

Vision should be tested periodically.

Laboratory Testing

Plasma amino acids and total homocysteine are measured to make the diagnosis and to monitor treatment.

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. [Genetics: 2011]

Other Testing

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

Specialty Collaborations & Other Services

Pediatric Genetic Counseling (see Services below for local providers)

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

Developmental - Behavioral Pediatrics (see Services below for local providers)

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

Pediatric Ophthalmology (see Services below for local providers)

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

Individuals with homocystinuria may present with a wide spectrum of signs and symptoms, depending on age of presentation and the organ system(s) involved. Manifestations such as psychiatric problems are treated symptomatically. Some patients may benefit by antiplatelet treatment such as daily baby aspirin.

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. DNA testing can confirm finding.

Thromboembolism risk

Individuals with homocystinuria are prone to thromboembolism, particularly in adolescence, pregnancy, and the post-partum period. Consider anticoagulation therapy. [American: 2012] 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.

Precautions when planning surgery

Some studies find anesthesia is contra-indicated if the total plasma homocysteine level is > 50 μ mol/L. If surgery is planned, ask the specialist biochemistry laboratory for an emergency plasma homocysteine level during working hours, also for clotting factor VII. Anti-coagulation, at an isocoagulant dosage, needs to be discussed after the procedure, depending on an assessment of the patient's metabolic function and vascular risk factors. [De: 2007]

Avoid oral contraceptive with estrogen

Estrogen containing oral contraceptives should be avoided due to hypercoagulability. [American: 2012]

Systems

Endocrine/Metabolism

Correction of biochemical abnormalities is the main goal of treatment, although the optimal serum level for homocystine is not known. 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, an amino acid formula is necessary. Plasma concentrations of homocystine, total homocysteine, methionine, and other amino acids are monitored and intake of protein 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 accumulated homocysteine is remethylated back to methionine consuming methylcobalamin and methylfolate. The dose of pyridoxine is about 200 mg/d in infants; the dose is increased as the patient grows older. Non-responsive 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. The usual dose is 250 mg/kg/d in three divided doses. Betaine favors the remethylation of homocysteine to methionine and should be used only after levels of methionine have been reduced by other means. Cerebral edema has been seen in patients receiving betaine, which may be related to 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. [Yap: 2001]

One study concluded that vitamin C ameliorates endothelial dysfunction in patients with homocystinuria, independent of changes in homocysteine concentration, and should therefore be considered as an additional adjunct to therapy to reduce the potential long-term risk of atherothrombotic disease. [Pullin: 2002]

Homocystinuria Letter of Medical Necessity (Nutricia), 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 Services below for local providers)

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 Services below for local providers)

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 Services below for local providers)

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

Early Intervention for Children with Disabilities/Delays (see Services below for local providers)

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 through 25 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 Services below for local providers)

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.

Vision Screening (see Services below for local providers)

Provides eye care services and education to families. The Parent Infant Program (PIP) program provides hearing and vision services to children under the age of 3 in Utah.

Nutrition/Growth/Bone

Orthopedic issues include osteoporosis, marfanoid habitus, scoliosis, pectus carinatum, and pectus excavatum or 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 Childhood Obesity can be found on the Portal.

Specialty Collaborations & Other Services

Pediatric Orthopedics (see Services below for local providers)

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

Issues Related to Homocystinuria

Financing Your Child's Healthcare
Health Insurance/Financial Aids

Funding & Access to Care

Writing Letters of Medical Necessity

Ask the Specialist

Questions Frequently Asked by Parents about Homocystinuria (NECMP)

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, orthopedist, neurologist, 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 the treatment is diet-based and important for reducing serious complications.

Resources for Clinicians

On the Web

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

ACT Sheet for Homocystinuria (ACMG) (PDF Document 347 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

Homocystinuria (GeneReviews)
Excellent review that includes a clinical description and information about differential diagnoses, management, genetic counseling, and molecular genetics; sponsored by the National Center for Biotechnology Information (NCBI).

Homocystinuria Resources (NLM)
Comprehensive compilation of links to information, articles, research, case studies, genetics, and more; National Library of Medicine and the Genetic Alliance.

Homocystinuria (OMIM)
Extensive literature review organized by description, clinical features, genetics, diagnosis, differential diagnosis, management, nomenclature, history, and animal models; Online Mendelian Inheritance in Man.

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.

Mudd SH.
Hypermethioninemias of genetic and non-genetic origin: A review.
Am J Med Genet C Semin Med Genet. 2011;157(1):3-32. PubMed abstract
Discusses briefly the genetic and non-genetic conditions that sometimes lead to abnormally elevated methionine. Focuses on recent developments and differential diagnosis of hypermethioninemia.

Clinical Tools

Care Processes & Protocols

Newborn Screening ACT Sheets & Confirmatory Algorithms (ACMG)
ACTion (ACT) Sheets and algorithms for responding to positive newborn screening test results, membership required; American College of Medical Genetics.

Questionnaires/Diaries/Data Tools

Care Notebook (UT Dept. of Health) (PDF Document 467 KB)
For families to track your child's care, health, and other information; with pages from 10 different states. Word document may be edited.

Toolkits

Transition Toolkit for Metabolic Conditions (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

Homocystinuria

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 (Genetics Home Reference)
Excellent, detailed review for patients and families affected by homocystinuria; a service of the U.S. 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).

Studies/Registries

Genetic Testing Registry - Homocystinuria (Genetics Home Reference)

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: February 2015
Current Authors and Reviewers:
Author: Nicola Longo, MD, Ph.D.
Reviewer: Meghan Candee, MD

Bibliography

American College of Medical Genetics.
Homocystinuria: transition to adult health care ACT sheet.
2012; 2. https://www.acmg.net/StaticContent/ACT/Homocystinuria_Transition.pdf
Educational resource for clinicians providing care for patients with homocystinuria.

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

De Lonlay P, Bagou G.
Classic Homocystinuria.
Translated by Orphanet; (2007) https://www.orpha.net/data/patho/Pro/en/Emergency_ClassicHomocystinuri.... Accessed on July 2014.
Document is a translation of the French recommendations drafted by Professor Pascale De Lonlay and Dr Gilles Bagou, reviewed and published by Orphanet in 2007.

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.

Genetics Home Reference.
Homocystinuria.
National Institute of Health; (2011) http://ghr.nlm.nih.gov/condition=homocystinuria. Accessed on 2/3/2015.

Mudd SH.
Hypermethioninemias of genetic and non-genetic origin: A review.
Am J Med Genet C Semin Med Genet. 2011;157(1):3-32. PubMed abstract
Discusses briefly the genetic and non-genetic conditions that sometimes lead to abnormally elevated methionine. Focuses on recent developments and differential diagnosis of hypermethioninemia.

New England Consortium of Metabolic Programs.
Homocystinuria: a guide for parents of babies recently screened for homocystinuria.
(2010) http://newenglandconsortium.org/for-families/other-metabolic-disorders.... Accessed on July 2014.

Pullin CH, Bonham JR, McDowell IF, Lee PJ, Powers HJ, Wilson JF, Lewis MJ, Moat SJ.
Vitamin C therapy ameliorates vascular endothelial dysfunction in treated patients with homocystinuria.
J Inherit Metab Dis. 2002;25(2):107-18. PubMed abstract

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 / Full Text

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