Fabry disease

Fabry disease is a hereditary disorder linked to the X chromosome of the metabolism of glycosphingolipids due to the lysosomal activity of α-galactosidase A (α-gal A) smooth or deficient.

The decrease in the lysosomal activity of α-gal A causes a progressive accumulation of globotriaosylceramide (Gb3 or GL-3) in the lysosomes of cells throughout the body.

What is Fabry’s disease?

Fabry disease (FD) is a rare and inherited disease. It is progressive and can endanger life. People with Fabry disease have a damaged gene that leads to a shortage of an essential enzyme. The deficiency causes the accumulation of specific proteins in the cells of the body, causing damage in:

  • Heart
  • Light
  • Kidneys
  • Skin
  • Brain
  • Stomach

The disease affects men and women in all ethnic groups, but men are often more severely affected.

There are two types of Fabry disease. Fabry disease type 1, also known as classic Fabry disease, begins in childhood and is less common than Fabry disease type 2, which has a later onset. It is estimated that 1 in every 117,000 people have Fabry disease.

Fabry’s disease is named after Johannes Fabry, a German doctor who first described his symptoms in 1898. It is also known as Anderson-Fabry disease by William Anderson, a British doctor who also noticed it in that same year.


Initially, Johannes Fabry and William Anderson separately described the disease in 1898 in 2 different patients with the progressive development of red-purple maculopapular skin lesions, or angiokeratoma, located on the torso and upper extremities; however, since then, the dermatological findings have been recognized as part of a systemic disease that predominantly affects the gastrointestinal tract, the nervous system, the kidneys, and the heart.

Other names for Fabry disease are:

  • Deficiency of the alpha-galactosidase (GLA) gene.
  • Enzyme alpha-galactosidase A deficiency.
  • Angioqueratoma body extended.
  • Diffuse angiokeratoma.
  • Deficiency of ceramide trihexosidase.

Patients with Fabry disease may have diverse phenotypes, ranging from the “classic” phenotype to atypical variants, such as a predominant renal or cardiac phenotype. Once considered asymptomatic carriers, female heterozygotes may have a clinically silent disease or manifest a severe phenotype.

Symptoms of Fabry Disease

Fabry disease has many different symptoms, which makes diagnosis difficult. Symptoms can vary between men and women and between Fabry Disease Type 1 and Type 2.

Symptoms of Fabry Disease Type 1

The first symptoms of Fabry Disease Type 1 include:

Burning pain or tingling in the hands and feet. This can happen as early as 2 to 8 years of age in men. In women, it occurs later in childhood or adolescence. Episodes of severe pain, which can last from minutes to days, are called “Fabry crises.”

The lack of sweat production. This affects more men than women.

Acne. This reddish-purple rash is slightly raised between the navel and the knees. It is called angiokeratoma.

Stomach problems. This includes cramping, gas, and diarrhea.

Abnormal corneas The blood vessels in the eyes may look different, but this does not affect vision.

General tiredness, dizziness, headache, nausea, and heat intolerance. Men can have swelling in their feet and legs.

As the Type 1 Fabry Disease progresses, the symptoms become more severe. When people with type 1 reach the age of 30 and 40, they can develop kidney disease, heart disease, and stroke.

Symptoms of Fabry Disease Type 2

People with Fabry Disease Type 2 also develop problems in these areas, although usually in their 30 to 60 years later in life.

Severe symptoms of Fabry disease vary from person to person and may include:

A progressive decrease in renal function, which progresses to renal failure.

Enlarged heart, angina (chest pain related to the heart), irregular heartbeat, thickening of the heart muscle, and heart failure.

A stroke occurs in some men and women with Fabry disease in their 40s. This may be more common in women with Fabry disease.

Stomach problems. About 50-60 percent of women with Fabry disease may have pain and diarrhea.

Other signs of Fabry disease include:

  • Hearing loss.
  • Ringing in the ears.
  • Lung disease.
  • Intolerance to strenuous exercise
  • Fever.

What Causes Fabry’s Disease?

A specific genetic mutation causes Fabry disease. You inherit the damaged gene from your parents. The damaged gene is located on the X chromosome, one of the two chromosomes that determine your sex. Men have an X chromosome and a Y chromosome, and women have two X chromosomes.

A man with the Fabry disease gene mutation on the X chromosome will continuously transmit it to his daughters but not to his children. The children get the Y chromosome, which does not have the damaged gene.

A woman with the Fabry disease mutation on an X chromosome has a 50 percent chance of transmitting it to her sons and daughters. If your child gets the X chromosome with the Fabry disease mutation, he will inherit Fabry disease.

Because a daughter has two X chromosomes, she may have less severe symptoms of DF. This is because not all cells in your body will activate the X chromosome that carries the defect. If the damaged X chromosome is activated or not occurs at the beginning of its development and remains so for the rest of his life.

How genetic mutations lead to Fabry disease

Fabry disease is caused by up to 370 mutations in the GLA gene. Particular mutations tend to occur in families.

The GLA gene controls the production of a particular enzyme called alpha-galactosidase A. This enzyme is responsible for breaking down a molecule in cells known as globotriaosylceramide (GL-3).

When the GLA gene is damaged, the enzyme that breaks GL-3 can not work correctly. As a result, GL-3 accumulates in body cells. Over time, this accumulation of fat damages the cell walls of blood vessels in:

  • Skin.
  • Nervous system.
  • Heart.
  • Kidneys

The degree of damage caused by Fabry disease depends on the severity of the mutation in the GLA gene. That is why the symptoms of Fabry disease can vary from person to person.

How is Fabry’s disease diagnosed?

Fabry disease can be challenging to diagnose because the symptoms are similar to those of other conditions. The symptoms are often present long before a diagnosis. Many people are not diagnosed until they have an FD crisis.

Type 1 Fabry Disease is usually diagnosed by doctors based on the child’s symptoms. Fabry disease is often diagnosed when tested or treated for heart or kidney problems in adults.

A diagnosis of Fabry disease for men can be confirmed by a blood test that measures the amount of the damaged enzyme.

This test is not enough for women because the damaged enzyme may look normal even though some organs are damaged. A genetic test for the defective GLA gene is necessary to confirm if a woman has Fabry disease.

For families with a known history of Fabry disease, prenatal tests can determine if a baby has Fabry disease.

Early diagnosis is essential. Fabry disease is a progressive disease, which means that the symptoms get worse over time. Early treatment can help.

General description of Fabry’s disease

Fabry disease is a lysosomal disorder linked to X that leads to excessive deposition of neutral glycosphingolipids in the vascular endothelium of various organs and epithelial and smooth muscle cells.

The progressive endothelial accumulation of glycosphingolipids explains the associated clinical abnormalities of the skin, eyes, kidneys, heart, brain, and peripheral nervous system.

When young patients show signs and symptoms of a stroke, along with a history of skin lesions, kidney failure or failure, and heart attacks, Fabry disease is a consideration.

Fabry disease is rare, although research suggests that Fabry mutations may be more frequent than previously thought in patients with cryptogenic stroke.

However, the patients studied invariably presented other signs of Fabry disease, which included proteinuria and acroparesthesia.

The diagnosis of Fabry disease has considerable implications concerning treatment, treatment, and counseling.

Specifically, physicians can be alert to the participation of other organs besides those of the central nervous system (CNS), which makes early intervention possible.

Counseling and prenatal diagnosis can be offered to family members with early identification.

Treatment and Diagnostic Considerations

Patients with Fabry disease seek care from various specialists, usually due to the involvement of multiple organ systems.

The diagnosis and treatment of Fabry disease can be a challenge. The signs and symptoms of Fabry disease can be nonspecific, and if the manifestations in different organs are considered in isolation, the unifying diagnosis may be overlooked.

The National Society of Genetic Counselors recommends testing for any patient with a family history of Fabry disease or corneal verticillata (“whorls”) on the slit lamp examination. In the absence of these factors, it is recommended to evaluate patients who have any of the following two characteristics:

  • Decreased sweating (anhidrosis or hypohidrosis).
  • The reddish-purple skin rash in the area of ​​the trunk of the bath (angiokeratomas).
  • Personal and family history of renal failure.
  • Unique or family history of “hot” or “hot” pain in the hands and feet, particularly during fevers (acroparesthesia).
  • Personal or family history of exercise, heat or cold intolerance.
  • Patients with sporadic or non-autosomal dominant transmission (not man to man) 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 gender.

The presence of Fabry symptoms in children of any age is a strong indication for the start of treatment. The recommendations of Fabry’s Pediatric Expert Panel include the following:

  • Treatment must begin before irreversible damage occurs in the final organ.
  • Asymptomatic children with Fabry mutations should be followed closely.
  • The treatment of Fabry disease requires a multidisciplinary approach to care.

Aggressive efforts to diagnose the etiology of stroke are necessary to plan secondary prevention strategies.

In this context, unusual presentations involving multiple organs or the lack of traditional vascular risk factors should lead to the consideration of Fabry disease.

Traditional strategies for secondary prevention of attacks are still necessary.

Treatment strategies involve combined efforts of multiple specialties. The diagnosis and care of these patients are generally better managed in tertiary care centers.

Acute strokes can be managed appropriately in community hospitals in the early stages. More care can be taken through consultations with tertiary care centers.

Research to replenish deficient enzymes using gene transfer through adenovirus is in its early stages.

Etiology and Pathophysiology of Fabry Disease

The deficiency or absence of alpha-galactosidase A activity (α-GAL A) due to the genetic mutation in the GLA gene (Xq21.3-q22) leads to the lysosomal accumulation glycosphingolipids, predominantly the cerebroside trihexosides.

The diffuse and 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 peripheral vessels, has been documented in magnetic resonance imaging (MRI), positron emission tomography (PET), transcranial Doppler (TCD), and plethysmography.

It is believed that alterations in intraluminal pressure and angioarchitecture produce dilation, telangiectasia, and dolichoectasia. The vertebrobasilar arteries seem particularly susceptible to dilatational arteriopathy.

The arteries of slight penetration often narrow and occlude. Cerebral infarcts result from direct vascular occlusion or stretching and enlargement of the branches of the dolichoectatic parental vessels.

Decreased levels of thrombomodulin (TM) and plasminogen activator inhibitor (PAI) have been found in patients with Fabry disease, suggesting that a prothrombotic state may cause a stroke.

The precise cause of the increased incidence of stroke has not been established.

The findings that could contribute to this increased risk include abnormal nitric oxide and endothelial dilatation not dependent on nitric oxide and abnormal activity of synthetic endothelial nitric oxide (eNOS) that leads to aberrant vascular functioning.

Paradoxical hyperperfusion is observed in strident-type lesions whose importance is unknown.

Non-ischemic and compressive complications of the dolichoectal intracranial arteries include hydrocephalus, optic atrophy, trigeminal neuralgia, and cranial nerve palsies.

Incidence of Fabry Disease

The prevalence of Fabry disease has been estimated at 1 per 40,000 people. In Caucasians, the majority can be as high as 1: 17,000, but it is also found in African-Americans and people of Hispanic or Asian descent.

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

Morbidity and Mortality in Fabry Disease

Because Fabry disease affects several organ systems, morbidity and mortality are related to kidney failure, heart failure, and stroke.

The stroke rate is reportedly 10-24%. However, this rate may be overestimated since the data come from tertiary referral centers.

About 70% of cerebral infarcts are found in the vertebrobasilar circulation; most of the rest involve the perforating arteries in the anterior circulation. Intracranial hemorrhage is rare.

Recurrence of cerebrovascular events is common, and the burden of injury (radiologically measured) increases with advancing age.

Left ventricular hypertrophy, conduction defects, valvular deficiencies, and myocardial infarctions are cardiac manifestations of the disease in some patients.

Proteinuria and progressive renal failure result from the accumulation of glycosphingolipids in the glomeruli and renal tubules.

Hemiparesis, vertigo, diplopia, dysarthria, hemianopsia, sensory loss, and other symptoms typical of stroke characterize CNS involvement.

Death due to kidney failure, heart failure, or stroke commonly occurs in the fourth or fifth decade of life.

Prognosis in Fabry Disease

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

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

Predilections of Sex and Age

Fabry’s disease follows X-linked genetics, which manifests predominantly in men. However, female heterozygotes also present clinical and laboratory characteristics of Fabry disease.

Different investigators have reported that the average age of hemizygous men at the beginning of the symptomatic stroke is 29-38 years. The average 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 boys from 9 years and women at 13 years.

History of the Patient in Fabry’s Disease

Hypertension occurs more frequently in patients with Fabry disease due to progressive renal failure. 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 a genetic inheritance pattern linked to X, the patient’s family history can be positive for the condition.

Physical examination in Fabry disease

The diffuse participation of different organ systems in Fabry disease leads to abnormalities discovered in the physical examination.

You can find large groups of ectatic blood vessels, dotted, not angular, from dark red to dark blue, just below the skin.

The clusters develop in different parts of the body, although they are found more frequently in a distribution of the trunk of a bath.

The groups are known as angiokeratomas, although known as angiokeratoma corporis diffusum universale.

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

Acroparesthesia reflects peripheral neuropathy with complaints of pain in the hands and feet that typically manifest in childhood and adolescence.

This pain can be both episodic and chronic. Acute episodes can be triggered by exposure to extreme temperatures, stress, emotion, and fatigue.

The palms and soles of the feet are affected without color change, the deep tendon reflexes are preserved, and the NCV can be average due to the disease of the tiny fibers.

Gastrointestinal manifestations can include diarrhea and abdominal pain. There may be altered sweating (anhidrosis, hypohidrosis, and, in rare cases, hyperhidrosis) and hearing loss, sensorineural hearing loss, and paroxysmal vertigo due to labyrinth damage.

The corneal verticillata is the corneal opacity observed by the slit lamp examination, which changes from diffuse opacity to ambiguity similar to a whorl. There are also lenticular cataracts, aneurysmal dilatation, and tortuosity of the conjunctival and retinal vessels.

Differential Diagnosis in Fabry Disease

Fabry disease must figure prominently in the list of differential diagnoses when a young man has signs and symptoms of stroke, along with other characteristic lesions.

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

  • Management of acute stroke.
  • Thrombosis of the basilar artery.
  • Cardioembolic Stroke.
  • Cavernous sinus syndromes
  • Dissection syndromes
  • Lacunar Syndromes.
  • Posterior cerebral stroke.
  • Transient Global Amnesia.
  • Multiple sclerosis.

Laboratory Studies in Fabry Disease

The microscopic examination of the urine may show mulberry bodies in the sediments, distal epithelial cells with accumulated globotriaosylceramide with a characteristic spiral-shaped appearance.

Electrolyte imbalances that reflect renal failure can be observed. Proteinuria may be present.

For clinical reasons, routine laboratory tests, such as determining complete blood count (CBC), electrolytes, prothrombin time, and activated partial thromboplastin time, should be requested when an acute stroke is suspected. You must begin a search for the etiology of the symptoms.

The level of globotriaosylceramide (Gb3 or GL-3), a glycosphingolipid, may be elevated.

Enzymatic analysis performed using plasma or leukocytes may show a deficiency of alpha-galactosidase A in men. Confirmation by molecular genetic testing of the pathogenic GLA hemizygous variant is necessary.

Levels of Gb3 and alpha-galactosidase A may be expected in women (heterozygous) patients with Fabry.

Therefore, genetic and molecular diagnosis is necessary to confirm Fabry disease if the disease is suspected based on the clinical characteristics 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 characteristics when they present with a stroke.

X-rays of Thorax and Echocardiography

Cardiomegaly can be easily seen on a chest x-ray.

Echocardiography may be indicated to investigate a possible source of emboli. Echocardiograms may reveal valvular abnormalities, ventricular hypertrophy, and flow abnormalities.

MRI y CT Scanning

Imaging of brain magnetic resonance or computed tomography (CT) should be obtained to visualize the site and extent of the infarction.

Magnetic resonance angiography (MRA), CT angiography (CTA), or cerebral angiography of 4 vessels should be performed to identify large vessels’ dilated arteriopathy, stenosis, or occlusion.

In patients with acute ischemic stroke, diffusion-weighted magnetic resonance imaging can be used to identify early lesions, and perfusion-weighted magnetic resonance imaging can be performed to identify perfusion defects.

MR spectroscopy, MR imaging with arterial labeling, and positron emission tomography (PET) have been performed experimentally to understand the pathophysiology of Fabry disease.

Neurological Exam

A detailed neurological examination may reveal peripheral neuropathy or nystagmus, internuclear ophthalmoplegia, dysarthria, aphasia, hemiparesis, and sensory loss caused by stroke lesions, especially posterior circulation.

Skin biopsy and histological findings

Skin biopsy with cells showing an increase in lipid content suggests Fabry disease.

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

Additional Exams

Electrocardiography may show conduction abnormalities and evidence of previous myocardial infarctions.

Nerve conduction studies may show decreases in conduction velocities and prolonged distal latencies.

Prenatal diagnosis can be made by using samples of chorionic villi and amniotic cells.

The evaluation of the newborn for Fabry disease is implemented in some states of the United States.

Pharmacological Therapy

Antiplatelet agents, including aspirin, ticlopidine, clopidogrel, and aspirin-dipyridamole, are routinely used to prevent recurrent ischemic attacks of the thrombotic type in Fabry disease. Still, their efficacy has not been demonstrated in this context.

The administration of the warfarin anticoagulant, often used to prevent cardioembolic attacks, may be necessary if embolic events from cardiac causes are a concern.

Painful neuropathies can be treated with a variety of medications. Carbamazepine, phenytoin, and gabapentin have been influential in treating neuropathic pain due to Fabry’s disease.

According to reports, two enzymes, agalsidase-alpha (Replagal) and agalsidase-beta (Fabrazyme), help normalize kidney function, cardiac function, and cerebrovascular flow.

Enzyme replacement therapy stabilizes and may slow the progression of Fabry disease, with more benefits when starting at an early age.

Kidney and Fetal Liver Transplant

Renal failure is a clear indication of kidney transplantation. However, kidney 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 evaluated, no changes were reported in alpha-galactosidase A levels in serum or leukocytes.

The clinical use of this experimental procedure should be done with caution since the literature published on the subject is scarce.

Consultations in Stroke, Renal Insufficiency, and Neuropathy

It is recommended to consult with a neurologist if you suspect that Fabry’s disease is a cause of stroke or if the usual causes of stroke are not present.

In addition, a neurologist can better manage 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 experience can be sought for diagnostic and therapeutic options.

A nephrologist should be consulted if a patient has kidney failure.

Sessions with a physiotherapist and an occupational therapist can be helpful in rehabilitation efforts.

Complications of Fabry’s Disease

A possible complication of Fabry disease is end-stage renal disease (ESRD). ESRD can be deadly if it is not treated with dialysis or a kidney transplant. Almost all men with DF develop ESRD. However, only about 10 percent of women with FD develop ESRD.

For people who are treated to control ESRD, heart disease is one of the leading causes of death.

The perspective of Fabry disease and life expectancy

FD can not be cured, but it can be treated. The awareness of FD is increasing. ERT is a relatively new treatment that helps stabilize symptoms and decrease the onset of Fabry’s disease crisis. The investigation is ongoing for other treatment possibilities.

Gene replacement therapy is in a clinical trial. Another approach in the research phase, called escort therapy, uses small molecules to stop the damaged enzyme.

The life expectancy of people with Fabry disease is lower than that of the general population of EE. UU For men, it is 58.2 years. For women, it is 75.4 years.

A frequently overlooked Fabry disease complication is depression. It can be helpful to reach other people who understand. Several organizations for people with Fabry disease have resources to help both people with Fabry disease and their families.