eMedicine Specialties > Neurology > Neuro-vascular Diseases
Metabolic Disease and Stroke - Homocystinuria/Homocysteinemia
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.
Differential Diagnoses
Blood Dyscrasias and Stroke
Metabolic Disease & Stroke: Fabry
Disease
Metabolic Disease & Stroke: Methylmalonic
Acidemia
Metabolic Disease & Stroke: Propionic
Acidemia
Other Problems to Be Considered
Carotid disease and stroke
Workup
Laboratory Studies
- Homocystinuria: If patients present with systemic signs and symptoms, screening tests followed by confirmatory tests may be done.
- The urine screening test for sulfur-containing amino acids, called the cyanide nitroprusside test, can be undertaken; however, high rates of false-negative as well as false-positive results are reported.
- A neonatal screening test, called the Guthrie test, detects high levels of methionine in heel-stick blood. This test is performed routinely in several states for detection of phenylalanine, leucine, and methionine. Because of high false-negative results in homocystinuric patients, a recent report suggested lowering the threshold of methionine to qualify as abnormal.
- Quantitative tests for homocystine in urine and blood are available commercially. The blood specimen needs to be handled in a specific manner described in the homocysteinemia testing section.
- Measurement of CBS activity in cultured fibroblasts provides definitive support for the diagnosis.
- Testing of amniotic cells and chorionic villi is also available.
- Homocysteinemia: Lab studies may be considered in patients who present with symptoms of acute stroke in the absence of traditional risk factors such as hypertension, smoking, and diabetes. Nutritional factors, environmental toxins, or medical conditions may worsen an inherent homocysteinemia. Some caveats follow:
- No consensus exists on the timing of the test with respect to an acute event.
- Whether a methionine challenge should be used for testing is not clear at this juncture. The methionine challenge test may be more appropriate if a deficiency is suspected in the transsulfuration pathway.
- Specimens for total and free homocystine measurement must be handled and processed in a specific way: they must be put on ice and spun within 1 hour. Whether the specifications are always followed by all laboratories or medical offices is unclear.
- The risk for vascular disease is graded with respect to the level of homocysteine; however, no threshold abnormal value is accepted widely.
- If homocysteinemia is determined by a test, then tests for deficiency in folic acid, vitamin B-12, and pyridoxine also may be performed.
- Genetic abnormalities are reported on chromosome 1 pertaining to MTHFR; however, the mere presence of this abnormality may not confer a risk for vascular disease.
Imaging Studies
- On routine imaging studies, bony abnormalities including osteoporosis may be readily apparent.
- A CT scan of the head is obtained routinely in patients presenting with acute stroke. Where available, MRI with newer techniques such as diffusion and perfusion imaging and MR angiography also may be used in the acute setting.
- MRI5 and CT findings with either homocystinuria or classic homocysteinemia may show both large-vessel or lacunar strokes, potentially in any vascular distribution.
Other Tests
Acute stroke diagnosis and treatment requires that certain laboratory studies such as complete blood count, chemistries, prothrombin/activated partial thromboplastin times (PT/aPTT), brain imaging, echocardiography, and vascular studies be done to exclude the usual causes, some of which may be treatable or preventable.
Treatment
Medical Care
- Homocystinuria
- Pyridoxine, at a dose of 100-500 mg/d, is the drug of choice.
- Measuring homocystine levels can be used to monitor the effectiveness of treatment. If pyridoxine alone is not effective, folic acid and vitamin B-12 can be added to the regimen.
- If patients are pyridoxine insensitive, a low-methionine diet initiated at diagnosis, along with betaine supplementation, may help reduce homocysteine levels.
- Homocysteinemia
- Plasma homocysteine levels are reduced by folic acid supplementation. With the mandated fortification of cereals with folic acid in the United States, B-12 deficiency (or relative B-12 deficiency) may influence homocysteinemia. The optimal dose and route of administration of B-12 and dose of folic acid and the effect on clinical outcome have not been studied prospectively. Initiation of therapy with B-12, folic acid, and B-6 tends to normalize homocysteine in 4-8 weeks.
- The VISP trial, completed in 2004, has shown no difference in stroke outcome between high- and low-dose vitamin (B-12, B-6, folic acid) supplementation groups.6 Subgroup analysis showed that patients with high baseline homocysteine and assigned to low-dose vitamins had higher risk of stroke.
- Reanalysis of the HOPE 2 trial showed reduced incidence of nonfatal stroke with long-term (>3 y) treatment with B vitamins.7
- A larger international trial VITATOPS is scheduled to be completed shortly and compares 2 groups (vitamin supplementation vs placebo) of patients and is studying the effect of vitamin therapy in secondary stroke prevention.
Consultations
- An experienced neurologist (adult or pediatric) should be consulted both for acute care of a patient with a stroke and for the diagnosis of uncommon causes of a stroke.
- Genetic counseling should be offered to the patient and the family on confirmation of homocystinuria.
- Dietary consultation may be required if a homocystinuric patient is found to be pyridoxine insensitive and requires dietary modification.
- Physical, occupational, and speech therapists may be consulted for patients with acute stroke.
Diet
A methionine-restricted diet is sometimes necessary if homocysteine is not controlled adequately by medications.
Medication
Homocystinuria: Patients may be divided into pyridoxine-sensitive and pyridoxine-insensitive groups. In the first group, pyridoxine, folic acid, and vitamin B-12 are prescribed. These 3 vitamins, in combination, reduce the homocysteine levels as well as provide clinical benefit. Secondary stroke prevention rests on risk factor reduction. Aspirin, clopidogrel, and aspirin-dipyridamole have been suggested for secondary stroke prophylaxis, but whether other antiplatelet agents or anticoagulation are equally or more effective is not known.
Homocysteinemia: No consensus exists on optimal approaches to the treatment of homocysteinemia.
Vitamins
These agents are essential for normal metabolic processes and DNA synthesis.
Pyridoxine (Nestrex)
Cofactor for cystathionine B-synthase in transsulfuration pathway of methionine metabolism.
Dosing
Adult
100-500 mg/d PO
Pediatric
Administer as in adults
Interactions
May decrease levodopa, phenytoin, and phenobarbital serum levels
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Extremely high doses may cause neuropathy; >200 mg/d may precipitate withdrawal effects when medication discontinued
Folic acid (Folvite)
Cofactor/precursor for methylene tetrahydrofolate reductase enzyme.
Dosing
Adult
0.45-10 mg/d PO/IM/SC
Pediatric
0.1-0.4 mg/d PO/IM/SC
Interactions
May cause levels of phenytoin to be subtherapeutic and thus increase in seizure frequency
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Some authors do not recommend treating with folic acid unless B-12 given concomitantly, as resolution of anemia may mask consequences of undiagnosed B-12 deficiency; resistance to treatment may occur in patients with alcoholism and deficiencies of other vitamins
Cyanocobalamin (Crystamine, Cyomin)
Deoxyadenosyl-cobalamin and hydroxocobalamin are active forms of vitamin B-12.
Dosing
Adult
200-1000 mcg/d IM
Pediatric
Administer as in adults
Interactions
None reported
Contraindications
Documented hypersensitivity; hereditary optic nerve atrophy
Precautions
Pregnancy
A - Fetal risk not revealed in controlled studies in humans
Precautions
Severe hypokalemia may result in patients with vitamin B-12–deficient megaloblastic anemia; this complication may be fatal and is thought to be due to increased cellular potassium requirements when anemia is corrected
Nutritional supplement
For pyridoxine-insensitive patients, betaine supplementation is an option.
Betaine (Cystadane)
Promotes conversion of homocysteine to methionine via a minor pathway.
Dosing
Adult
250 mg/kg/d PO tid
Pediatric
Administer as in adults
Interactions
None reported
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Prescriber should be knowledgeable in management of homocystinuria
Follow-up
Transfer
- Treatment of acute stroke is discussed elsewhere in this journal (see Thrombolytic Therapy in Stroke and Acute Stroke Management). Certain well-established protocols, if followed, may benefit the patient.
- If homocystinuria is suspected on the basis of history, physical examination, and family history, the patient may be transferred to a tertiary care center, where expertise in a variety of relevant fields is more likely to be available.
Deterrence/Prevention
Early diagnosis of homocystinuria along with prophylactic medical and dietary care is a key to better long-term prognosis; it can halt or even reverse some of the complications.
Complications
- Patients with homocystinuria are prone to thromboembolic events in the perioperative and postoperative periods, even with minor surgeries.
- Preoperative levels of homocysteine should be reduced to a near normal level.
- During and after surgery, aggressive hydration and prophylaxis for deep vein thrombosis (DVT) are strongly recommended.
Patient Education
For excellent patient education resources, visit eMedicine's Stroke Center. Also, see eMedicine's patient education article Stroke.
Miscellaneous
Medicolegal Pitfalls
- Several studies have pointed out that early diagnosis and institution of treatment and dietary restriction is likely to slow the progression of disease in homocystinuria as well as to reverse some of the features. If family history and sibling history suggest homocystinuria, screening tests should be advised.
- Early signs of myopia and lens abnormalities cannot be ignored.8 Bony abnormalities and body habitus can be confused with Marfan syndrome; however, Marfan syndrome follows an autosomal dominant inheritance pattern, while homocystinuria follows a recessive pattern.
References
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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
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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