eMedicine Specialties > Neurology > Neuro-vascular Diseases

Metabolic Disease and Stroke - Homocystinuria/Homocysteinemia

Author: Pitchaiah Mandava, MD, PhD, Assistant Professor, Department of Neurology, Baylor College of Medicine; Consulting Staff, Department of Neurology, Michael E DeBakey Veterans Affairs Medical Center
Coauthor(s): Thomas A Kent, MD, Professor, Department of Neurology, Baylor College of Medicine; Neurology Care Line Executive, Michael E DeBakey Veterans Affairs Medical Center
Contributor Information and Disclosures

Updated: May 25, 2009

Introduction

Background

Homocystinuria is a disorder of methionine metabolism, leading to an abnormal accumulation of homocysteine and its metabolites (homocystine, homocysteine-cysteine complex, and others) in blood and urine. Normally, these metabolites are not found in appreciable quantities in blood or urine. Homocysteinemia, a separate but related entity, is defined as elevation of homocysteine level in blood. This condition has also been referred to as homocyst(e)inemia to reflect metabolites that may accumulate. A mild elevation of plasma homocysteine may exist without homocystinuria.

Pathophysiology

The accumulation of homocysteine and its metabolites is caused by disruption of any of the 3 interrelated pathways of methionine metabolism—deficiency in the cystathionine B-synthase (CBS) enzyme, defective methylcobalamin synthesis, or abnormality in methylene tetrahydrofolate reductase (MTHFR).

Clinical syndromes resulting from each of these metabolic abnormalities have been termed homocystinuria I, II, and III. Three different cofactors/vitamins—pyridoxal 5-phosphate, methylcobalamin, and folate—are necessary for the 3 different metabolic paths.

The pathway, starting at methionine, progressing through homocysteine, and onwards to cysteine, is termed the transsulfuration pathway. Conversion of homocysteine back to methionine, catalyzed by MTHFR and methylcobalamin, is termed as the remethylation pathway. A minor amount of remethylation takes place via an alternate route using betaine as the methyl donor.

Homocysteinemia theoretically could be a result of defects at any of these 3 locations. These abnormalities could arise from a genetic predisposition or from genetic predisposition worsened by comorbid conditions and/or nutritional and environmental factors. These conditions and factors may be related to abnormal MTHFR, chronic renal failure, hypothyroidism, malignancies, methotrexate treatment, oral contraceptive use, consumption of animal proteins, and smoking.

An abnormal gene on chromosome 1 has been proposed as the cause of reduction in MTHFR; however, whether this mutation alone can lead to cerebrovascular events or whether it requires additional environmental or nutritional lack of folic acid to cause symptomatic homocysteinemia is unclear.1

Increased homocysteine level is associated with a higher risk of strokes. Carotid stenosis appears to have a graded response to increased levels of homocysteine. Increased carotid plaque thickness has been associated with high homocysteine and low B-12 levels. Yoo et al studied both intracranial and extracranial vessels by MR angiography and reported that homocysteine levels were higher in patients with 2- or 3-vessel stenoses than in those with 1-vessel stenosis.2  In patients with baseline homocysteine level exceeding 9.1 umol/L, supplementation with B vitamins resulted in slowed progression of carotid intimal medial thickness (CIMT). 

Several mechanisms have been suggested as the possible cause of accelerated vascular disease. These include (1) endothelial cell damage, (2) smooth muscle cell proliferation, (3) lipid peroxidation, (4) up-regulation of prothrombotic factors (XII and V), and (5) down-regulation of antithrombotic factors or endothelial-derived nitric oxide.

Frequency

United States

Incidence of homocystinuria is approximately 1 per 100,000.

International

Reported incidence of homocystinuria varies between 1 in 50,000 and 1 in 200,000.

Mortality/Morbidity

  • Early diagnosis and intervention have helped in preventing some of the complications of homocystinuria, including ectopia lentis, mental retardation, and thromboembolic events.
  • A mortality rate of 18% by age 30 has been reported by Mudd et al from a worldwide series of 629 patients with CBS enzyme deficiency.3
  • Death is predominantly due to cerebrovascular or cardiovascular causes.

Age

  • Homocystinuria
    • Children with CBS deficiency (homocystinuria I) may be normal at birth.
    • Data from Mudd et al suggest that, starting at around age 20 years, these patients have an increasing likelihood of suffering a thromboembolic event.
    • Patients with either defective methylcobalamin synthesis or defective tetrahydrofolate metabolism may present in early infancy.

Clinical

History

  • Homocystinuria
    • Patients with classic homocystinuria may first be recognized because of downward dislocation of the lens (ectopia lentis)4 , marfanoid habitus, mental retardation4 , and/or seizures.
    • Patients with defective methylcobalamin synthesis may have all of these features, along with symptoms of methylmalonic acidemia (see Metabolic Disease and Stroke - Methylmalonic Acidemia).
    • Acute stroke symptoms may occur in these patients.
    • Traditional risk factors—hypertension, smoking, and diabetes—may or may not be present.
  • Homocysteinemia
    • These patients may present with vascular thrombotic events, with or without the traditional risk factors for a stroke.
    • If the usual risk factors are not present, a more rigorous search for rarer causes of stroke should be undertaken.
    • This group of patients may already have a history of strokes and myocardial infarctions in the third or fourth decade of life.

Physical

Homocystinuria is associated with the following physical findings:

  • Downward dislocation of lens (ectopia lentis)
  • Marfanoid habitus
  • Pes excavatum, pes carinatum, and genu valgum
  • Mental retardation
  • Signs and symptoms of strokes in any vascular distribution: Hemiplegia, aphasia, ataxia, and pseudobulbar palsy are among the most common findings.

Causes

  • Homocystinuria is an autosomal recessively inherited defect in the transsulfuration pathway (homocystinuria I) or methylation pathway (homocystinuria II and III).
  • Homocysteinemia also may be due to a genetic predisposition to abnormal activity in the same pathways. Nutritional and environmental factors, as well as specific medications, may worsen this abnormality and provoke symptoms.

More on Metabolic Disease and Stroke - Homocystinuria/Homocysteinemia

Overview: Metabolic Disease and Stroke - Homocystinuria/Homocysteinemia
Differential Diagnoses & Workup: Metabolic Disease and Stroke - Homocystinuria/Homocysteinemia
Treatment & Medication: Metabolic Disease and Stroke - Homocystinuria/Homocysteinemia
Follow-up: Metabolic Disease and Stroke - Homocystinuria/Homocysteinemia
References
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References

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  2. Yoo JH, Chung CS, Kang SS. Relation of plasma homocyst(e)ine to cerebral infarction and cerebral atherosclerosis. Stroke. Dec 1998;29(12):2478-83. [Medline].

  3. Mudd SH, Skovby F, Levy HL. The natural history of homocystinuria due to cystathionine beta- synthase deficiency. Am J Hum Genet. Jan 1985;37(1):1-31. [Medline].

  4. Kaur M, Kabra M, Das GP. Clinical and biochemical studies in homocystinuria. Indian Pediatr. Oct 1995;32(10):1067-75. [Medline].

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  14. Giles WH, Croft JB, Greenlund KJ. Total homocyst(e)ine concentration and the likelihood of nonfatal stroke: results from the Third National Health and Nutrition Examination Survey, 1988-1994. Stroke. Dec 1998;29(12):2473-7. [Medline].

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  31. Soriente L, Coppola A, Madonna P. Homozygous C677T mutation of the 5,10 methylenetetrahydrofolate reductase gene and hyperhomocysteinemia in Italian patients with a history of early-onset ischemic stroke [letter; comment]. Stroke. Apr 1998;29(4):869-71. [Medline].

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Further Reading

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Keywords

homocysteinuria, homocystinemia, metabolic disease, stroke, disorder of methionine metabolism, stroke treatment, stroke symptoms, abnormal accumulation of homocysteine in blood and urine

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Contributor Information and Disclosures

Author

Pitchaiah Mandava, MD, PhD, Assistant Professor, Department of Neurology, Baylor College of Medicine; Consulting Staff, Department of Neurology, Michael E DeBakey Veterans Affairs Medical Center
Pitchaiah Mandava, MD, PhD is a member of the following medical societies: American Academy of Neurology, Sigma Xi, and Stroke Council of the American Heart Association
Disclosure: Nothing to disclose.

Coauthor(s)

Thomas A Kent, MD, Professor, Department of Neurology, Baylor College of Medicine; Neurology Care Line Executive, Michael E DeBakey Veterans Affairs Medical Center
Thomas A Kent, MD is a member of the following medical societies: American Academy of Neurology, American Neurological Association, New York Academy of Sciences, Royal Society of Medicine, Sigma Xi, and Stroke Council of the American Heart Association
Disclosure: Nothing to disclose.

Medical Editor

Richard M Zweifler, MD, Chief of Neurology, Sentara Healthcare, Norfolk, VA; Professor of Neurology, Eastern Virginia Medical School, Norfolk, VA
Richard M Zweifler, MD is a member of the following medical societies: American Academy of Neurology, American Heart Association, American Medical Association, American Stroke Association, Royal Society of Medicine, and Stroke Council of the American Heart Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Howard S Kirshner, MD, Professor of Neurology, Psychiatry and Hearing and Speech Sciences, Vice Chairman, Department of Neurology, Vanderbilt University School of Medicine; Director, Vanderbilt Stroke Center; Program Director, Stroke Service, Vanderbilt Stallworth Rehabilitation Hospital; Consulting Staff, Department of Neurology, Nashville Veterans Affairs Medical Center
Howard S Kirshner, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Heart Association, American Medical Association, American Neurological Association, American Society of Neurorehabilitation, National Stroke Association, Phi Beta Kappa, and Tennessee Medical Association
Disclosure: Boehringer Ingelheim Honoraria Speaking and teaching; BMS/Sanofi Honoraria Speaking and teaching; Novartis Honoraria Speaking and teaching

CME Editor

Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital
Matthew J Baker, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Chief Editor

Helmi L Lutsep, MD, Professor, Department of Neurology, Oregon Health & Science University; Associate Director, Oregon Stroke Center
Helmi L Lutsep, MD is a member of the following medical societies: American Academy of Neurology and American Stroke Association
Disclosure: Co-Axia Consulting fee Review panel membership; Talecris Consulting fee Review panel membership; AGA Medical Consulting fee Review panel membership; Boehringer Ingelheim Honoraria Speaking and teaching; Concentric Medical Consulting fee Review panel membership; Abbott Consulting fee Consulting; Sanofi  Consulting

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