Fabry Disease - Description
Fabry disease was first described independently by Drs. William Anderson
in England and Johann Fabry in
in 1898. Fabry disease is a rare, X-linked recessive lysosomal storage disorder,
seen in all ethnic groups, caused by a deficiency of the lysosomal enzyme alpha-galactosidase A
Partial or complete deficiency of alpha-GAL
leads to progressive accumulation of glycosphingolipids,
particularly globotriaosylceramide (GL-3),
in visceral tissues and the vascular endothelium throughout the body.
The inability to breakdown GL-3 leads to progressive damage to the kidney,
heart, and nervous system. The clinical course of Fabry disease is usually marked by chronic pain,
hypohidrosis, heat and cold intolerance, corneal opacities, renal failure, stroke,
and cardiac complications. As the disease progresses, complications may become life-threatening.
Since Fabry is
the disease predominantly affects males (hemizygotes), who have little if any
Although an X-linked recessive
disease, females with Fabry often experience varying degrees of disease manifestations.
It is believed that X-chromosomal inactivation
(lyonization), which can block expression of the
functional alpha-GAL gene
in all or some parts of the body, is responsible for disease onset in females. Although the
prevalence of female carriers who develop overt clinical manifestations is not definitiely
known, recent studies indicate that manifestations in carrier females are more
common than previously thought.
Clinical presentation and progression
Classical Fabry disease usually presents in childhood (with pain, fever, hypohidrosis, fatigue, and exercise intolerance) but diagnosis may not be confirmed until there has been considerable accumulation of GL-3.
The average age of diagnosis is approximately 30 years. Delayed diagnosis may be due in part to
under-recognition of the disease and/or misattribution of Fabry disease symptoms to other disorders.
Progressive organ and tissue damage associated with Fabry disease may result
in substantially decreased life expectancy. Before the availability of renal dialysis or transplantation,
the average age of death among patients with classical Fabry disease was 41 years; today, average
life expectancy is still only 50 years.
Growing evidence indicates there may be a significant number of "atypical variants" -
hemizygotes who have few or none of the
hallmark symptoms of classical Fabry disease. Atypical variants have residual plasma
levels (1% to 30% of normal) and present much later in life than patients with classical Fabry
disease. They are often identified by chance, and usually have manifestations predominately
in one organ system.
Signs & Symptoms of Fabry Disease
The cardinal presenting features of Fabry disease are intermittent
and episodic crises of pain and fever (especially in childhood),
heat and cold intolerance, and a characteristic
that does not affect vision.
Progressive accumulation of
in the vascular endothelium and other tissues leads to life-threatening manifestations in adulthood
involving the heart, kidneys, central and peripheral nervous system, and cerebrovascular system.
The list below provides an overview of the signs and symptoms
of Fabry disease that may be seen at different stages of life. Both male and female
patients may experience some or all of these manifestations to varying degrees.
Signs & Symptoms
are the most visibly recognizable clinical feature of Fabry disease. These dark red or purple skin
lesions (ranging in size from pinpoint to several millimeters in diameter) do not blanch with pressure
and are usually distributed on the buttocks, groin, umbilicus, and upper thighs (bathing trunk distribution).
Lesions generally appear in adolescence or young adulthood. Angiokeratomas are almost universal in male
they occur in approximately 30% of heterozygous females.
Because angiokeratomas may be concealed by undergarments,
their presence can be missed during routine physical examinations.
There are two types of pain common to Fabry disease:
Acroparesthesias occur in the majority of hemizygotes, and in many of the heterozygotes. These sensory symptoms are characterized by tingling, burning pain and discomfort in the palms of the hands and the soles of the feet.
The accumulation of GL-3 in the walls of blood vessels in skin tissue leads to nerve fiber degeneration. Degeneration of small myelinated and unmyelinated fibers and/or loss of small peripheral sensory neurons in the dorsal root ganglia and the resultant small fiber dysfunction are thought to contribute to the characteristic
acroparesthesias in Fabry disease.
- Fabry pain crises
Fabry pain crises are episodes of acute agonizing pain,
typically beginning in the extremities and radiating inward, lasting from several
minutes to several days, and are often induced by emotional stress, changes in
temperature, exercise, and/or fatigue.
Pain crises are often one of the first symptoms
experienced in Fabry disease and may lead a child to his/her first
Fabry-related physician visit. Because the pain is often accompanied
by fever and elevated erythrocyte sedimentation rates, it may be
erroneously identified as rheumatic in origin.
Impaired sweating, either hypohidrosis or anhidrosis, usually presents in childhood or adolescence and has been attributed to selective peripheral nerve damage or to intracytoplasmic lipid deposits in the small blood vessels surrounding sweat glands. This may result in dry skin and heat and exercise intolerance. In approximately 40% of Fabry disease patients, production of tears and saliva is also reduced.
Heat and Cold Intolerance
Temperature sensitivity is common in Fabry disease.
It presumably results from lipid deposition in small vessel walls, perineural cells,
and unmyelinated or myelinated nerve cells resulting in small fiber neuropathy.
Hypohydrosis and androsis may also contribute to heat intolerance.
(particularly GL-3) accumulation may
lead to irreversible and potentially life-threatening clinical
sequelae in the kidney.
While GL-3 deposits are primarily found
in the lysosomes of the vascular endothelium, renal biopsy studies
of young hemizygotes show diffuse lipid accumulation in the glomerular,
vascular, and interstitial cells, and tubular involvement primarily in
distal convoluted tubules and loops of Henle. With age, intimal thickening
and degenerative glomerular and tubular changes are apparent.
Proteinuria, isosthenuria, and azotemia
Most patients with classical Fabry disease
in late adolescence, which progresses to isosthenuria
and alterations of tubular reabsorption, secretion, and excretion. Azotemia usually occurs by the third to
fifth decade of life, although renal failure has also been reported in patients as young as 16 years old.
Renal complications tend to be less evident in female carriers than in hemizygotes.
Urinalysis is also characterized by hematuria and lipiduria,
often beginning in childhood. Polarization microscopy of free urine or urinary sediment
reveals birefringent lipid globules with characteristic "Maltese crosses."
Strokes and transient ischemic attacks are associated with Fabry disease.
Thrombosis of small arteries thickened by the vascular accumulation of GL-3 lipids makes Fabry patients
vulnerable to early ischemic stroke. Thrombus formation may also be enhanced in Fabry disease due to
adhesion of neutrophils and monocytes to endothelial cell walls. Hypertension associated with renal
dysfunction may also increase the risk for hemorrhagic stroke. Co-morbid prothrombotic genetic risk
may influence stroke risk.
Other Fabry-related cerebrovascular signs and symptoms associated with Fabry disease
- Basilar artery ischema and aneurism
- Labyrinthine disorders
- Cerebral hemorrhage
Common ophthalmologic findings in Fabry disease include:
Corneal opacities, beginning with a diffuse haziness and progressing to a
characteristic "whorled" or "spoke-like" pattern, are found almost universally among classically
hemizygotes and in a high proportion of
heterozygous females (estimated to be approximately 70%).
This finding can be visualized through slit lamp microscopy. Corneal opacities do not impair vision.
Two types of lens opacities have been noted in Fabry patients: cream-colored anterior capsular deposits in the lens (sometimes distributed like a propeller), and whitish, granular spoke-like deposits on the posterior lens (referred to as Fabry cataracts). Fabry cataracts are more commonly observed than capsular deposits; they can be visualized by retroillumination.
Eye Vascular Findings
Conjunctival and retinal vascular lesions resulting from the generalized disease process are common. Lesions may appear to be sausage-like, with markedly dilated vessels. The presence of several lesions of this type, which do not affect vision, may be pathognomonic for Fabry disease.
There is considerable clinical variability in regards to cardiac involvement in Fabry disease. Cardiac manifestations generally develop in patients older than 30 years of age.
Cardiac-related signs and symptoms of Fabry disease may include:
- Left ventricular hypertrophy
- Valvular disease (especially mitral valve prolapse and/or regurgitation)
- Premature coronary artery disease
- Myocardial infarction
- Conduction abnormalities
- Congestive heart failure
Left ventricular hypertrophy
Progressive GL-3 accumulation in myocardial cells may lead to significant
enlargement of the heart, particularly the left ventricle. The main determinants of left
ventricular mass appear to be age and alpha-GAL
Electrocardiographic and Echocardiographic findings
Characteristic electrocardiographic findings include AV conduction
abnormalities (short P-R intervals or AV block), signs of left ventricular hypertrophy, and
repolarization abnormalities (ST-T wave changes). Supraventricular arrhythmias may also be noted.
Echocardiographic findings may include aortic root dilatation,
enlarged ventricular mass, and valvular disease (especially of the mitral valve).
Left ventricular enlargement tends to increase with disease severity and age.
Cardiac variants are the most widely recognized and studied of
these subtypes. In cardiac variants, disease manifestations typically present later in
life and are limited to the heart. The vascular endothelium is generally not affected.
A recent study in Japan suggests that the cardiac variants of
Fabry disease may be under-recognized. Among the 230 unselected males with left ventricular
hypertrophy, 3% were found to have low alpha-GAL
activity (4-14% of normal). None of these men exhibited signs and symptoms considered typical of Fabry disease, such
as angiokeratomas, acroparesthesias,
or hypohidrosis. An additional study of 79 men with late-onset hypertrophic cardiomyopathy found
6.3% of the hemizygotes to have low alpha-GAL
Gastrointestinal symptoms are thought to be due to the deposition of glycosphingolipids
in mesenteric blood vessels and autonomic ganglia.
Up to two thirds of affected
males and about half of symptomatic females may experience gastrointestinal symptoms associated
with Fabry disease. Gastrointestinal symptoms may include:
- Postprandial bloating
- Abdominal cramping and pain
- Early satiety
Genetics and inheritance of Fabry disease
The alpha-GAL gene
gene is localized to the long arm of the X chromosome (locus Xq22.1).  The gene, which encodes a
429 amino acid polypeptide; including a 31 amino acid signal peptide, is 12 kilobases long and contains 7 exons.
 The defect that causes Fabry disease is heterogeneous - to date, over 200 mutations of the
alpha-GAL gene have been recorded.
Moreover, most families have "private" mutations (found only in that family)  that may explain
variations in the clinical presentation of Fabry disease.
Fabry is an X-linked
recessive disease. It is inherited through the mother who, with each conception, has a 50% chance of passing
the defective gene on to all offspring. Her sons who inherit the gene will have Fabry disease. Daughters who
inherit the mutated Fabry gene will be carriers. Because of X-chromosomal inactivation, some female carriers
develop symptoms of mild, moderate, or classical Fabry disease.
Males with Fabry disease pass on the defective gene to none of their sons and
all of their daughters.
Although a positive family history is a strong indicator for Fabry disease,
de novo or spontaneous mutations have been documented.
Thus, absence of a family history does not
rule out a diagnosis of Fabry disease.
Diagnosis of Fabry Disease
Clinical heterogeneity and the rarity of Fabry disease makes the diagnosis of Fabry disease a challenge. The age of presentation, presenting symptoms, and clinical course vary from individual to individual. Although symptoms generally appear in childhood, they may go unrecognized until adulthood when organ system damage has already occurred. Greater recognition of Fabry disease symptoms may lead to earlier suspicion and diagnosis, which in turn may result in more effective disease management.
The following signs and symptoms are characteristic of Fabry disease and may lead to a presumptive clinical diagnosis:
One confounding factor in diagnosis is the fact that many common signs and symptoms of Fabry disease are common in other conditions.
Once a presumptive diagnosis of Fabry disease has been made based on clinical signs and symptoms,
definitive diagnosis can be made by testing for deficient alpha-GAL enzyme activity in plasma, leukocytes, tears, or biopsied tissue.
DNA mutational analysis is clinically available and can be an important tool in family genetic risk assessment particularly in females.
Diagnosis in women
Although females carrying the Fabry
gene may be asymptomatic or present with mild clinical manifestations,
definitive identification of carriers is important. Diagnosis allows
practitioners to monitor for new or worsening symptoms, and can help
with identifying other family members with the disease.
females may be able to be diagnosed with Fabry disease when they have very
low or absent
activity and/or by lipid deposition in biopsied tissues or urinary sediment.
Many female carriers (with or without symptoms) have below-normal levels of
activity and/or the characteristic corneal opacities.
However, this is not true for all carriers - some have
activity in the low normal range. In families with an identified mutation,
mutation analysis is the definitive way to clarify diagnosis in potential
carrier females. In families for whom a specific mutation is not documented,
linkage analysis if possible, may establish carrier status.
Fabry disease can be diagnosed prenatally via cultured
amniotic fluid cells and by chorionic villus
sampling (at 9-10 weeks) and
amniocentesis (at approximately 15 weeks).
Current Treatments in Fabry Disease
Disease management strategies may include medications and lifestyle approaches to symptom relief and interventions to delay serious sequelae due to organ damage (eg, kidney transplantation, cardiac pacemaker insertion).
Treatment of Fabry disease includes management of symptoms and of life threatening complications. Because the disease affects multiple organ systems, a multidisciplinary team approach (geneticist, genetic counselor, gastroenterologist, nephrologist, neurologist, dermatologist, ophthalmologist, cardiologist, pediatrician) to management may be necessary.
If possible, patients should avoid stimuli that precipitate pain:
- Heat or sun exposure
- Temperature changes
- Physical exertion
Drinking large amounts of fluid, especially
during hot weather and before and during exercise may also help prevent
For patients with frequent and severe painful attacks, prophylactic therapy with anticonvulsant drugs (diphenylhydantoin, carbamazepine, gabapentin, topiramate) or anti-dpressants [amitriptyline] may be helpful. Phenoxybenzamine has also been shown to provide pain relief.
Angiokeratomas can be removed for cosmetic reasons by argon laser treatment, usually with little scarring.
The pathology that underlies cardiac complications in Fabry disease differs from that of most heart diseases in the general population. However, standard treatment modalities such as valve replacement, pacemaker insertion, angioplasty, and coronary artery bypass grafting are employed as warranted by presenting signs and symptoms.
Cerebrovascular complications associated with Fabry disease, like cardiovascular complications, are managed with standard treatment modalities. Oral anticoagulant or antiplatelet agents may be administered to prevent stroke. Delineation of possible co-morbid pro-thromobotic risk factors may allow important therapy initiation.
complications are one of the more common and concerning aspects of Fabry disease.
The degree of renal involvement generally correlates with the progressions of
GL-3 accumulation and may lead to renal insufficiency and failure may ensue.
Mild reductions in renal function may be managed in part by a low-protein diet. When renal function becomes severely compromised,
dialysis and/or renal transplantation may be warranted.
Renal transplantation has been shown to improve
uremia, prolongs life, and may even improve clinical
symptoms in Fabry disease. However, renal transplantation
is not a cure as it does not address the underlying
pathology of the disease - progressive
Cardiac disease progression has been noted in renal
transplant patients, and renal allografts have demonstrated
GL-3 deposition after transplantation.
A low fat diet and/or pancrelipase or metoclopramide taken before meals can temporarily ameliorate gastrointestinal symptoms associated with Fabry disease. Other symptomatic therapies that may be helpful include:
While symptom management may
improve a patient's quality of life, treatment to
prevent or reverse accumulation of GL-3 may offer the potential to stem disease progression and prevent organ damage.
Enzyme Replacement Therapy (ERT)
Enzyme replacement therapy [ERT] has been approved for use in many countries throughout the world including the United States and those in the European Union.
There are other treatments for Fabry disease that are currently under investigation. They include:
Gene therapy for Fabry disease is in the early stages of investigation. Research has identified two different approaches:
- Direct delivery of the alpha-GAL gene using modified adenoviral and adeno-associated viral vectors in order to genetically modify the liver, lung, or muscle of the patient and use these organs as internal sources of alpha- GAL
- Genetic alteration of hematopoietic stem cells from Fabry patients to produce alpha-GAL and restoration of the altered cells to the patient through bone marrow transplantation
Both methods have shown potential promise in pre-clinical studies in Fabry mice.
Small molecule therapies
Research has also identified two approaches involving "small molecules." Both of these require some residual alpha-GAL activity to be effective and could potentially be used in conjunction with either gene therapy or enzyme replacement therapy.
The first approach involves substrate inhibition therapy to reduce cellular synthesis of glycosphingolipids. Two potentially promising small molecules are N-butyldeoxynojirimycin and D-threo-1-ethylendioxyphenyl-2-palmitoylamino-3-pyrrolidino-propanol (D-t-EtDO-P4).
A second approach involves use of a competitive inhibitor of
alpha-GAL to increase
the activity of residual enzyme. In animal studies, oral administration
of small doses of 1-deoxy-galactonojirinmycin increased
the transport and maturation of mutant alpha-GAL, and
increased activity in some organs.
The Fabry Registry - A Collective Resource to Optimize Outcomes
The Fabry Registry is a global outcomes assessment and disease management program that compiles patient data from routine clinical practice to provide the medical community with information to help optimize patient care by:
- Facilitating significant research publications.
- Encouraging collaboration and shared expertise with your colleagues.
- Enabling the clinical practice of evidence-based medicine.
- Developing individualized care plans based on benchmark comparisons of similar patients.
Through the Fabry Registry, the Fabry community has access to an important resource on a disease that affects a small patient population. Management guidelines and publications from the Fabry Registry may contribute to:
- Earlier diagnosis.
- Earlier intervention.
- Enhanced clinical evaluation and monitoring.
- Defining the therapeutic goals of treatment.
- Improved quality of care.
- Optimal patient outcomes.
This open database allows for the exploration of issues, evaluation of trends, and the generation of peer-reviewed. Physicians may publish their own data or on the Registry population as a whole (aggregate data analyses). They may do this by:
- Requesting individualized patient reports and informative clinical summaries to monitor disease status.
- Build a decision support system by exchanging aggregate clinical data among physicians to facilitate clinical decision-making.
- Access new information on current treatment guidelines and practice patterns.
- Tap into an international "virtual practice" of patients with Fabry disease.
The Fabry Registry complies with applicable national privacy regulations and other state and local laws relating to medical information. All patient and physician information submitted to the Fabry Registry is maintained as confidential.
- Confidentiality is maintained as patients are referenced by Registry ID number only.
- Patients must authorize release of their clinical data.
- No site-to-site data comparisons are made.
Contact the Fabry Registry
In the United States
617- 591-7024 or
800-745-4447, ext. 17024
+31 (0) 35 699 1232