eMedicine Specialties > Neurology > Neuro-vascular Diseases

Metabolic Disease and Stroke - Fabry Disease

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: 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.

More on Metabolic Disease and Stroke - Fabry Disease

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

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Further Reading

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Keywords

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

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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

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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