eMedicine Specialties > Neurology > Neuro-vascular Diseases

Metabolic Disease and Stroke - Fabry Disease

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
Thomas A Kent, MD, Professor, Department of Neurology, Baylor College of Medicine; Neurology Care Line Executive, Michael E DeBakey Veterans Affairs Medical Center

Updated: Dec 11, 2008

Introduction

Background

Fabry disease is an X-linked lysosomal disorder that leads to excessive deposition of neutral glycosphingolipids in the vascular endothelium of several organs in the body and epithelial and smooth muscle cells. Progressive endothelial accumulation of glycosphingolipids accounts for the associated clinical abnormalities of skin, eye, kidney, heart, brain, and peripheral nervous system.

When young patients present with signs and symptoms of a stroke, along with a history of skin lesions, renal insufficiency or failure, and heart attacks, Fabry disease is a consideration. Research suggests that Fabry mutations may be more frequent than previously thought in cryptogenic stroke patients, but these patients invariably had other signs of Fabry disease, including proteinuria and acroparesthesias. The diagnosis of Fabry disease has considerable implications regarding treatment, management, and counseling. Specifically, physicians may be alert to the involvement of other organs besides those of the CNS and thus make early intervention possible. With early identification, counseling and prenatal diagnosis may be offered to family members.

Pathophysiology

Deficiency of alpha-galactosidase A activity leads to lysosomal accumulation of glycosphingolipids, predominantly the cerebroside trihexosides. Diffuse abnormal accumulation of glycosphingolipids occurs in all tissues.

Accumulation of glycosphingolipids produces swelling and proliferation of endothelial cells. Abnormal reactivity of endothelial cells with changes in blood flow in the brain and in peripheral vessels has been documented on magnetic resonance imaging (MRI), positron emission tomography (PET), transcranial Doppler imaging (TCD), and plethysmography.

Disturbances in intraluminal pressure and angioarchitecture are thought to lead to dilatation, angiectasia, and dolichoectasia. The vertebrobasilar arteries appear particularly susceptible to dilatational arteriopathy. Small penetrating arteries frequently become narrowed and occluded. Cerebral infarcts result from direct vascular occlusion or stretching and from distention of branches of the dolichoectatic parent vessels.

Decreased levels of thrombomodulin (TM) and increased plasminogen activator inhibitor (PAI) were found in Fabry disease patients thus suggesting that a prothrombotic state may be one cause of stroke in these patients. 

The precise cause of increased incidence of stroke is not established. Findings that could contribute to this increased risk include abnormal nitric oxide and non-nitric oxide dependent endothelial dilation and abnormal endothelial nitric oxide synthase (eNOS) activity leading to aberrant vascular functioning. Paradoxical hyperperfusion is seen in strokelike lesions whose significance is not known.

Nonischemic compressive complications of dolichoectatic intracranial arteries include hydrocephalus, optic atrophy, trigeminal neuralgia, and cranial nerve palsies.

Frequency

International

The prevalence of Fabry disease has been previously estimated to be 1 per 40,000. Most of the patients are Caucasian, but it is also found in African Americans and those of Hispanic or Asian descent.

A prospective multicenter study of cryptogenic strokes from Germany suggests that the prevalence could be as high as 1.2%.¹ This would mean that the prevalence rate is higher than mutations of factor V Leiden.

Mortality/Morbidity

Because Fabry disease affects several organ systems, morbidity and mortality are related to the combined effects of renal failure, heart failure, and stroke.

• The rate of stroke is reportedly 10-24%. However, this rate may be an overestimation because the data are from tertiary referral centers. About 70% of cerebral infarcts are in the vertebrobasilar circulation; most of the remainder involves the perforating arteries in the anterior circulation. Intracranial hemorrhage is rare.
• Recurrence of cerebrovascular events is common, and lesion load (measured radiologically) increases with advancing age.
• Death, as a result of renal failure, heart failure, or strokes, commonly occurs by the fourth or fifth decade of life.

Sex

• Fabry disease follows X-linked genetics, manifesting predominantly in men.
• Female heterozygotes also present with clinical and laboratory features of Fabry disease.

Age

• Different investigators have reported that the mean age of hemizygotic men at the onset of symptomatic stroke is 29-38 years.
• The mean age of female heterozygotes at the onset of symptomatic strokes is 40-43 years.
• Other symptoms and signs of Fabry disease may be present in male children as young as 9 years and in females by age 13 years.

Clinical

History

Patients with Fabry disease seek care from a variety of specialists, usually because of the involvement of a number of organ systems. Hypertension occurs with increased frequency in patients with Fabry disease because of progressive renal impairment. Other traditional risk factors for stroke, such as diabetes, hypercholesterolemia, and smoking, may or may not be present in these patients. Fabry disease must be high on the list of differential diagnoses when a young man presents with signs and symptoms of stroke, along with other characteristic lesions, as described below.

• Vague complaints of pain in hands and feet may be a presenting feature. These symptoms are called acroparesthesias, as they reflect the peripheral neuropathy that is a frequent manifestation of the disease.
  • This pain may be both episodic and chronic.
  • Acute episodes may be triggered by exposure to extremes of temperature, stress, emotion, and/or fatigue.
• Punctate, nonblanching, dark red to blue-black cutaneous vascular lesions (angiokeratomas) may be discovered on different parts of the body.
• Lens opacities and retinal and conjunctival vascular malformations may be found in the eyes.
• Left ventricular hypertrophy, conduction defects, valvular deficiencies, and myocardial infarctions are cardiac manifestations of disease in some patients.
• Proteinuria and progressive renal failure are a result of glycosphingolipid accumulation in the renal glomeruli and tubules.
• Hemiparesis, vertigo, diplopia, dysarthria, hemianopia, sensory loss, and other typical stroke symptoms characterize CNS involvement.
• The patient's family history, mostly in men and rarely in women may be positive for Fabry disease because of its X-linked genetic inheritance pattern.

Physical

The diffuse involvement of different organ systems leads to a number of abnormalities that can be discovered on physical examination.

• Abundant punctate, nonblanching clusters of ectatic blood vessels may be found just below the skin on different parts of the body, especially in a bathing-trunk distribution. These are the angiokeratomas, also referred to as angiokeratoma corporis diffusum universale.
• Lenticular opacities and vascular lesions of the conjunctiva and retina may be present.
• Cardiomegaly and rhythm abnormalities may be evident on chest palpation and auscultation.
• A detailed neurologic examination may reveal peripheral neuropathy, or nystagmus, internuclear ophthalmoplegia, dysarthria, aphasia, hemiparesis, and sensory loss caused by stroke lesions, especially in the posterior circulation.

Causes

Fabry disease is an X-linked genetic disease.

Differential Diagnoses

Workup

Laboratory Studies

• Microscopic examination of urine may show lipid-laden epithelial cells.
• Electrolyte imbalances reflecting renal failure may be seen.
• When an acute stroke is suspected on clinical grounds, customary laboratory tests such as determinations of the CBC count, electrolytes, prothrombin time, and activated partial thromboplastin time should be ordered. A search for the etiology of the symptoms should commence.
• Level of globotriaosylceramide (Gb₃ or GL-3) a glycosphingolipid may be elevated.
• Enzymatic analysis performed by using plasma or leukocytes may show a deficiency of alpha-galactosidase A.
• Levels of Gb₃ and alpha-galactosidase A may be normal in female heterozygote Fabry patients. Therefore, genetic and/or molecular diagnosis is necessary to confirm Fabry disease if suspected based on clinical features of proteinuria and acroparesthesias that were invariably present in both men and women with Fabry mutation and cryptogenic stroke. Men with Fabry mutation tend to have more clinical features when presenting with stroke.

Imaging Studies

• Cardiomegaly may be readily evident on a chest radiograph.
• Echocardiography may be indicated to investigate a possible source of emboli. Echocardiograms may reveal valvular abnormalities, ventricular hypertrophy, and flow abnormalities.
• Brain MRIs or CT scans should be obtained to visualize the site and extent of infarction.
• MR angiography (MRA), CT angiography (CTA), or four-vessel cerebral angiography should be performed to identify large-vessel dilated arteriopathy, stenosis, or occlusion.
• In patients with acute ischemic stroke, diffusion-weighted MRI may be used to identify early lesions, and perfusion-weighted MRI can be performed to identify perfusion defects.
• MR spectroscopy, arterial spin tagged MR imaging, and positron emission tomography (PET) have been performed on an experimental basis to understand the pathophysiology of this disease.

Other Tests

• ECG may show conduction abnormalities and evidence of previous myocardial infarctions.
• Nerve conduction studies may show decreased conduction velocities and prolonged distal latencies.
• Prenatal diagnosis can be made by using samples of chorionic villi and amniotic cells.

Procedures

• Skin biopsy with cells showing increased lipid content is suggestive of Fabry disease.

Histologic Findings

Lipid-laden cells have been described in endothelial cells, epithelial cells, muscle fibers, and ganglion cells.

Treatment

Medical Care

• Antiplatelet agents have been used for secondary stroke prevention in Fabry disease, but their effectiveness in this setting has not been proved.
• Anticoagulants may be necessary if embolic events that stem from cardiac causes are a concern.
• Painful neuropathies may be treated with a variety of medications. Carbamazepine and phenytoin have been used anecdotally in Fabry disease.
• Two enzymes, agalsidase-alpha (Replagal) and agalsidase-beta (Fabrazyme), reportedly help in normalizing renal function, cardiac function, and cerebrovascular flow.
  • Whether therapy with these enzymes changes the natural history of strokes attributable to Fabry disease is unclear.
  • Medical regulatory requirements are different in various parts of the world, and the appropriate authorities should be consulted regarding the approval status of these enzymes.
  • Research to replenish deficient enzymes by means of gene transfer via adenovirus is in its early stages.

Surgical Care

• Renal failure is a clear indication for renal transplantation. However, renal transplantation may not alter the course of disease progression in other organ systems.
• Fetal liver transplantation has been tried in a small number of patients.
  • In the limited group of patients tested, no changes in serum or leukocyte alpha-galactosidase A levels were reported.
  • Clinical use of this experimental procedure should be undertaken with caution, since published literature on this topic is sparse.

Consultations

• Consultation with a neurologist is recommended if Fabry disease is suspected as a cause of stroke or if the usual causes of stroke are not present. A neurologist also better handles painful neuropathies not amenable to treatment in the primary care setting.
• If an embolic event is thought to have caused a stroke, a cardiologist's expertise can be sought for both diagnostic and therapeutic options.
• A nephrologist should be consulted if a patient has renal failure.
• Sessions with a physical therapist and an occupational therapist can be helpful in rehabilitative efforts.

Medication

Antiplatelet agents are used for secondary stroke prevention. Anticoagulation with warfarin is prescribed when a cardioembolic stroke is suspected. Painful neuropathies can be treated with a variety of medications, including carbamazepine or phenytoin.

Two enzymes, agalsidase-alpha (Replagal) and agalsidase-beta (Fabrazyme), reportedly help in normalizing renal function, cardiac function, and cerebrovascular flow. Whether therapy with these enzymes changes the natural history of strokes attributable to Fabry disease is unclear.

Antiplatelet agents

These agents inhibit the cyclooxygenase system, decreasing the level of thromboxane A₂, which is a potent platelet activator.

Aspirin (Anacin, Ascriptin, Bayer Aspirin)

Inhibits prostaglandin synthesis, which prevents formation of platelet-aggregating thromboxane A2.

Dosing

Adult

50-325 mg PO qd; may use in combination with dipyridamole 200 mg PO bid

Pediatric

Not established

Interactions

Antacids and urinary alkalinizers may decrease effects; corticosteroids decrease salicylate serum levels; anticoagulants may cause additive hypoprothrombinemic effects and increase bleeding time; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses > 2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs

Contraindications

Documented hypersensitivity; liver damage; hypoprothrombinemia; vitamin K deficiency; bleeding disorders; asthma; because of association with Reye syndrome, do not use in children (<16 y) with flu

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May cause transient decrease in renal function and aggravate chronic renal disease; avoid use in patients with severe anemia, or history of blood coagulation defects or those taking anticoagulants

Ticlopidine (Ticlid)

Second-line antiplatelet therapy for patients who cannot tolerate or do not respond to aspirin therapy.

Dosing

Adult

250 mg PO bid

Pediatric

Not established

Interactions

Corticosteroids and antacids may decrease effects; theophylline, cimetidine, aspirin, and NSAIDS increase toxicity

Contraindications

Documented hypersensitivity; neutropenia or thrombocytopenia; liver damage; active bleeding disorders

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Life-threatening neutropenia and thrombotic thrombocytopenic purpura reported; manufacturer suggests close monitoring of CBC count, especially at start of therapy; discontinue if absolute neutrophil count <1200/mm³ or if platelet count <80,000/mm³

Clopidogrel (Plavix)

Selectively inhibits ADP binding to platelet receptor and subsequent ADP-mediated activation of glycoprotein GPIIb/IIIa complex, inhibiting platelet aggregation.

Dosing

Adult

75 mg PO qd

Pediatric

Not established

Interactions

Naproxen associated with increased occult GI blood loss; safety of coadministration with warfarin not established

Contraindications

Documented hypersensitivity; active pathological bleeding, such as peptic ulcer or intracranial hemorrhage

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

TTP reported in 1 person per 15,000-100,000; prolongs bleeding time; caution in patients at increased risk of bleeding from trauma, surgery, or pathologic conditions; caution in patients with lesions with propensity to bleed (eg, ulcers)

Aspirin 25 mg/dipirydamole 200 mg (Aggrenox)

To complement usual warfarin or aspirin therapy. Platelet adhesion inhibitor, possibly inhibits RBC uptake of adenosine, itself an inhibitor of platelet reactivity. May inhibit phosphodiesterase activity, leading to increased cyclic-3', 5'-AMP in platelets and formation of potent platelet activator thromboxane A₂.

Dosing

Adult

200 mg dipirydamole PO bid; used in combination with 25 mg aspirin bid

Pediatric

Not established

Interactions

Theophylline may decrease hypotensive effects; antiplatelet activity may increase heparin toxicity

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in hypotension; has peripheral vasodilating effects

Anticoagulants

These agents are used in the treatment of clinically evident intravascular thrombosis.

Warfarin (Coumadin)

Interferes with hepatic synthesis of vitamin K-dependent coagulation factors. For prophylaxis and treatment of deep venous thrombosis, pulmonary embolism, and thromboembolic disorders.

Dosing

Adult

5-10 mg/d PO qd for 2-5 d; adjust dose according to desired INR of 2-3

Pediatric

Not established

Interactions

Griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, oral contraceptives, and sucralfate may decrease effects; oral antibiotics, phenylbutazone, salicylates, sulfonamides, chloral hydrate, clofibrate, diazoxide, anabolic steroids, ketoconazole, ethacrynic acid, miconazole, nalidixic acid, sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram, metronidazole, phenylbutazone, phenytoin, propoxyphene, sulfonamides, gemfibrozil, acetaminophen, and sulindac may increase effects

Contraindications

Documented hypersensitivity; severe liver or kidney disease; open wounds; GI ulcers

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Patients with suspected protein C or S deficiency may have skin necrosis and should receive heparin first; increased risk of intracerebral and systemic hemorrhage; many toxic effects possible

Enzyme replacement agents

These agents are the recombinant form of the enzyme alpha-galactosidase and beta-galactosidase-A.

Agalsidase alfa (Replagal)

Recombinant form of the human enzyme alpha-galactosidase A, levels of which are deficient in Fabry disease. Data from clinical trials show a decrease in GL-3 levels following enzyme replacement, reversal in lipid tissue storage, stabilized or improved renal and cardiac function, and reduced or relief from neuropathic pain. Following enzyme replacement, the long-term use of neuropathic pain medication has been reduced.
Manufactured by Transkaryotic Therapies, Inc (Cambridge, Mass) and is based on activation of the human GLA gene expression in human (skin) fibroblasts.

Dosing

Adult

0.2 mg/kg IV infused over 40 min q2wk

Pediatric

Not established; appropriate time to initiate treatment in children has not been determined

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May cause IgG antibody production in 55% of treated patients; may cause allergic reactions in 10% of treated patients (prevented by premedication with hydrocortisone and/or antihistamines before IV infusion); infusion-related events (ie, fever, rigors, hypertension) may be reduced or eliminated by slower rate of administration or interruption of treatment

Agalsidase beta (Fabrazyme)

Recombinant form of the human enzyme alpha-galactosidase A, levels of which are deficient in Fabry disease. Data from clinical trials show a decrease in GL-3 levels following enzyme replacement, reversal in lipid tissue storage, stabilized or improved renal and cardiac function, and reduced or relief from neuropathic pain. Following enzyme replacement, the long-term use of neuropathic pain medication has been reduced.
Manufactured by Genzyme Corporation (Cambridge, Mass) and is based on expression of the human GLA gene in CHO cells.

Dosing

Adult

1 mg/kg IV infused over 4-6 h (initial infusion); subsequent infusions may be administered at a rate of 3-5 mg/min; repeat q2wk

Pediatric

Not established; appropriate time to initiate treatment in children has not been determined

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May cause IgG antibody production in 83% of patients treated with Fabrazyme; may cause allergic reactions (which are prevented by premedication with hydrocortisone and/or antihistamines [standard] before IV infusion) in 59% of patients treated with Fabrazyme; infusion-related events (ie, fever, rigors, hypertension) may be reduced or eliminated by slower rate of administration or interruption of treatment

Follow-up

Inpatient & Outpatient Medications

• Antiplatelet agents: Aspirin, ticlopidine, clopidogrel, and aspirin-dipyridamole in doses mentioned in the Medication section are used routinely to prevent recurrent ischemic strokes of thrombotic type.
• Anticoagulant: Warfarin is often used to prevent cardioembolic strokes.

Transfer

• Fabry disease is uncommon, and its diagnosis and treatment can be challenging.
• Treatment strategies involve combined efforts from multiple specialties. The diagnosis and care of these patients usually is best handled at tertiary care centers.
• Acute strokes may be managed adequately in community hospitals in the initial phases.
• Aggressive efforts to diagnose the etiology of stroke are necessary to plan secondary prevention strategies. In this context, unusual presentations with multiple organ involvement or lack of traditional vascular risk factors should suggest consideration of Fabry disease. Traditional secondary stroke prevention strategies are still necessary.
• Further care can be accomplished by means of consultation with tertiary care centers.

Prognosis

• Fabry disease affects multiple organ systems in the body. Death, a result of renal failure, heart involvement, or stroke, usually occurs by the fifth decade.
• After a first stroke, recurrent stroke is frequent, with a median interval to first recurrence of 6.4 years in hemizygotes.

Patient Education

For excellent patient education resources, visit eMedicine's Stroke Center. Also, see eMedicine's patient education article Stroke.

Miscellaneous

Medicolegal Pitfalls

• Signs and symptoms of Fabry disease may be nonspecific. If manifestations in different organs are considered in isolation, the unifying diagnosis may be missed.
• If the family history suggests a diagnosis of Fabry disease, genetic testing and counseling should be offered to all family members, regardless of their sex.

References

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Keywords

Fabry's disease, angiokeratoma corporis diffusum, glycolipid lipidosis, metabolic disease and stroke, Fabry disease, lysosomal disorder, glycosphingolipids

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

Jeffrey L Saver, MD, Director, Stroke Center, Professor, Department of Neurology, University of California at Los Angeles Medical Center
Jeffrey L Saver, MD is a member of the following medical societies: American Academy of Neurology, American Heart Association, American Neurological Association, and National Stroke Association
Disclosure: Boehringer-Ingelheim - Secondary Prevention Consulting fee Consulting; Talacris Consulting fee Consulting; ImaRx Consulting fee Consulting

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 and 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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