- Author: Pitchaiah Mandava, MD, PhD; Chief Editor: Helmi L Lutsep, MD more...
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.
Homocystinuria is an autosomal recessively inherited defect in the transsulfuration pathway (homocystinuria I) or methylation pathway (homocystinuria II and III).
Homocysteinemia, a separate but related entity, is defined as elevation of the 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.
Homocysteinemia may be due to a genetic predisposition to abnormal activity in the same pathways as homocystinuria. Nutritional and environmental factors, as well as specific medications, may worsen this abnormality and provoke symptoms.
Homocysteine level and stroke
An 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.
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 onward to cysteine, is termed the transsulfuration pathway. Conversion of homocysteine back to methionine, catalyzed by MTHFR and methylcobalamin, is termed the remethylation pathway. A minor amount of remethylation takes place via an alternative 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 solely a genetic predisposition or from a 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.
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. In patients with a 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, including the following:
Endothelial cell damage
Smooth muscle cell proliferation
Upregulation of prothrombotic factors (XII and V)
Downregulation of antithrombotic factors or endothelial-derived nitric oxide
The incidence of homocystinuria in the United States is approximately 1 per 100,000. Internationally, the reported incidence of homocystinuria varies between 1 in 50,000 and 1 in 200,000.
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. Death is predominantly due to cerebrovascular or cardiovascular causes.
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.
Homocystinuria is associated with the following physical findings:
Downward dislocation of lens (ectopia lentis)
Pes excavatum, pes carinatum, and genu valgum
Signs and symptoms of strokes in any vascular distribution: hemiplegia, aphasia, ataxia, and pseudobulbar palsy are among the most common findings.
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.
The oral health of 14 patients with homozygote cystathionine beta synthase-deficient homocystinuria was evaluated in a Swedish study and found to be compromised in a majority of cases. The authors suggested that methionine restriction (low-protein diet) in the treatment of homocystinuria may result in a diet high in sugars. They therefore noted the need for regular dental checkups and preventive oral care for individuals suffering from homocystinuria. In addition, the authors noted that all patients had short dental roots, particularly of the central maxillary incisors.
In a Spanish cross-sectional survey sent to 35 hospitals, 75 patients were identified with homocystinuria: 41 with transsulfuration defects (1 death), 27 with remethylation defects (6 deaths), and 7 without a syndromic diagnosis. In 18 cases, more than one sibling was affected. Patients with remethylation defects had the most severe clinical manifestations. There was a high percentage of cognitive impairment, followed by lens diseases. Neurologic disorders were present in almost half of the patients, and there was increased vascular involvement in CBS-deficient adults.
Patients with homocysteinemia 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.
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. 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.
The differential diagnosis includes the following:
Other problems to be considered include carotid disease and stroke.
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.
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.
Laboratory studies for 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.
Laboratory studies for homocysteinemia
Laboratory 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. 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 methylene tetrahydrofolate reductase (MTHFR); however, the mere presence of this abnormality may not confer a risk for vascular disease.
CT scanning and MRI
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.
MRI and CT findings with either homocystinuria or classic homocysteinemia may show both large-vessel or lacunar strokes, potentially in any vascular distribution.
Treatment & Management
Pyridoxine, at a dose of 100-500 mg/d, is the drug of choice.
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.
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.
No consensus exists on optimal approaches to the treatment of 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 Vitamin Intervention for Stroke Prevention (VISP) trial showed no difference in stroke outcome between high- and low-dose vitamin (B-12, B-6, folic acid) supplementation groups. Subgroup analysis showed that patients with a high baseline homocysteine who were assigned to low-dose vitamins had a higher risk of stroke.
Reanalysis of the Heart Outcomes Prevention Evaluation 2 (HOPE 2) trial showed a reduced incidence of nonfatal stroke with long-term (>3 y) treatment with B vitamins.
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.
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.
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.
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