What is Fabry disease?

Fabry disease, also known as Anderson-Fabry disease, was first described in 1898 and is observed in all ethnic, racial and demographic groups.1-3 Fabry disease is one of the most common lysosomal storage disorders caused by variants in the GLA gene encoding the enzyme alpha-galactosidase (α-Gal A) (see genetic inheritance of Fabry disease).4-6 The disease is a progressive, life-threatening, multisystemic condition6,7 whereby the deficiency in the enzymatic activity of α-Gal A leads to accumulation of the glycosphingolipids globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) at a cellular level. Accumulation of these glycosphingolipids causes a wide range of clinical manifestations and organ damage (Figure 1).6-11

Figure 1.
Variants in the GLA gene encoding the enzyme α-Gal A lead to the accumulation of the glycosphingolipids Gb3 and lyso-Gb3 within various organs in patients with Fabry disease.6,8-10

What are the symptoms of Fabry disease?
Early signs and symptoms of classical Fabry disease may manifest in childhood and include pain, oedema, abnormalities in hearing, eye changes (corneal verticillata or corneal whorling), dyshidrosis (abnormal sweat production or release), gastrointestinal disturbances and angiokeratomas (small, dark red or bluish benign skin lesions comprised of dilated capillaries in the upper epidermis, with additional overgrowth of the epidermis).12-14 In patients with Fabry disease, angiokeratomas may develop slowly and appear on the buttocks, genitalia, inner thighs, back and oral cavity.10 The phenotype of Fabry disease can vary between patients; this may manifest as pain crises, gastrointestinal symptoms, progressive renal dysfunction, cerebral white-matter disease, early-onset stroke, hypertrophic cardiomyopathy, development of corneal whorls in the eyes, and angiokeratomas.9 Patients with Fabry disease may also develop peripheral neuropathy leading to degeneration or disease of the peripheral nerves, causing muscle weakness and atrophy, pain and numbness.9,15 Moreover, the disease phenotype may differ between patients who have the classical or late-onset phenotype.9 Examples of the clinical characteristics of Fabry disease are presented in Figure 2.


Acroparaesthesia or pain crises: chronic or episodic, burning sensation in the palms of hands or soles of feet, exacerbated by temperature changes, fever, stress and physical exercise

Angiokeratomas: small, raised, dark red spots that develop slowly and can be found on the back, buttocks, genitalia, inner thighs and oral cavity

History of lethargy and fatigue

History of non-specific bowel disturbances

Hypohidrosis (abnormally diminished secretion of sweat)16 or anhidrosis (absence of sweating)17

Increased albuminuria

Ophthalmological abnormalities: cornea verticillata (whorl-shaped opacity), dilated vessels on upper lid margin, posterior subcapsular cataracts, tortuous vascular lesions in the retina and conjunctiva

Sensorineural hearing loss


Abdominal pain, diarrhoea

Cardiac: bradycardia, conduction defects, left ventricular hypertrophy, short PR interval


Heat sensitivity

High albuminuria (>1 g/24 hours)

Hypohidrosis (abnormally diminished secretion of sweat)16 or anhidrosis (absence of sweating)17

Lymphadenopathy (enlargement of the lymph nodes18)

More extensive angiokeratomas

Oedema or lymphoedema

Chronic kidney disease including end-stage renal disease requiring renal replacement therapy with dialysis or renal transplantation

Deafness of acute or chronic onset

Heart disease: angina, cardiac transplantation, diastolic heart failure, heart valve abnormalities and dysrhythmias, fibrotic, left and right ventricular hypertrophy, sudden cardiac death

Stroke or transient ischaemic attacks

Figure 2.
Examples of the clinical manifestations of Fabry disease. Reproduced and adapted with permission from Schiffmann R et al. Kidney Int 2017; 91: 284-293.10

What is the pathophysiology of Fabry disease?
During the catabolism of macromolecules, α-Gal A catalyses the removal of galactose from oligosaccharides, glycoproteins and glycolipids.19 In unaffected individuals without Fabry disease, α-Gal A induces the degradation of Gb3 to galactosylceramide within lysosomes.9 However, in patients with Fabry disease, deficient enzymatic activity of α-Gal A leads to an accumulation of the glycosphingolipids Gb3 and lyso-Gb3 within almost all cell types and various organs. Progressive glycosphingolipid accumulation within cells leads to the clinical manifestations of Fabry disease.8-10 To date, more than 1000 variants in the GLA gene leading to a deficiency of α-Gal A activity have been identified.9,10,20,21 Evidence from one study suggests that the enzymatic activity of α-Gal A in male patients with Fabry disease ranges from 0‒1.7 μmol/h/L, compared with 4.2‒17.3 μmol/h/L in unaffected individuals without Fabry disease. Female patients who are heterozygous for variants in the GLA gene have enzymatic activity levels of α-Gal A ranging from 0‒12.6 μmol/h/L.22

Deposition of glycosphingolipids in different cell types, tissues and organs is likely due to differences in the rate of glycosphingolipid metabolism.23 Evidence suggests that accumulation of Gb3 and lyso-Gb3 leads to inflammation and simultaneous activation of the innate immune system. Continuous exposure to these glycosphingolipids leads to chronic inflammation in patients with Fabry disease, such that following the initial deposition of Gb3, tissue damage may progress independently, resulting in irreversible changes in tissues and ultimately organ failure (Figure 3).24 Renal, cardiac and cerebrovascular complications cause premature death in patients with Fabry disease.12 The life expectancy of patients with Fabry disease is reduced by approximately 20 years in males and by approximately 15 years in females, compared with the general population.25,26

Figure 3.
Pathophysiology of Fabry disease. Reproduced and adapted with permission from Sharma A et al. Heart Fail Rev 2015; 20: 689-708.27

Initiated in 2001, the Fabry Outcome Survey (FOS; sponsored by Shire, now part of Takeda) is an ongoing disease registry available to patients with Fabry disease.28 Data published in 2006 from children (aged <18 years) enrolled in FOS were used to describe the demographics and early clinical characteristics of Fabry disease. At the time of data analysis, 82 paediatric patients with Fabry disease, from 58 families, were enrolled from 11 European countries. The proportions of males (n=40; median age, 12.5 years) and females (n=42; median age, 13.2 years) were similar in the study cohort.29

The most frequently reported early clinical manifestations of Fabry disease were neurological symptoms, including acroparaesthesia (tingling, numbness, or pins and needles in the hands and fingers),30 generalised pain, altered temperature sensitivity and dyshidrosis, which affected approximately 80% of patients.29 Gastrointestinal symptoms, such as abdominal pain and altered bowel habits, affected approximately 60% of patients. Approximately 60% of children had ophthalmological symptoms, including cornea verticillata and tortuous vessels; these symptoms were observed even in children aged <5 years. Many patients also reported auditory and dermatological symptoms (approximately 40%), for example, tinnitus, vertigo and angiokeratomas. Common signs and symptoms of Fabry disease, such as acroparaesthesia, pain crises, angiokeratomas and gastrointestinal manifestations, were generally found to be equally prevalent in males and females, and even evident in children aged <10 years. In this patient cohort, the onset of Fabry disease typically developed 2‒5 years later in females than in males, despite the frequency of signs and symptoms being similar between groups.29

Although stroke, end-stage renal failure and heart failure were not observed in this cohort of paediatric patients with Fabry disease, cerebrovascular, renal and cardiac signs were reported. These symptoms are predominantly responsible for the decreased lifespan in adult patients with Fabry disease, with these data suggesting that there may be early onset of major organ involvement even in childhood.29

The Fabry Registry (sponsored by Sanofi Genzyme), initiated in 2001, is an ongoing, international, multicentre, observational programme for patients with Fabry disease.31 Data published in 2007 of 352 paediatric patients (aged <18 years at the time of enrolment) included in the Fabry Registry aimed to characterise the clinical manifestations during childhood and adolescence prior to initiation of disease-specific treatment. The study included 194 males and 158 females; median age was 12 years for both patient groups.32

In general, the onset of Fabry disease symptoms occurred earlier in male paediatric patients than females. The proportion of male patients experiencing neuropathic pain (episodic pain crises, chronic pain and acroparaesthesia), gastrointestinal symptoms (abdominal pain and diarrhoea) and skin symptoms (angiokeratomas) was also significantly higher than female patients (p<0.05)32:

  • Neuropathic pain: males, 58.8%; females, 40.5%
  • Gastrointestinal symptoms: males, 23.2%; females, 11.4%
  • Skin symptoms: males, 19.6%; females, 7.6%.

No paediatric patient had experienced major cerebrovascular or renal events such as stroke, renal transplant or chronic dialysis; however, one patient exhibited cerebrovascular signs, one presented with renal signs and two patients had cardiovascular signs. Moreover, of the patients with cardiac examination data available (males, n=93; females, n=79), valvular dysfunction was found in 22.6% of males (n=21) and 13.9% of females (n=11). In terms of renal function, three patients had abnormally low estimated glomerular filtration rate values, and among the 86 patients with available data, four male patients and five female patients (aged 2‒17 years) exhibited proteinuria. These data highlight that, in this cohort, many paediatric patients with Fabry disease experienced clinical manifestations, and a small percentage presented with severe renal and cardiac symptoms even during childhood.32

Baseline clinical characteristics of 1765 patients (males, n=956 [13 patients aged ≥10 to <20 years]; females, n=809 [10 patients aged ≥10 to <20 years]) enrolled in the Fabry Registry were published in 2007. The median age of symptom onset was earlier for male patients versus female patients (9 vs 13 years); the median age at diagnosis was also earlier for male versus female patients (23 vs 32 years).33

The most frequently presenting symptoms in male patients (n=713) included33:

  • Neurological pain (62%)
  • Skin abnormalities (31%)
  • Gastroenterological symptoms (19%)
  • Renal signs (unspecified, 17%)
  • Cardiovascular symptoms (13%)
  • Neurological other (12%)
  • Ophthalmological signs (11%)
  • Cerebrovascular manifestations (5%).

In female patients with Fabry disease (n=430), the most frequently reported presenting symptoms included33:

  • Neurological pain (41%)
  • Gastroenterological symptoms (13%)
  • Neurological other (12%)
  • Ophthalmological signs (12%)
  • Skin abnormalities (12%)
  • Renal signs (11%)
  • Cardiovascular symptoms (10%)
  • Cerebrovascular manifestations (4%).

For both male and female patients who reported renal progression, the median age at occurrence was 38 years. The median age at onset was older in females compared with males for cerebrovascular events (43 vs 38 years) and cardiovascular events (47 vs 41 years). These data highlight that onset of Fabry disease symptoms can occur in childhood in both males and females; however, time to diagnosis can be delayed, particularly in female patients with Fabry disease.33

The clinical manifestations in 366 adults with Fabry disease (males, n=201; females, n= 165) from 11 European countries were assessed based on patients enrolled in FOS; data were published in 2004. Female patients (mean [standard deviation (SD)] age, 41.4 [17.1] years) were significantly older than males (mean [SD] age, 35.5 [13.1] years; p<0.001). In most patients with Fabry disease, ≥1 organ system was involved in the disease manifestation. Moreover, in this study the number of organ systems affected by the disease increased progressively with age in both males and females; however, the number of organ systems involved was higher for males. For example, by age 50‒60 years, the mean number of organ systems involved in males was 9.5 (range, 5‒13) and in females was
6 (range, 1–12).7

The most frequently reported signs and symptoms of Fabry disease were7:

  • Neurological symptoms, affecting 84% and 79% of male and female patients, respectively. Neuropathic pain was the most common neurological symptom, and began at a mean age of 9.4 years and 16.9 years in males and females, respectively.
  • Dermatological symptoms were reported by 78% of male patients and 50% of female patients; angiokeratomas were present from a mean age of 17.9 years and 29.1 years, respectively.
  • Half of the patients enrolled in FOS experienced renal signs and symptoms of Fabry disease; the most frequently reported sign was proteinuria (males, 44%; females, 33%). End-stage renal failure was evident for 17% of male patients but only 1% of female patients aged >18 years.
  • Cardiac symptoms (angina, arrhythmias and dyspnoea) occurred in 69% of males and 65% of females with Fabry disease; the prevalence of left ventricular hypertrophy was higher for males compared with females (46% vs 28%).
  • Conversely, the frequency of cerebrovascular events (stroke, transient ischaemic attack or prolonged reversible ischaemic neurological deficit) was higher in females (27%) than males (12%). However, the mean age at onset of such events was younger in males versus females (28.8 vs 43.4 years).
  • Other signs and symptoms of Fabry disease in male and female patients, respectively, were: vascular (45% and 35%); auditory, such as tinnitus and hearing loss (57% and 47%); ocular (62% and 53%); gastrointestinal, including abdominal pain and diarrhoea (55% and 50%); and fatigue (24% and 28%).

Data of the cause of death in relatives of patients enrolled in FOS who also had Fabry disease were available for 42 males and 24 females. The primary cause of death was renal failure, which occurred in 54.5% of affected males, and was significantly more common in males than affected female relatives (p<0.001). Cardiac disease was the most frequent cause of death in affected female relatives, occurring in 26.7% of cases.7

Together, data from FOS of 366 adults with Fabry disease suggest that both male and female patients may exhibit the full range of disease manifestations, yet the signs and symptoms are variable between males and females, with a slower rate of progression in female patients. Moreover, although these data highlight that Fabry disease is a progressive condition with renal, cardiac and cerebrovascular manifestations that can be life-threatening, many symptoms occur in childhood. The presence of neurological pain, gastrointestinal symptoms, angiokeratomas and corneal dystrophy (cornea verticillata) are particularly common in childhood and could alert physicians to the possibility of Fabry disease, as could proteinuria of unknown aetiology.7


C-ANPROM/INT/FAB/0015; Date of preparation: March 2021