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Fabry disease

Author: Qiuyu Jin, Medical Student, University of Auckland, New Zealand. DermNet NZ Editor in Chief: Adjunct A/Prof Amanda Oakley, Dermatologist, Hamilton, New Zealand. Copy edited by Gus Mitchell. July 2019.

What is Fabry disease?

Fabry disease is a rare inherited lysosomal storage disorder [1]. It is also known as Anderson-Fabry disease and angiokeratoma corporis diffusum.

Fabry disease causes clusters of small, dark red spots on the skin (angiokeratomas) and many systemic symptoms due to the deposition of globotriaosylceramide in multiple organs.

Angiokeratomas in suspected Fabry diseas

Who gets Fabry disease?

The estimated prevalence in males is about one in 40,000 to 60,000 of the population [4]. Fabry disease generally affects males more severely and at an earlier age than females because its inheritance is X-linked (males only carry one X chromosome whereas females have two). Fabry disease can occur in all ethnic groups [5].

The age of onset of Fabry disease can range from the second to the fifth decade of life or later.

Fabry disease often presents with non-specific symptoms that can be mild and subtle and it is commonly missed or misdiagnosed, leading to an underestimation of its prevalence [6].

What causes Fabry disease?

Fabry disease is caused by a mutation of the alpha-galactosidase A gene (GLA) mapped to the long arm of the X chromosome [7]. There are hundreds of different pathogenic variants of the mutation, resulting in differing symptoms and variable severity [8]. Males with Fabry disease pass the gene on to all daughters but to none of their sons. Females with Fabry disease have a 50% chance of passing the gene onto their daughters or to their sons. Some females are affected as severely as males due to random X chromosome inactivation [9].

The enzyme alpha-galactosidase A catalyses the separation (cleavage) of the terminal galactose from globotriaosylceramide (Gb3). Gb3 is an intermediate in the degradative pathway of globoside (a glycosphingolipid), a major component of some cell membranes. Lack of the alpha-galactosidase A enzyme leads to accumulation of Gb3 in various tissues, leading to cell death. The most clinically significant sites of accumulation of Gb3 are blood vessels of the skin, heart, nerves, and kidneys [10].

What are the clinical features of Fabry disease?

The characteristic features of Fabry disease are:

  • Clusters of small, dark red papules (angiokeratomas)
  • Heat intolerance and reduced sweating (hypohidrosis)
  • Episodes of neuropathic pain in the hands and feet (acroparesthesia), precipitated by stress or extremes of temperature
  • Cloudiness of the cornea
  • Hearing loss [2]
  • Abdominal symptoms such as pain, nausea, vomiting, and either diarrhoea or constipation [3]
  • Recurrent fever, fatigue, psychological, and social issues
  • Serious and potentially life-threatening complications including kidney damage, heart disease, and stroke.

Dermatological manifestations occur in more than 70% of patients with Fabry disease, with a mean age of onset of 17 years [5].


Angiokeratomas are dilated blood vessels in the upper dermis, presenting as red or black papules. The papules do not blanch with pressure, and older lesions can become warty. Clusters or diffuse angiokeratomas first appearing in young adults must alert to a possible diagnosis of Fabry disease.

In Fabry disease, angiokeratomas are caused by the accumulation of Gb3 in the dermal endothelial cells, which leads to bulge and incompetence of the vessel wall [12]. The angiokeratomas usually localise to the bathing suit area (from the umbilicus to the upper thighs, including the genitals). More than one-third of patients also develop angiokeratomas and telangiectasia on the lips and inside the mouth [13].

There is no correlation between the severity of the disease and the extent of angiokeratomas [11].


Hypohidrosis is a common feature of Fabry disease which leads to dry skin and heat intolerance [11]. It is likely the result of abnormal autonomic nerve response due to Gb3 deposition.

Other cutaneous manifestations of Fabry disease

Fabry disease is identifiable by other skin signs, such as:

What are the complications of Fabry disease?

The three most serious complications of Fabry disease are kidney disease, cardiac disease, and cerebrovascular disease [5].

  • Kidney disease ranges from isolated proteinuria to end-stage renal failure [5].
  • The cardiac disease includes left ventricular hypertrophy, heart failure, coronary artery disease, and arrhythmias.
  • Cerebrovascular disease includes transient ischaemic attacks and ischaemic strokes.

How is Fabry disease diagnosed?

Male and female patients are diagnosed differently.

  • Male patients can be diagnosed by a blood test. A very low level of alpha-galactosidase A activity (< 3%) is enough to diagnose Fabry disease while a level above 35% excludes Fabry disease. Levels of activity in between these figures require genetic analysis to confirm the diagnosis.
  • Female patients have variable enzyme activities with a significant proportion showing normal activity, thus the diagnosis of Fabry disease should be done by genetic analysis.
  • If the genetic analysis does not identify a disease-causing mutation specific for Fabry disease, a biopsy of the affected organs (including skin biopsy) can be considered; this may show intracellular accumulation of Gb3 [5,11].

Family members of the diagnosed patient should also be tested for Fabry disease.

Urinalysis and ECG should be undertaken to detect cardiac and renal abnormalities.

What is the differential diagnosis for Fabry disease?

Due to its rarity and the wide range of non-specific clinical features, Fabry disease is often misdiagnosed. It may be considered a “great imposter” [15].

Angiokeratomas are not characteristic of Fabry disease, as solitary lesions can occur in healthy individuals. They are also found in patients with hereditary haemorrhagic telangiectasia, and the other lysosomal disorders; Schindler disease, fucosidosis, aspartylglucosaminuria, beta-mannosidosis, and sialidosis [11,12].

The most commonly mistaken diagnoses are the following:

  • Rheumatological conditions such as rheumatic fever or dermatomyositis — the dermatological manifestations are different in appearance and time course
  • Neuropsychological disease and fibromyalgia — in which there is an absence of cardiac, kidney, nerve, and skin involvement
  • Polycythaemia vera and essential thrombocythaemia — Fabry disease does not cause an increased platelet count
  • Hereditary haemorrhagic telangiectasia — Fabry disease does not usually cause spontaneous epistaxis or gastrointestinal bleeding
  • Irritable bowel syndrome — this has no other systemic manifestations [6,16].

What is the treatment for Fabry disease?

Once diagnosed, male patients with Fabry disease are often prescribed enzyme replacement therapy, regardless of clinical features [2,11,18]. Female patients should only receive treatment if they have significant clinical manifestations.
Enzyme replacement therapy provides patients with the deficient enzyme alpha-galactosidase A. It reduces the severity and progression of disease manifestations, especially neuropathic pain and kidney disease, by reducing tissue deposition of Gb3. Its effect on cardiovascular manifestations is less clear [18].

Patients with Fabry disease may require multi-speciality input including GPs, cardiologists, nephrologists, neurologists, and dermatologists to manage their individual organ manifestations. Neuropathic pain of the hand and feet may respond to anticonvulsants, such as carbamazepine [18,19].

Treatment for angiokeratomas includes cryotherapy, electrocoagulation, excisional surgery, and laser therapy [11,12,20].

What is the outcome for Fabry disease?

Fabry disease is progressive and it can be life-threatening. The prognosis varies from patient to patient [21]. Survival is significantly reduced in male patients with severe forms of Fabry disease to below 60 years, often 40 or 50 years. Most deaths are due to cardiovascular disease including stroke, myocardial infarction, and heart failure. Death from renal failure, sepsis, and suicide have also been reported [18]. The benefit of enzyme replacement therapy on overall prognosis is unclear due to a lack of current evidence [18,22,23].

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Related information



  1. Germain DP. Fabry disease. Orphanet J Rare Dis 2010; 5: 30. doi: 10.1186/1750-1172-5-30. PubMed
  2. Lysosomal Disease New Zealand. Fabry disease. Available at: (accessed 4 June, 2019)
  3. Hoffmann B, Schwarz M, Mehta A et al. Gastrointestinal symptoms in 342 patients with Fabry disease: prevalence and response to enzyme replacement therapy. Clin Gastroenterol Hepatol 2007; 5: 1447–53. PubMed
  4. Genetic Home Reference. Fabry Disease. Jun 2018. Available at: (accessed June 4, 2019)
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