What are the early signs and symptoms of Fabry disease?

Following the onset of Fabry disease, diagnosis can be delayed for many years because the early disease indicators are often non-specific and there is limited awareness of the disease among clinicians. One of the major challenges in making a correct and timely diagnosis of Fabry disease is its lack of inclusion in a clinician’s differential diagnosis, particularly in young patients (see getting the diagnosis right). Moreover, children may initially present with non-specific or unusual symptoms that may not be associated with Fabry disease, especially if no family member has been diagnosed with the disease.1


What are the typical signs and symptoms of Fabry disease?
Fabry disease is characterised by severe multisystemic involvement, which ultimately leads to major organ failure and premature death.2,3 The prevalence of signs and symptoms and age at onset of disease manifestations in males and females with Fabry disease can vary.3 Moreover, the disease phenotype may differ between patients who have the classical or late-onset phenotype.4 Data from December 2007 from 1453 adult patients (males, n=699; females, n=754) from the Fabry Outcome Survey (FOS; sponsored by Shire, now part of Takeda), indicated that the most common overall clinical manifestations were neurological (68%), followed by cardiac symptoms (55%) and ocular involvement (53%) (Table 1).3 Initiated in 2001, FOS is an ongoing disease registry available to patients with Fabry disease.5 Of the 42 patients enrolled in FOS whose deaths were reported between 2001 and 2007, cardiac disease was the main cause of mortality in both male (34%) and female (57%) patients.3 Similarly, data from August 2008 from the Fabry Registry (sponsored by Sanofi Genzyme), an ongoing, international, multicentre, observational programme for patients with Fabry disease initiated in 2001,6 indicated that most deceased patients (40.2%; 35/87) had died due to cardiovascular disease.7 The median age at death for male and female patients was 55.5 years and 66.0 years, respectively. Compared with other enrolled patients in the Fabry Registry, the median age at Fabry disease diagnosis was older for deceased patients (males, 40 vs 24 years; females, 55 vs 33 years). The life expectancy of male patients included in the Fabry Registry was 58.2 years, compared with 74.7 years in the general US population. In female patients with Fabry disease, the life expectancy was 75.4 years, versus 80.0 years in the general US population. Together, these studies highlight that patients with Fabry disease can exhibit serious clinical manifestations, and late diagnosis may contribute to early death in some cases.7

Table 1.
Prevalence of signs and symptoms and age at onset of organ system involvement in patients with Fabry disease enrolled in FOS (data from December 2007). Reproduced with permission from Mehta A et al. J Med Genet 2009; 46: 548-552.3


The neurological manifestations of Fabry disease involve the peripheral and central nervous system (CNS) and are attributed to globotriaosylceramide (Gb3) accumulation within Schwann cells and dorsal root ganglion, and deposition within neurons in the CNS. Cerebral vasculopathy, with an increased incidence of stroke, is one of the key neurological manifestations in patients with Fabry disease. Although the pathogenesis of vasculopathy in Fabry disease is not clearly understood, accumulation of Gb3 is likely to lead to abnormal control of vessels, secondary to endothelial dysfunction. Accumulation of Gb3­and consequent inflammation, in addition to confounding vascular risk factors, may develop as a result of abnormal endothelial and vessel wall function. Altered autonomic function including hypohidrosis (abnormally diminished sweating), and neuropathic pain, in Fabry disease are likely to be attributed to alterations in nervous system functioning.8-10 The signs and symptoms of Fabry disease may also relate to autonomic dysfunction, including orthostatic intolerance, vasomotor impairment and gastoparesis.11

Data from March 2005 of 688 patients (males, n=330; females, n=358) enrolled in FOS indicated that 13.2% of patients (15.1% males; 11.5% females) had experienced an ischaemic stroke or transient ischaemic attack, typically at an early age. In males and females with Fabry disease the number of observed ischaemic strokes was 20.1-times and 7.8-times greater, respectively, than expected for the general population (p<0.001).12 A retrospective study of 43 Italian patients with Fabry disease (males, n=25; females, n=18) aimed to describe the neurological manifestations of the disease and CNS involvement. The mean (standard deviation [SD]) age of enrolled female patients (52.5 [17.5] years) was higher than that of male patients (41.9 [10.8] years). All patients had Fabry disease manifestations in ≥1 organ; 24 of 25 male patients (96%) had multiple organ involvement, as did 11 of 18 female patients (61%). Brain abnormalities, as shown by magnetic resonance imaging, were evident for 64% of male patients (16/25) and 81% of female patients (13/16). The majority of male (64%; 16/25) and female (72%; 13/18) patients had ≥1 neurological disease manifestation. Of these patients, five males and three females had exhibited transient ischaemic attack, followed by stroke. In total, six males and five females had experienced a stroke. Mean (SD) age at onset of cerebrovascular events was younger for male versus female patients (33.6 [13.7] vs 53.7 [11.7] years).13 Other minor neurological manifestations in this cohort of male and female patients, respectively, included diplopia (double vision; 20% and 17%),14 migraine or recurrent headache (20% and 28%), vertigo (32% and 11%), hearing loss (36% and 33%) and cognitive problems (12% and 22%).13 Cognitive problems, ranging from very mild amnesic deficits to moderate dementia, affected three male patients with Fabry disease and four females. The findings from this study highlight the high frequency of CNS involvement in both males and females with Fabry disease in this patient cohort.13

Moreover, studies of patients with cryptogenic strokes and acute cerebrovascular events suggest that these disease manifestations can be attributed to Fabry disease and, specifically, a cerebrovascular variant of the disease (see late-onset Fabry disease).15-17 Data from the Fabry Registry indicated that for many patients with Fabry disease, renal or cardiac disease manifestations were not evident prior to their first stroke. Data from October 2007 indicated that 138 of 2446 patients enrolled in the Fabry Registry had experienced a stroke: 6.9% of male patients (86/1243) and 4.3% of female patients (52/1203). The median age at first stroke was younger for males versus females (39.0 vs 45.7 years). Stroke type was reported for 121 patients, of whom 105 (86.8%) had ischaemic strokes and 16 (13.2%) had haemorrhagic strokes. For female patients, stroke was more likely to be their only clinical event (50.0%; 26/52) compared with male patients (22.1%; 19/86). Moreover, 38.3% of female patients (5/52) and 50.0% of male patients (43/86) experienced their first stroke before they were diagnosed with Fabry disease. These findings suggest that many patients in this study had either not experienced other major disease complications or had not been diagnosed with Fabry disease prior to their first stroke.18 As recommended by Rolfs et al. Lancet 2015, Fabry disease may be considered in all cases of unexplained stroke in young patients.16

Cardiac involvement is common in male and female patients with Fabry disease, and is a major cause of morbidity and mortality.19,20 In some patients, the disease manifestations of Fabry disease may be limited to the heart (see late-onset Fabry disease).2,21 In patients with Fabry disease, accumulation of Gb3 occurs within many cell types within the heart, including cardiomyocytes, conduction system cells, valvular fibroblasts, endothelial cells within all forms of vessels, and vascular smooth muscle cells. Gradual storage of Gb3 may induce progressive lysosomal and cellular malfunctioning that activates signalling pathways linked to hypertrophy, apoptosis, necrosis and fibrosis.21The primary manifestation of cardiac involvement in Fabry disease is the progressive thickening of the heart walls, which may be expressed as hypertrophic cardiomyopathy. Patients with cardiac symptoms may also present with atrioventricular conduction disturbances, arrhythmias, valvular involvement and coronary disease.22

The clinically important symptoms of cardiac manifestations in Fabry disease include dyspnoea, chest pain, palpitations and syncope, and mainly relate to the development of progressive hypertrophic cardiomyopathy, conduction abnormalities and arrhythmias.21In many patients with Fabry disease, dyspnoea and chest pain are related to left ventricular hypertrophy.21 This clinical manifestation is an early cardiac abnormality in Fabry disease and can be observed by echocardiography.23 Left ventricular hypertrophy is typically concentric in patients but can also exhibit asymmetrical shapes on an echocardiogram.22 Diastolic dysfunction is the primary cause of dyspnoea; however, in some patients, valvular regurgitation and/or systolic left ventricular dysfunction may cause dyspnoea. Some patients with Fabry disease and cardiac manifestations may develop angina, even in the absence of stenotic coronary lesions. Angina may be due to an increase in oxygen consumption and a reduction in coronary flow reserve. High degrees of atrioventricular blockade or, more rarely, severe dynamic obstruction of the left ventricular outflow tract, may lead to syncope in patients with Fabry disease.21

In October 2005, clinical data from 714 patients (males, n=345; females, n=369) from 11 European countries enrolled in FOS were available. At study entry, 124 male patients and 254 female patients with Fabry disease were untreated, whereas 221 males and 115 females had received enzyme replacement therapy prior to FOS enrolment. In untreated patients, the prevalence of any cardiac symptom was higher for males versus females (52.4% vs 39.0%); however, the mean (SD) age at onset of cardiac symptoms was later in females compared with males (39.9 [17.5] vs 31.5 [15.6] years, respectively). In treated patients, the prevalence of any cardiac symptoms was similar between male (66.5%) and female (62.6%) patients; although, the mean (SD) age at onset of symptoms was later in females versus males (40.9 [15.8] vs 33.3 [12.2] years). In both the treated and untreated cohorts, the prevalence of cardiac symptoms (dyspnoea or heart failure; angina or chest pain; palpitations or documented arrhythmias; and syncope) was generally similar between males and females with Fabry disease; although, age at onset was delayed in female compared with male patients (except for treated females with syncope).24

The most common major cardiac event in untreated (33.1% and 21.3%) and treated (47.5% and 37.4%) male and female patients, respectively, was left ventricular hypertrophy. The mean (SD) age at onset of left ventricular hypertrophy was significantly delayed in females compared with males (untreated: 50.1 [12.0] vs 42.0 [14.5] years, p=0.05; treated: 48.8 [10.1] vs 38.4 [10.8] years, p<0.0001, respectively). Conduction abnormality, valvular heart disease, pacemaker implantation and myocardial infarction were also common major cardiac events that affected both male and female patients in the treated and untreated cohorts. In this study, data on the cause of death were also available for 113 affected relatives who also had Fabry disease (males, n=72; females, n=41), where cardiac death (defined as sudden death or death related to heart failure, myocardial infarction or infective endocarditis) affected 29.2% of male relatives (mean [SD] age at death, 47 [9] years; p=0.001) and 29.3% of female relatives (mean [SD] age at death, 61 [8] years). End-stage renal disease was the most frequent cause of death in affected male relatives, whereas cardiac death was the most common cause of mortality in females. The results from this study highlight that cardiac disease manifestations substantially affect morbidity in male and female patients with Fabry disease. Moreover, the high prevalence of cardiac-related deaths in affected relatives of patients suggests that these manifestations contribute to the reduced life expectancy observed in patients with Fabry disease.24

It is common for patients with Fabry disease to experience ophthalmological manifestations as a result of progressive glycosphingolipid deposition within various ocular structures. However, these symptoms do not typically cause visual impairment in patients with Fabry disease.25

Specifically, ophthalmological manifestations in Fabry disease include25:

  • Conjunctival vascular abnormalities, such as increased vessel tortuosity, venous vascular aneurysmal dilation and ‘sludging’ of the blood in small blood vessels
  • Corneal opacities (also known as corneal verticillata), which consist of bilateral whorl-like opacities located within the superficial corneal layers, most likely in the inferior corneal area
  • Lens opacities, such as an anterior capsular or subcapsular cataract or a radial posterior subcapsular cataract
  • Retinal vascular abnormalities, including increased tortuosity of the retinal vessels associated with segmental venous dilation, arteriolar narrowing and arteriovenous nicking.

Study results published in 2006 of 82 paediatric patients aged <18 years (males, n=40; females, n=42) enrolled in FOS indicated that diagnosis of Fabry disease was suspected by an ophthalmologist in 4% of cases. Moreover, ophthalmological disease manifestations, such as cornea verticillata and tortuous vessels, occurred in approximately 60% of patients and were even present in patients aged <5 years.26 In a case series of five Colombian patients with Fabry disease (age range, 14‒43 years), one of the most prevalent ophthalmological findings was cornea verticillata, which was observed in all patients. The majority of these patients (4/5) had lens opacities with tortuosity and dilatation of the retinal and conjunctival vessels. However, no patients developed retinal venous–arterial occlusions or presented with optic disc oedema.27 Similarly, a study of 173 adult patients (males, n=82; females, n=91) with ophthalmological data enrolled in FOS in March 2005 indicated that cornea verticillata was the most prevalent ocular abnormality. This disease manifestation was present in 73.1% of male patients and 76.9% of female patients (age range, 3‒71 years). The occurrence of tortuous vessels (48.7% and 21.9%) and Fabry cataracts (23.1% and 9.8%) was higher in male patients compared with female patients, respectively.28Together, these studies highlight that ophthalmological disease manifestations can be present in both paediatric and adult patients with Fabry disease, and can act as a disease marker with diagnostic and prognostic implications.25-28

Gastrointestinal involvement is considered a common but under-appreciated manifestation of Fabry disease.29,30 Many patients with Fabry disease report gastrointestinal symptoms, such as abdominal bloating and pain, diarrhoea, difficultly gaining weight, early satiety, epigastric discomfort, nausea and vomiting, which can negatively affect quality of life.29,31 As a consequence, some patients may avoid meals and have a reduced appetite. It is likely that accumulation of Gb3 within neurons of the submucosal and myenteric nerve plexuses causes enteric neuropathy and underlies the pathophysiology of gastrointestinal involvement in Fabry disease.31 Similar to other clinical manifestations of Fabry disease, gastrointestinal symptoms follow an incessantly progressive disease course and may originate in childhood.26,31 In a study published in 2006 of 82 paediatric patients (males, n=40; females, n=42) enrolled in FOS, gastrointestinal symptoms were the most frequent early clinical manifestation for approximately 60% of patients. The most common symptom in both males (44.4%; 16/36) and females (51.7%; 15/29) was abdominal pain, followed by diarrhoea (males, 33.3% [12/36]; females, 27.6% [8/29]). Constipation, nausea and vomiting were also reported in this patient cohort.26

The pattern of gastrointestinal manifestations was also evaluated in an Italian study of 33 patients with Fabry disease (adults, n=25; children, n=8). The median age at onset of gastrointestinal symptoms was 10 years. In the adult cohort, patients reported that the following gastrointestinal symptoms had persisted for ≥3 months32:

  • Feeling uncomfortably full after a regular-sized meal (n=14)
  • Complaints of having <3 bowel movements per week (n=13)
  • Bloating or distension (n=12)
  • Pain or discomfort anywhere in the abdomen (n=12).

For paediatric patients, all patients had experienced abdominal pain within the last 2 months. The majority of patients (n=5) experienced abdominal pain 1‒3 times per month; however, two patients complained of abdominal pain once per week, and for one patient this symptom was experienced every day. Abdominal pain had persisted for ≥1 year for four children.32

Information on 342 patients with gastrointestinal data enrolled in FOS in October 2005 was also evaluated to determine the prevalence and nature of these disease manifestations. Data were available for 271 adults (males, n=139; females, n=203) and 71 children with Fabry disease. In total, 52.0% of patients (n=178) had experienced gastrointestinal complaints, which was more prevalent in female versus male patients (54.2% vs 48.9%) and in children (60.8% vs 49.8% in adults). The most frequently reported gastrointestinal symptom overall was abdominal pain (32.5%), which was more common in children versus adults (49.3% vs 28.0%). In line with these data, the median age at onset of abdominal pain was 14.0 years (range, 0‒69 years).33

Other gastrointestinal symptoms reported in the total study population included33:

  • Diarrhoea (20.5%)
  • Constipation (13.5%)
  • Nausea and vomiting (12.3%)
  • Haemorrhoids (8.5%)
  • Gastritis or ulcer (4.4%)
  • Pancreatitis (0.9%).

The most commonly reported combined gastrointestinal symptoms were abdominal pain and diarrhoea (14.3%), followed by abdominal pain and nausea (9.4%), and abdominal pain and constipation (7.3%). The findings from this study highlight that gastrointestinal symptoms are often observed in patients with Fabry disease and may have a negative impact on quality of life.33

The early manifestations of Fabry disease may include dermatological and soft-tissue symptoms. These symptoms often occur in childhood and are attributed to accumulation of Gb3 within lysosomes of endothelial cells in the superficial dermis. Angiokeratomas are the main cutaneous lesions observed in patients with Fabry disease and are often the first physical sign of the disease, initiated in childhood.34

In a study published in 2006 of children enrolled in FOS, angiokeratomas were evident in 41.7% of males (15/36) and 37.9% of females (11/29), with a median age at onset of 9.1 years and 14.4 years, respectively.26 Angiokeratomas are non-blanching, small, dark red or bluish benign skin lesions comprised of dilated capillaries in the upper dermis with additional overgrowth of the epidermis.35,36 These skin lesions typically appear either singly or in clusters as a raised spot with a scaly or wart-like surface.35,36 Angiokeratomas are a result of Gb3 accumulation in dermal endothelial cells leading to vessel bulging, incompetence of the vessel wall and secondary dilatation.34 In patients with Fabry disease, angiokeratomas may develop slowly and appear on the buttocks, genitalia, inner thighs, back and oral cavity.37With age, angiokeratomas can become more visible and may spread to the lips, hands and toes in patients with Fabry disease.34 Data published in 2004 of adult patients with Fabry disease showed that dermatological symptoms were present in 78% of male patients (157/201) and 50% of female patients (83/165) included in FOS, and were evident from a mean age of 17.9 years and 29.1 years, respectively.19

Other dermatological manifestations of Fabry disease include:

  • Sweating abnormalities in patients with Fabry disease are due to deposition of Gb3­ in eccrine sweat glands and reduced sympathetic innervation of the sweat glands.38,39
  • Lymphoedema (swelling due to obstruction of the lymph nodes) is related to the accumulation of glycolipids in the lymph vessels, and can be complicated by erysipelas (a skin infection) and the risk of systemic infection in patients with Fabry disease.34,40-42
  • Facial dysmorphia is associated with Fabry disease, specifically in male patients who may have a characteristic facial appearance with prominent supraorbital ridges, frontal bossing and thickening of the lips.34

Using information from FOS, the dermatological manifestations of Fabry disease were documented from 714 patients enrolled (males, n=345; females, n=369) in October 2005. The mean (SD) age of patients included in the study was similar between males (35.1 [15] years) and females (38 [18.1] years). In total, 78% of males and 50% of females had ≥1 dermatological disease manifestation. Angiokeratomas were the most frequently reported dermatological symptom in both male (66%; mean [SD] age at onset, 19 [14] years) and female (36%; mean [SD] age at onset, 28 [17] years) patients. In terms of sweating abnormalities, in both male and female patients, hypohidrosis (53% and 28%, respectively) was the most frequently reported, followed by anhidrosis (25% and 4%, respectively) and hyperhidrosis (6% and 13%, respectively). Reversible peripheral oedema was evident in 25% of male patients and 17% of females, and had a later mean (SD) age at onset in females versus males (42 [16] vs 32 [13] years). Lymphoedema was more common in males than females (16% vs 6%), with a mean age at onset of 37 years in male patients (range, 13‒70 years) and 47 years (range, 11‒72 years) in females. Based on these data, lymphoedema appears to occur approximately 5 years later than reversible oedema in patients with Fabry disease.40

In the 127 children aged <16 years (males, n=57; females, n=70) included in this study, the following dermatological symptoms were observed in male and female patients, respectively40:

  • Angiokeratomas (37% and 23%)
  • Telangiectasia (11% and 9%)
  • Anhidrosis (16% and 0%)
  • Hypohidrosis (49% and 21%)
  • Hyperhidrosis (9% and 6%)
  • Heat intolerance (37% and 29%).

In paediatric patients, these dermatological symptoms were generally evident from a younger age in males versus females. The results from this study highlight that dermatological manifestations are an important clinical feature of Fabry disease.40

Although not life-threatening, it is evident that many patients with Fabry disease experience otological clinical manifestations, such as hearing loss and tinnitus (Ménière’s disease),43 which may adversely affect quality of life.44 In a single-centre study conducted in Germany, in 57 patients with Fabry disease (age range, 19‒77 years) 35.1% of patients had experienced hearing loss and 54.4% had exhibited vertigo; 28.1% of patients had complained of both symptoms.45 In a South American study of 36 adult patients with Fabry disease (males, n=11; females, n=25), neuro-otological symptoms were assessed. In total, 75% of patients experienced neuro-otological symptoms: tinnitus (33%), vertigo (27.8%), vertigo and hearing loss (25%), and hearing loss (22.2%). In this cohort, no patient presented with sudden hearing loss; however, five patients exhibited progressive hearing loss. In the patients who experienced vertigo, two forms were described: brief and recurrent episodes of non-positional vertigo lasting for minutes (33%; 11/36) and protracted crises lasting for hours or days (13%; 5/36). These data highlight that neuro-otological involvement may be observed in patients with Fabry disease and may be under-recognised.46

In a separate study, the hearing status of 83 patients (males, n=29; females, n=54) with audiogram data from the Danish Fabry cohort was assessed. The median age of enrolled patients was 35 years (range, 9‒72 years); all male patients except one, and 41 of 54 female patients, were diagnosed with classical Fabry disease. Hearing thresholds at all frequencies (250‒8000 Hz) were significantly different from the expected thresholds of a comparison cohort with no otological impairments (p<0.001). Moreover, for patients with Fabry disease, hearing loss was more pronounced at the highest frequencies (4000‒8000 Hz) and was also noticeable at the lower frequency (250 Hz) in male patients.47 It is suspected that histopathological changes causing otological dysfunction in patients with Fabry disease are due to accumulation of glycosphingolipids within the stria vascularis and ganglion cells within the ears, and also as a result of vascular damage to other tissues.44

The renal manifestations of Fabry disease, such as proteinuria or a decreased glomerular filtration rate, occur early in the disease course and affect many paediatric and adult patients.48 These symptoms are considered ‘red flags’ for Fabry disease.49 Progression of proteinuria or a decreased glomerular filtration rate and deterioration of renal function over time can lead to end-stage renal disease in almost all male and some female patients with Fabry disease.48 Electron microscopy imaging of renal biopsies of patients with Fabry disease revealed myelin-like inclusions known as ‘zebra bodies’. These lesions can be observed in lysosomes of cells, primarily within the glomerular and distal tubule, due to deposition of Gb3. Podocytes and endothelial cells become increasingly hypertrophic with foamy-looking vacuoles as renal disease progresses in patients with Fabry disease.50 The earliest functional manifestation of renal disease in patients with Fabry disease may be urinary concentration defects, leading to polyuria (excessive urination) and nocturia (urination at night).51-53 Referral to a nephrologist is typically initiated upon the development of proteinuria. This symptom may develop during adolescence and become more frequent once patients are aged 20‒30 years.53

In a study of 82 paediatric patients (aged <18 years) with Fabry disease enrolled in FOS, published in 2006, 8.3% of males and 31.0% of females had proteinuria, with a median age at onset of 13.8 years (range, 10.3‒17.3 years) and 14.1 years (range, 8.1‒17.3 years), respectively. Although end-stage renal failure was not observed in this cohort of paediatric patients, signs of renal disease were present during adolescence for some patients, indicating early onset of major kidney involvement.26

In a separate study of 1453 adult patients (males, n=699; females, n=754) enrolled in FOS in December 2007, renal signs and symptoms of Fabry disease were evident in 47.7% of patients with a mean (SD) age at onset of 35.0 (14.5) years. The most common renal manifestation was proteinuria, affecting 39.8% of patients; renal failure was observed in 10.7% of patients, and 12.7% of male patients (n=89) and 0.7% of female patients (n=5) had end-stage renal disease (mean [SD] age at onset, 32.3 [19.7] and 23.3 [21.3] years, respectively). In this study, data on the cause of death of 181 affected relatives also with Fabry disease were available; the most common cause of mortality in 58% of male relatives (aged 21‒50 years) was renal failure.3

An analysis of kidney function of adults enrolled in the Fabry Registry in July 2009 revealed that patients with overt proteinuria lose renal function more rapidly compared with those with little or no proteinuria. Data on kidney functioning were available for 462 adults (males, n=121; females, n=341) and demonstrated that the majority of male patients (71%; 86/121) had a more rapid loss of kidney function compared with an adult population with normal kidney functioning; however, this was evident in fewer female patients (39%; 133/341). Moreover, patients with rapid loss of kidney function had significantly higher urinary protein to urinary creatinine ratios compared with patients with slower decreases in kidney functioning (p<0.0001). Results from this study suggest that proteinuria appears to be the most important predictor of renal disease progression in patients with Fabry disease.54 However, some patients do not experience the early-onset symptoms of classical Fabry disease and instead only experience a renal phenotype, resulting in end-stage renal disease when they are aged 40‒60 years (see late-onset Fabry disease).54-56

Patients with Fabry disease may also exhibit type 5 cardio-renal syndrome (CRS-5), which comprises simultaneous development of kidney injury and cardiac dysfunction. For patients with Fabry disease and CRS-5, kidney and cardiac dysfunction may develop slowly until a threshold is reached, leading to complete organ decompensation. The sequence of organ involvement and time to development of CRS-5 is dependent upon the nature of the underlying disease and its influence on renal and cardiac functioning. In patients with Fabry disease, clinical manifestations in the kidney and heart can lead to acute or chronic organ cross-talk and the development of CRS-5. Accumulation of Gb3 within cells in the kidney and heart leads to symptoms of renal (proteinuria, microalbuminuria, isosthenuria, altered tubular reabsorption, secretion and excretion) and cardiac (left or right ventricular hypertrophy, diastolic dysfunction and arrhythmias) involvement. These symptoms may lead to more progressive renal and cardiac involvement, such as fibrosis, sclerosis, tubular atrophy and gradual renal function loss within the kidney, and myocardial replacement fibrosis within the heart. Cross-talk between the two organs may lead to end-stage renal involvement, such that patients become dependent upon dialysis, and demonstrate end-stage cardiac involvement (cardiac failure, malignant arrhythmias, myocardial infarction or sudden cardiac death).57

Patients with Fabry disease and cardio-renal involvement have a >4-fold increased risk for the development of the following complications58:

  • Requirement of renal replacement therapy (kidney transplant or chronic dialysis)
  • New-onset atrial fibrillation
  • Implant of a pacemaker and/or an implantable cardioverter-defibrillator
  • Hospitalisation due to decompensated heart failure
  • Cerebrovascular events (stroke or transient ischaemic attack)
  • Death.

A study of 104 adult Swiss patients with Fabry disease (males, n=40; females, n=64) aimed to assess the impact of comorbid cardio-renal syndrome on clinical outcomes. The mean (SD) age of enrolled patients was 45 (16) years. As a consequence of cardio-renal involvement, the following events occurred58:

  • ≥1 stroke or transient ischaemic attack (n=8)
  • New-onset atrial fibrillation (n=6)
  • Implant of a pacemaker and/or an implantable cardioverter-defibrillator (n=6)
  • New kidney transplantation (n=3)
  • Initiation of chronic kidney dialysis (n=3)
  • Hospitalisation due to decompensated heart failure (n=2).

Moreover, of the 11 patients who died during the study, death was attributed to cardio-renal syndrome in six cases. The findings from this study indicate that cardio-renal syndrome is a potential disease marker for patients with Fabry disease and is associated with an increased risk of mortality.58

Due to the disease manifestations of Fabry disease, patients are at risk for developing neuropsychiatric symptoms, such as depression, suicidal tendencies and neuropsychological deficits. Moreover, patients with Fabry disease may have a reduced quality of life because of the somatic and psychological impairments associated with the disease (see impact of Fabry disease).59 In a study of 25 adult patients with Fabry disease (mean [SD] age, 36.5 [11.0] years; n=15 females) from Germany, cognitive performance, depression and psychotic symptoms were quantified and compared with individuals without Fabry disease (mean [SD] age, 36.8 [10.0] years; females, n=11). The most commonly reported clinical manifestation in patients with Fabry disease was cardiac dysfunction (80%), renal dysfunction (80%) and neuropathic pain (80%), followed by angiokeratomas (52%) and cerebrovascular events (20%). Patients with Fabry disease demonstrated impairments in attention and 60% exhibited depressive symptoms. Additionally, patients with Fabry disease also had more negative general psychopathology, suffered more pain and had lower quality of life compared with individuals without Fabry disease. The volume of white matter lesions (independent of stroke, n=7) was also higher in patients with Fabry disease versus unaffected individuals, and was associated with greater deficits in learning and memory, but not depression. The findings from this study suggest that patients with Fabry disease may exhibit only mild cognitive deficits; however, the higher frequency of depression, compared with unaffected individuals, could be linked to the burden and chronicity of Fabry disease.60

In a separate study of 81 adult Dutch patients with Fabry disease (males, n=28; females, n=53), depressive symptoms were investigated. The mean (SD) age of enrolled patients was 44.5 (14.3) years; the majority of patients had classical Fabry disease (74.1%). Depressive symptoms were experienced by 31 patients (38.3%), and 22 patients (27.2%) had either a history of or were currently diagnosed with depression or burnout (14.8%; n=12). Loneliness was reported by 11 patients (13.6%) with Fabry disease. Symptoms of depression were lower in patients who had a better perception of their health and exhibited more “positivity and problem solving”, whereas depressive symptoms were higher in those experiencing more pain and who displayed “brooding and avoidance”. The results from this study suggest that symptoms related to depression in Fabry disease may be related to pain, negative health perceptions and use of specific coping strategies.61

It is hypothesised that interstitial lung disease may develop in patients with Fabry disease as a result of tissue remodelling in the alveolar surroundings, causing fibrosis induced by glycosphingolipid accumulation. A systematic review of pulmonary manifestations in Fabry disease indicated that the most common symptoms were dyspnoea, wheezing, dry cough and obstructive airway limitation. Moreover, histological abnormalities including lamellar inclusion bodies in epithelial cells and smooth muscle hyperplasia were found.62

A Swiss study of 95 patients with data from ≥2 pulmonary function tests (males, n=56; females, n=39) aimed to characterise the impact of pulmonary involvement in Fabry disease. Among these patients, 13 (14%) had obstructive lung disease. Of the 82 patients with no obstructive lung disease, 31 developed bronchial obstruction over time. These data indicated that at any time point, 46% of patients with Fabry disease (n=44) in this cohort developed bronchial obstruction. The prevalence of bronchial obstruction was higher in male patients and in smokers. These data suggest a causal relationship between Fabry disease and bronchial obstruction, and that pulmonary involvement may be a relevant but underestimated disease manifestation.63


C-ANPROM/INT/FAB/0016; Date of preparation: March 2021



20 years of treatment for Fabry disease

An interactive video experience



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The WORLDSymposium™ was held as a hybrid meeting this year (7–11 February 2022) and brought together key opinion leaders from the field of lysosomal disorders and rare diseases. Here you can access summaries from the meeting, including reports with a specific focus on Fabry disease.

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Getting the diagnosis right

Why can diagnosing Fabry disease be difficult for clinicians?

Diagnosis of Fabry disease can be difficult due to the diversity of clinical symptoms. Lack of knowledge of clinical findings and disease awareness can lead to misdiagnosis of Fabry disease by clinicians.

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Diagnosis of Fabry disease

How can Fabry disease be diagnosed?

Genetic testing can confirm and support a diagnosis in females and males. The α-Gal A enzyme assay can diagnose Fabry disease in males.

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