Fabry disease, also known as Anderson–Fabry disease, is a rare
genetic disease
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders are ...
that can affect many parts of the body, including the
kidney
In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...
s,
heart
The heart is a muscular Organ (biology), organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrie ...
,
brain
The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
, and
skin
Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation.
Other animal coverings, such as the arthropod exoskeleton, have different ...
.
Fabry disease is one of a group of conditions known as
lysosomal storage disease
Lysosomal storage diseases (LSDs; ) are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other ...
s. The
genetic mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosis ...
that causes Fabry disease interferes with the function of an
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
that processes
biomolecule
A biomolecule or biological molecule is loosely defined as a molecule produced by a living organism and essential to one or more typically biological processes. Biomolecules include large macromolecules such as proteins, carbohydrates, lipids ...
s known as
sphingolipids
Sphingolipids are a class of lipids containing a backbone of sphingoid bases, which are a set of aliphatic amino alcohols that includes sphingosine. They were discovered in brain extracts in the 1870s and were named after the mythological sphi ...
, leading to these substances building up in the walls of
blood vessel
Blood vessels are the tubular structures of a circulatory system that transport blood throughout many Animal, animals’ bodies. Blood vessels transport blood cells, nutrients, and oxygen to most of the Tissue (biology), tissues of a Body (bi ...
s and other organs. It is inherited in an
X-linked
Sex linkage describes the sex-specific patterns of inheritance and expression when a gene is present on a sex chromosome (allosome) rather than a non-sex chromosome ( autosome). Genes situated on the X-chromosome are thus termed X-linked, and ...
manner.
Fabry disease is sometimes diagnosed using a
blood test
A blood test is a medical laboratory, laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a hypodermic needle, or via fingerprick. Multiple tests for specific blood components, such as a glucose ...
that measures the activity of the affected enzyme called
alpha-galactosidase, but
genetic testing
Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...
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
Dermatology is the branch of medicine dealing with the skin.''Random House Webster's Unabridged Dictionary.'' Random House, Inc. 2001. Page 537. . It is a speciality with both medical and surgical aspects. A dermatologist is a specialist medi ...
Johannes Fabry and the surgeon
William Anderson William Anderson may refer to:
Arts and entertainment
* William Anderson (artist) (1757–1837), painter of marine and historical paintings
* William Anderson (theatre) (1868–1940), Australian stage entrepreneur
* William Anderson (1911–1986 ...
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
Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three mo ...
and
kidney failure
Kidney failure, also known as renal failure or end-stage renal disease (ESRD), is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney fa ...
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
The heart is a muscular Organ (biology), organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrie ...
in several ways. The accumulation of sphingolipids within
heart muscle cells causes an abnormal thickening of the
heart muscle
Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall of ...
or
hypertrophy
Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It is distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number. Although hypertro ...
. This hypertrophy can cause the heart muscle to become abnormally stiff and unable to relax, leading to a
hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM, or HOCM when obstructive) is a condition in which muscle tissues of the heart become thickened without an obvious cause. The parts of the heart most commonly affected are the interventricular septum and the ...
causing
shortness of breath
Shortness of breath (SOB), known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing discomfort that con ...
.
Fabry disease can also affect how the heart
conducts electrical impulses, leading to both
abnormally slow heart rhythms such as
complete heart block
Third-degree atrioventricular block (AV block) is a medical condition in which the electrical impulse generated in the sinoatrial node (SA node) in the atrium (heart), atrium of the heart can not propagate to the ventricle (heart), ventricles.
Be ...
, and abnormally rapid heart rhythms such as
ventricular tachycardia
Ventricular tachycardia (V-tach or VT) is a cardiovascular disorder in which fast heart rate occurs in the ventricles of the heart. Although a few seconds of VT may not result in permanent problems, longer periods are dangerous; and multiple ...
. These abnormal heart rhythms can cause blackouts,
palpitations
Palpitations occur when a person becomes aware of their heartbeat. The heartbeat may feel hard, fast, or uneven in their chest.
Symptoms include a very fast or irregular heartbeat. Palpitations are a sensory symptom. They are often described as ...
, or even
sudden cardiac death
Cardiac arrest (also known as sudden cardiac arrest ''SCA is when the heart suddenly and unexpectedly stops beating. When the heart stops beating, blood cannot properly circulate around the body and the blood flow to the brain and other org ...
.
Sphingolipids can also build up within the
heart valve
A heart valve is a biological one-way valve that allows blood to flow in one direction through the chambers of the heart. A mammalian heart usually has four valves. Together, the valves determine the direction of blood flow through the heart. Hea ...
s, 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
Stenosis () is the abnormal narrowing of a blood vessel or other tubular organ or structure such as foramina and canals. It is also sometimes called a stricture (as in urethral stricture).
''Stricture'' as a term is usually used when narrowing ...
). The
aortic and
mitral valve
The mitral valve ( ), also known as the bicuspid valve or left atrioventricular valve, is one of the four heart valves. It has two Cusps of heart valves, cusps or flaps and lies between the atrium (heart), left atrium and the ventricle (heart), ...
s are more commonly affected than the
valves on the right side of the heart.
Skin
Angiokeratomas (tiny, painless
papules
A papule is a small, well-defined bump in the skin. It may have a rounded, pointed or flat top, and may have a dip. It can appear with a stalk, be thread-like or look warty. It can be soft or firm and its surface may be rough or smooth. Some ...
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
Hyperhidrosis is a medical condition in which a person exhibits excessive perspiration, sweating, more than is required for the Thermoregulation, regulation of body temperature. Although it is primarily a physical burden, hyperhidrosis can deterio ...
(excessive sweating).
Additionally, patients can exhibit
Raynaud's disease
Raynaud syndrome, also known as Raynaud's phenomenon, is a medical condition in which the spasm of small arteries causes episodes of reduced blood flow to end arterioles. Typically the fingers, and, less commonly, the toes, are involved. Rare ...
-like symptoms with
neuropathy
Peripheral neuropathy, often shortened to neuropathy, refers to damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerve fibers are affected. Neuropa ...
(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
Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself.
Fatigue (in the medical sense) is sometimes associated wit ...
,
neuropathy
Peripheral neuropathy, often shortened to neuropathy, refers to damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerve fibers are affected. Neuropa ...
(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
Tinnitus is a condition when a person hears a ringing sound or a different variety of sound when no corresponding external sound is present and other people cannot hear it. Nearly everyone experiences faint "normal tinnitus" in a completely ...
(ringing in the ears),
vertigo
Vertigo is a condition in which a person has the sensation that they are moving, or that objects around them are moving, when they are not. Often it feels like a spinning or swaying movement. It may be associated with nausea, vomiting, perspira ...
, 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
Glycolipids () are lipids with a carbohydrate attached by a glycosidic (covalent) bond. Their role is to maintain the stability of the cell membrane and to facilitate cellular recognition, which is crucial to the immune response and in the c ...
known as
globotriaosylceramide (abbreviated as Gb3, GL-3, or ceramide trihexoside) to accumulate within the
blood vessel
Blood vessels are the tubular structures of a circulatory system that transport blood throughout many Animal, animals’ bodies. Blood vessels transport blood cells, nutrients, and oxygen to most of the Tissue (biology), tissues of a Body (bi ...
s, 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
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mos ...
males (i.e. all non-intersex males), as well as
homozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mos ...
, and in many cases
heterozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mos ...
females. While males typically experience severe symptoms, women can range from being
asymptomatic
Asymptomatic (or clinically silent) is an adjective categorising the medical conditions (i.e., injuries or diseases) that patients carry but without experiencing their symptoms, despite an explicit diagnosis (e.g., a positive medical test).
P ...
to having severe symptoms. Research suggests many women experience severe symptoms ranging from early
cataract
A cataract is a cloudy area in the lens (anatomy), lens of the eye that leads to a visual impairment, decrease in vision of the eye. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colours, blurry or ...
s or strokes to
hypertrophic
Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It is distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number. Although hypertro ...
left ventricular heart problems and kidney failure. This variability is thought to be due to
X-inactivation
X-inactivation (also called Lyonization, after English geneticist Mary Lyon) is a process by which one of the copies of the X chromosome is inactivated in therian female mammals. The inactive X chromosome is silenced by being packaged into ...
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
glycosphingolipid
Glycosphingolipids are a subtype of glycolipids containing the amino alcohol sphingosine. They may be considered as sphingolipids with an attached carbohydrate. Glycosphingolipids are a group of lipids (more specifically, sphingolipids) and are ...
s found in the
lysosome
A lysosome () is a membrane-bound organelle that is found in all mammalian cells, with the exception of red blood cells (erythrocytes). There are normally hundreds of lysosomes in the cytosol, where they function as the cell’s degradation cent ...
s and most cell types and tissues, which leads it to be considered a multisystem disease. Indications include painful crisis, angiokeratomas,
corneal dystrophy
Corneal dystrophy is a group of rare hereditary disorders characterised by bilateral abnormal deposition of substances in the transparent front part of the eye called the cornea.
Signs and symptoms
Corneal dystrophy may not significantly affect ...
, 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
Sex linkage describes the sex-specific patterns of inheritance and expression when a gene is present on a sex chromosome (allosome) rather than a non-sex chromosome ( autosome). Genes situated on the X-chromosome are thus termed X-linked, and ...
and manifests mostly in
homozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mos ...
males but also in
heterozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mos ...
females. Cardiac involvement is recurrent in Fabry patients. Patients have developed
hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM, or HOCM when obstructive) is a condition in which muscle tissues of the heart become thickened without an obvious cause. The parts of the heart most commonly affected are the interventricular septum and the ...
,
arrhythmia
Arrhythmias, also known as cardiac arrhythmias, are irregularities in the cardiac cycle, heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – ab ...
s, 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 Genotyping is the process of determining differences in the genetic make-up (genotype) of an individual by examining the individual's DNA sequence using bioassay, biological assays and comparing it to another individual's sequence or a reference seq ...
) 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
White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...
) 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
Enzyme replacement therapy (ERT) is a medical treatment which replaces an enzyme that is deficient or absent in the body. Usually, this is done by giving the patient an intravenous (IV) infusion of a solution containing the enzyme.
ERT is availa ...
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