Fabry Disease

Updated: May 23, 2023
  • Author: Nusrat Ahsan, MD; Chief Editor: Helmi L Lutsep, MD  more...
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Fabry disease is an X-linked lysosomal disorder that leads to excessive deposition of neutral glycosphingolipids in the vascular endothelium of several organs and in 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.

Fabry disease is uncommon, although research suggests that Fabry mutations may be more frequent than previously thought in cryptogenic stroke patients. However, the patients studied invariably had other signs of Fabry disease, including proteinuria and acroparesthesias. [1]

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 central nervous system (CNS), thus making early intervention possible. With early identification, counseling and prenatal diagnosis may be offered to family members. [2, 3]

Treatment and diagnostic considerations

Patients with Fabry disease seek care from a variety of specialists, usually because of the involvement of a number of organ systems.

The diagnosis and treatment of Fabry disease can be challenging. The signs and symptoms of Fabry disease may be nonspecific, and if manifestations in different organs are considered in isolation, the unifying diagnosis may be missed. [4, 5]

The National Society of Genetic Counselors recommends testing for any patient with a family history of Fabry disease or corneal verticillata ("whorls") on slit lamp exam. In the absence of these factors, it is recommended to test patients who have any of the following two features: [6]

  1. Decreased sweating (anhidrosis or hypohidrosis)
  2. Reddish-purple skin rash in the bathing trunk area (angiokeratomas)
  3. Personal and/or family history of kidney failure
  4. Personal or family history of "burning" or "hot" pain in the hands and feet, particularly during fevers (acroparesthesias)
  5. Personal or family history of exercise, heat, or cold intolerance
  6. Patients with sporadic or non-autosomal dominant (no male-to-male) transmission of unexplained cardiac hypertrophy

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.

The presence of Fabry symptoms in boys and girls of any age is a strong indication for treatment initiation. Recommendations from the Fabry Pediatric Expert Panel include the following: [7]

  • Treatment should be initiated before irreversible end-organ damage has occurred.
  • Asymptomatic children with Fabry mutations should be followed closely.
  • The management of Fabry disease requires a multidisciplinary care approach.

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 lead to the consideration of Fabry disease. Traditional secondary stroke prevention strategies are still necessary.

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. Further care can be accomplished by means of consultation with tertiary care centers.

Research to replenish deficient enzymes by means of gene transfer via adenovirus is in its early stages.

For patient education information, see eMedicineHealth's Brain and Nervous System Center and Stroke.

See Medscape Reference article Ischemic Stroke in Emergency Medicine for more complete information on this topic.


Etiology and Pathophysiology

Deficiency or absence of alpha-galactosidase A (α-GAL A) activity as a result of genetic mutation in the GLA gene (Xq21.3-q22) leads to lysosomal accumulation of glycosphingolipids, predominantly the cerebroside trihexosides. Diffuse, abnormal accumulation of glycosphingolipids occurs in all tissues, producing 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) scanning, transcranial Doppler imaging (TCD), and plethysmography. [8]

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 the distension of branches of the dolichoectatic parent vessels.

Decreased levels of thrombomodulin (TM) and increased plasminogen activator inhibitor (PAI) have been 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 has not been 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. [9]

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


Incidence of Fabry Disease

The prevalence of Fabry disease has been estimated to be 1 per 40,000 people. [10, 11] In Caucasians the prevalence can be as high as 1:17000, but it is also found in African Americans and in persons of Hispanic or Asian descent. [12]

A prospective, multicenter study of cryptogenic strokes from Germany suggested that the prevalence of Fabry disease could be as high as 1.2%. [13] This would mean that the prevalence rate is higher than that for mutations of factor V Leiden.


Morbidity and Mortality in Fabry Disease

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.

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.

Death, as a result of renal failure, heart failure, or strokes, commonly occurs by the fourth or fifth decade of life.


Prognosis in Fabry Disease

After a first stroke, recurrent stroke is frequent, with a median interval to first recurrence of 6.4 years in hemizygotes.

Heterozygous females usually have mild symptoms and later age of onset than males. However, they may be asymptomatic or have severe symptoms similar to classically affected males.


Sex and Age Predilections

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

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 age 9 years and in females by age 13 years.


Patient History in Fabry Disease

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.

Because Fabry disease has an X-linked genetic inheritance pattern, the patient’s family history may be positive for the condition.


Physical Examination in Fabry Disease

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

Abundant punctate, nonblanching, dark red to blue-black clusters of ectatic blood vessels may be found just below the skin. The clusters develop in different parts of the body, although they are most commonly found in a bathing-trunk distribution. The clusters are known as angiokeratomas, although they are also referred to as angiokeratoma corporis diffusum universale.

Cardiomegaly and rhythm abnormalities may be evident on chest palpation and auscultation.

Acroparesthesia is a reflection of peipheral neuropathy with complaints of pain in hands and feet typically manifesting in childhood and adolescence. This pain may be both episodic and chronic. Acute episodes may be triggered by exposure to extremes of temperature, stress, emotion, and/or fatigue. Palms and soles of feet appear affected without change in color, preserved deep tendon reflexes, and NCV can be normal due to small fiber disease.

GI manifestations can include diarrhea and abdominal pain. Altered sweating (anhidrosis, hypohidrosis, and rarely hyperhidrosis) may be present, as well as hypoacusia, sensorineural hearing loss and paroxysmal vertigo from labyrinth damage.

Corneal verticillata is the corneal opacity observed by slit-lamp exam, which changes from diffuse haziness to whorl-like opacity. Lenticular cataracts, aneurysmal dilation, and tortuosity of conjunctival and retinal vessels also occur.


Differential Diagnosis in Fabry Disease

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.

Conditions that mimic the symptoms of Fabry disease include the following:


Laboratory Studies in Fabry Disease

Microscopic examination of urine may show mulberry bodies in the sediments, which are distal epithelial cells with accumulated globotriaosylceramide with chracteristic whorl-like appearance. [14]

Electrolyte imbalances reflecting renal failure may be seen. Proteinuria may be present.

When an acute stroke is suspected on clinical grounds, customary laboratory tests, such as determination of the complete blood count (CBC), electrolytes, prothrombin time, and activated partial thromboplastin time, should be ordered. A search for the etiology of the symptoms should commence.

The 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 in males. Confirmation by the molecular genetic testing of hemizygous GLA pathogenic variant is needed.

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 the disease is suspected based on clinical features of proteinuria and acroparesthesias that were invariably present in men and women with Fabry mutation and cryptogenic stroke. Men with Fabry mutation tend to have more clinical features when presenting with stroke.


Chest Radiographs and Echocardiography

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.


MRI and CT Scanning

Brain MRI or computed tomography (CT) scans should be obtained to visualize the site and extent of infarction.

MR angiography (MRA), CT angiography (CTA), or 4-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) scanning have been performed on an experimental basis to understand the pathophysiology of Fabry disease. [15]


Neurologic Examination

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.


Skin Biopsy and Histologic Findings

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

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


Additional Tests

Electrocardiography 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.

Newborn screening for Fabry disaese is implemented in a few states in the United States.


Pharmacologic Therapy

Antiplatelet agents, including aspirin, ticlopidine, clopidogrel, and aspirin-dipyridamole, are used routinely to prevent recurrent ischemic strokes of thrombotic type in Fabry disease, but their effectiveness in this setting has not been proved.

Administration of the anticoagulant warfarin, which is often used to prevent cardioembolic strokes, 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, phenytoin, and gabapentin have been effecitve in treating neuropathic pain due to Fabry disease. [16]

Enzyme replacement therapies

Enzymes available in the United States include agalsidase-beta (Fabrazyme) and pegunigalsidase alfa (Elfabrio). Agalsidase beta was approved in 2003 and is indicated for adults and children aged 2 years and older with confirmed Fabry disease. Pegunigalsidase alfa was approved in May 2023 for adults with Fabry disease. Enzyme replacement therapy helps in normalizing renal function, cardiac function, and cerebrovascular flow.

Fabry disease is caused by deficiency of the lysosomal enzyme alpha-galactosidase A involved in the metabolism of globotriaosylceramide (GL-3). The enzyme replacement  is internalized and transported into lysosomes where it is thought to exert enzymatic activity and reduce accumulated globotriaosylceramide Gb3 and reduce GL-3 deposition in capillary endothelium, thereby improving associated clinical manifestations (eg, vascular occlusion, stroke, renal failure, heart failure). Enzyme replacement therapy stabilizes and may slow progression of Fabry disease, with more benefit when started at an early age. [17]  

Enzyme stabilizers

The first alpha-galactosidase A (alpha-Gal A) stabilizer, migalastat (Galafold), was approved for treatment of adults with a confirmed diagnosis of Fabry disease and an amenable galactosidase alpha gene (GLA) variant based on in vitro assay data.

Efficacy of migalastat is supported by the FACETS and ATTRACT clinical trials. Results from the FACETS trial showed that after 6 months, significantly more patients receiving migalastat experienced improvement in diarrhea compared with placebo (43% vs 11%; p = 0.02), including the subset with baseline diarrhea (71% vs 20%; p = 0.02). A decline in kidney peritubular capillary globotriaosylceramide inclusions correlated with diarrhea improvement; patients with a reduction > 0.1 were 5.6 times more likely to have an improvement in diarrhea than those without (p = .031). [18]  

Results from the ATTRACT trial showed migalastat and ERT had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment (-6.6 g/m2 [-11.0 to -2.2]); there was no significant change with ERT. Predefined renal, cardiac or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following the switch from ERT to migalastat. [19]


Renal and Fetal Liver Transplantation

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 the topic is sparse.


Consultations in Stroke, Renal Failure, and Neuropathy

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. In addition, a neurologist can better handle painful neuropathies that are 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 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.