Fabry's Disease

Fabry disease, also known as Anderson–Fabry disease, is a rare genetic disease that can affect many parts of the body, including the kidneys, heart, brain, and skin. Fabry disease is one of a group of conditions known as lysosomal storage diseases. The genetic mutation that causes Fabry disease interferes with the function of an enzyme that processes biomolecules known as sphingolipids, leading to these substances building up in the walls of blood vessels and other organs. It is inherited in an X-linked manner.

Fabry disease is sometimes diagnosed using a blood test that measures the activity of the affected enzyme called alpha-galactosidase, but genetic testing is also sometimes used, particularly in females.

The treatment for Fabry disease varies depending on the organs affected by the condition, and the underlying cause can be addressed by replacing the enzyme that is lacking.

The first descriptions of the condition were made simultaneously by dermatologist Johannes Fabry and the surgeon William Anderson in 1898.

Signs and symptoms

Symptoms are typically first experienced in early childhood and can be very difficult to diagnose; the rarity of Fabry disease to many clinicians sometimes leads to misdiagnoses. Manifestations of the disease usually increase in number and severity as an individual ages.

Pain

Full-body or localized pain to the extremities (known as acroparesthesia) or gastrointestinal (GI) tract is common in patients with Fabry disease. This pain can increase over time. This acroparesthesia is believed to be related to the damage of peripheral nerve fibers that transmit pain. Gastrointestinal tract pain is likely caused by the accumulation of lipids in the small vasculature of the GI tract, which obstructs blood flow and causes pain.

Kidney

Kidney complications are common and serious effects of the disease; chronic kidney disease and kidney failure may worsen throughout life. The presence of protein in the urine (which causes foamy urine) is often the first sign of kidney involvement. End-stage kidney failure in those with Fabry disease typically occurs in the third decade of life and is a common cause of death due to the disease.

Heart

Fabry disease can affect the heart in several ways. The accumulation of sphingolipids within heart muscle cells causes an abnormal thickening of the heart muscle or hypertrophy. This hypertrophy can cause the heart muscle to become abnormally stiff and unable to relax, leading to a hypertrophic cardiomyopathy causing shortness of breath.

Fabry disease can also affect how the heart conducts electrical impulses, leading to both abnormally slow heart rhythms such as complete heart block, and abnormally rapid heart rhythms such as ventricular tachycardia. These abnormal heart rhythms can cause blackouts, palpitations, or even sudden cardiac death.

Sphingolipids can also build up within the heart valves, thickening the valves and affecting the way they open and close. If severe, this can cause the valves to leak ( regurgitation) or restrict the forward flow of blood (stenosis). The aortic and mitral valves are more commonly affected than the valves on the right side of the heart.

Skin

Angiokeratomas (tiny, painless papules that can appear on any region of the body, but are predominant on the thighs, around the navel, buttocks, lower abdomen, and groin) are common.

Anhidrosis (lack of sweating) is a common symptom, and less commonly hyperhidrosis (excessive sweating).

Additionally, patients can exhibit Raynaud's disease-like symptoms with neuropathy (in particular, burning extremity pain).

Ocular involvement may be present showing cornea verticillata (also known as vortex keratopathy), i.e. clouding of the corneas. Keratopathy may be the presenting feature in asymptomatic patients and must be differentiated from other causes of vortex keratopathy (e.g. drug deposition in the cornea). This clouding does not affect vision.

Other ocular findings can include conjunctival and retinal vascular abnormalities and anterior/posterior spoke-like cataracts. Visual reduction from these manifestations is uncommon.

Other manifestations

Fatigue, neuropathy (in particular, burning extremity pain, red hands and feet on and off), cerebrovascular effects leading to an increased risk of stroke - early strokes, mostly vertebrobasilar system tinnitus (ringing in the ears), vertigo, nausea, inability to gain weight, chemical imbalances, and diarrhea are other common symptoms.

Causes

Fabry disease is caused by a DNA sequence (gene) that is not functioning as it should. A person who inherits this gene does not have enough of a functioning enzyme known as alpha-galactosidase A. The lack of alpha-galactosidase leads to Fabry disease. A deficiency of alpha-galactosidase A (a-GAL A, encoded b
''GLA''
due to mutation causes a glycolipid known as globotriaosylceramide (abbreviated as Gb3, GL-3, or ceramide trihexoside) to accumulate within the blood vessels, other tissues, and organs. This accumulation leads to an impairment of their proper functions.

At least 443 disease-causing mutations in the GLA gene have been discovered. The DNA mutations that cause the disease are X-linked recessive with incomplete penetrance in heterozygous females. The condition affects hemizygous males (i.e. all non-intersex males), as well as homozygous, and in many cases heterozygous females. While males typically experience severe symptoms, women can range from being asymptomatic to having severe symptoms. Research suggests many women experience severe symptoms ranging from early cataracts or strokes to hypertrophic left ventricular heart problems and kidney failure. This variability is thought to be due to X-inactivation patterns during embryonic development of the female.

Mechanism

Fabry disease is an inherited lysosomal storage disorder that is caused by a deficiency of alpha-galactosidase A. This enzyme deficiency is a result of an accumulation of glycosphingolipids found in the lysosomes and most cell types and tissues, which leads it to be considered a multisystem disease. Indications include painful crisis, angiokeratomas, corneal dystrophy, and hypohidrosis. In severe cases there is renal, cerebrovascular, and cardiac involvement and it is predominately responsible for premature mortality in Fabry patients. Fabry disease is X-linked and manifests mostly in homozygous males but also in heterozygous females. Cardiac involvement is recurrent in Fabry patients. Patients have developed hypertrophic cardiomyopathy, arrhythmias, conduction abnormalities, and valvular abnormalities. Deficient activity of lysosomal alpha-galactosidase results in progressive accumulation of globotriaosylceramide (GL-3) within lysosomes, that is believed to trigger a cascade of cellular events. The demonstration of marked alpha-galactosidase deficiency is the conclusive method for the diagnosis in homozygous males. It may be detected in heterozygous females, but it is often inconclusive due to random X-chromosomal inactivation, so molecular testing (genotyping) of females is mandatory.

Diagnosis

Fabry disease is suspected based on the individual's clinical presentation and can be diagnosed by an enzyme assay (usually done on leukocytes) to measure the level of alpha-galactosidase activity. An enzyme assay is not reliable for the diagnosis of disease in females due to the random nature of X-inactivation. Molecular genetic analysis of the ''GLA'' gene is the most accurate method of diagnosis in females, particularly if the mutations have already been identified in male family members. Many disease-causing mutations have been noted. Kidney biopsy may also be suggestive of Fabry disease if excessive lipid buildup is noted. Pediatricians, as well as internists, commonly misdiagnose Fabry disease. All immediate and extended family members in the same family have the same family mutation, so if one member of a family has a DNA sequence analysis performed, other members of the family can be diagnosed by performing a targeted sequence analysis instead of testing the entire gene. Targeted sequencing is quicker and less expensive to perform. One study reported that for every first diagnosis in a family, on average five more family members (immediate and extended) are also diagnosed.

MRI is accurate in accessing left ventricular mass and thickness and hypertrophy. Late gadolinium enhancement shows an increased signal of the mid wall at the inferolateral wall of the base of the left ventricle, usually in the non-hypertrophic ventricle. T1-weighted imaging can show low T1 signal due to sphingolipid storage in the heart even without ventricular hypertrophy in 40% of those affected by the disease. Thus, MRI is a useful way of diagnosing the disease early. T2 signal is increased in inflammation and oedema.

Treatment

The treatments available for Fabry disease can be divided into therapies that aim to correct the underlying problem of decreased activity of the alpha-galactosidase A enzyme and thereby reduce the risk of organ damage, and therapies to improve symptoms and life expectancy once organ damage has already occurred.

Therapies targeting enzyme activity

* Enzyme replacement therapy is designed to provide the enzyme the patient is missing as a result of a genetic malfunction. This treatment is not a cure, but can partially prevent disease progression, and potentially reverse some symptoms. , three medical drugs based on enzyme replacement therapy are available for Fabry disease:
** Agalsidase alfa, sold under the brand name Replagal by the company Takeda