Why is it important to diagnose Fabry disease early?

Fabry disease is a complex, multisystemic disorder with a wide spectrum of clinical manifestations, including dermatological, ophthalmological, cardiovascular, renal and neurological findings (see signs and symptoms of Fabry disease). Consequently, Fabry disease should be considered in the differential diagnosis of many systemic diseases. Nevertheless, diagnosis of Fabry disease can be challenging due to the diversity of clinical symptoms.1 Diagnosis can also be delayed for several years following the onset of signs and symptoms of Fabry disease, because the early disease manifestations may be non-specific or unusual. Moreover, if other family members have not been diagnosed with the disease, these symptoms are often not attributed to Fabry disease.2 Although specialists in Fabry disease will encounter many patients, the diagnosing clinician may only see one patient with the disease during their entire career, and unless they are aware of the potential clinical features of Fabry disease and the tests involved, this patient may go undiagnosed.3 Therefore, lack of knowledge of clinical findings and disease awareness may also lead to misdiagnosis of Fabry disease by clinicians.1,2

Management of Fabry disease was previously limited to only symptom control and supportive therapies to maintain end-organ function. However, specific therapies for disease management of Fabry disease are now available, including enzyme replacement therapy and chaperone therapy. Diagnosing Fabry disease early allows timely introduction of these therapies. Moreover, a diagnosis of Fabry disease enables other potentially affected family members to be identified and provides an explanation for a patient’s symptoms following what may have been a long clinical investigative journey. A diagnosis of Fabry disease also enables a full assessment of potentially affected organs, which may identify other disease complications that would benefit from supportive therapies and prevent the onset of irreversible end-organ damage.3

An interview-based study of 30 patients with Fabry disease (males, n=13; females, n=17) in The Netherlands was performed to determine patients’ experiences of the timing of their diagnosis. The median age of included patients was 43 years (range, 12‒68 years). Five children were interviewed (three patients were aged <16 years); parents of four children with Fabry disease were also included in the study. The median age at diagnosis was 25.5 years (range, 5‒55 years), and the majority of patients (77%; n=23) had experienced symptoms related to Fabry disease prior to diagnosis. The median time between symptom onset and diagnosis was 13 years (range, 0‒39 years). In total, 17 patients, 12 of whom were females, were diagnosed with the disease as a result of family screening following a family member’s diagnosis of Fabry disease. Based on the clinical signs and symptoms of Fabry disease, nine patients, seven of whom were males, were diagnosed with the disease following a diagnostic work-up. For the remaining four patients, diagnosis of Fabry disease occurred by chance (cornea verticillata, n=3; renal biopsy glomeronephritis, n=1).4

A diagnostic delay of >5 years was experienced by 16 patients. Patients with severe symptoms and a delayed diagnosis reported that their symptoms (primarily acroparaesthesia, fatigue and heat intolerance) were misunderstood and not taken seriously by parents, physicians and teachers. Patients were often told they “were being overdramatic”, which may have affected their self-esteem. Patients with severe symptoms were also more likely to have visited different physicians and to have been admitted to hospital before a diagnosis of Fabry disease was made. For some patients, symptoms were often attributed to psychosocial problems rather than a somatic disease. Patients expressed relief when a correct diagnosis of Fabry disease was made and their symptoms finally acknowledged. Many of these patients felt that an earlier diagnosis of Fabry disease “would have made things easier”. Moreover, some patients felt that an early diagnosis of Fabry disease enabled them to anticipate future problems related to the disease, helping them to make choices in life. The majority of patients in this study also stated that an early diagnosis of Fabry disease meant they could receive treatment earlier and that the prevention of complications was an important advantage (Figure 1). The findings from this study highlight that a delayed diagnosis of Fabry disease can lead some patients to feel misunderstood if they are misdiagnosed. An early diagnosis of Fabry disease enabled patients to anticipate the future and possibly helped to prevent complications associated with the disease due to timely initiation of treatment.4

Figure 1.
Examples of patients’ reactions to the timing of their Fabry disease diagnosis. Reproduced with permission from Bouwman MG et al. Mol Genet Metab 2013; 109: 201-207.4

What clinicians may be involved in diagnosing Fabry disease?
The Fabry Outcome Survey (FOS; sponsored by Shire, now part of Takeda) is an ongoing disease registry initiated in 2001 for patients with Fabry disease.5 Data published in 2006 from 82 paediatric patients with Fabry disease suggested that many patients may be diagnosed as a result of their family history.6 In addition, one study in the United States of four lysosomal storage disorder centres found that, on average, five family members are diagnosed with Fabry disease as a result of family screening.7  Nevertheless, a range of medical specialities may also be involved in diagnosing Fabry disease in childhood, such as paediatricians (Figure 2A).6 In a separate analysis of FOS, published in 2016, the medical specialities involved in suspecting a diagnosis of Fabry disease in 472 paediatric and adult patients are presented in Figure 2B. In this analysis, only “index” patients were included, which was defined as the first patient diagnosed with Fabry disease from a family with several or no additional members registered in FOS. Nephrologists, followed by cardiologists and ophthalmologists, were the most likely specialities to suspect Fabry disease in this patient group.8

Figure 2.
Specialities involved in making a diagnosis of Fabry disease in (A) 82 paediatric patients and (B) 472 paediatric and adult patients enrolled in FOS. Developed using data from Ramaswami U et al. Acta Paediatr 2006; 95: 86-92 and Reisin R et al. Int J Clin Pract 2017; 71.6,8

How can clinicians include Fabry disease in their differential diagnosis?
According to the 2018 Canadian Fabry Disease Treatment Guidelines, no clinical manifestations of Fabry disease are diagnostic in their own right. Some features of the disease (e.g., nephropathy, hypertrophic cardiomyopathy and stroke) are non-specific, with a variety of differential diagnoses. Some disease manifestations of Fabry disease have a more limited differential diagnosis (e.g., cornea verticillata, angiokeratomas); however, these symptoms can still be present in other conditions. Therefore, clinical findings alone cannot be used to confirm a diagnosis of Fabry disease, although more weight can be attributed in the diagnostic process to symptoms that are more specific to the disease.9

 

Paediatricians and family practitioners should be aware of the following signs and symptoms, which may be attributed to Fabry disease in children10,11:

  • Acute, unexplained episodes of pain often accompanied by fever and unresponsiveness to conventional analgesics
  • Chronic pain or discomfort in the extremities
  • Heat or cold and exercise intolerance
  • Electrocardiogram abnormalities
  • Unexplained gastrointestinal disturbances (diarrhoea, vomiting, nausea and abdominal pain)
  • Angiokeratomas
  • Hypohidrosis
  • Mild proteinuria.

An expert panel published recommendations in 2003 stating that in adults, Fabry disease should be considered in cases of unexplained10,12:

  • Renal dysfunction progressing to end-stage renal disease
  • Cardiomyopathy (particularly left ventricular hypertrophy)
  • Arrhythmias
  • Valvular abnormalities
  • Early stroke
  • Fatigue or heat intolerance
  • Hearing loss
  • Obstructive pulmonary disease
  • Characteristic cornea verticillata.

 

A suspected diagnosis of Fabry disease must be determined from the individual patient’s clinical manifestations as the range of possible differential diagnoses is broad. If in doubt, clinicians should include Fabry disease in the range of possible diagnoses. A suggested diagnostic flowchart for patients with Fabry disease is presented in Figure 3.13

Figure 3.
Diagnostic flow chart from unspecific symptoms of Fabry disease to diagnosis. Reproduced and adapted with permission from Hoffmann B, Mayatepek E. Dtsch Arztebl Int 2009; 106: 440-447.13

An additional complication in diagnosing Fabry disease is that many patients may express only one single non-specific symptom, such as left ventricular hypertrophy or stroke, which may be attributed to late-onset Fabry disease. A systematic review of Fabry disease screening studies in high-risk populations indicated that the prevalence of variants in the GLA gene encoding alpha-galactosidase A (α-Gal A) was 0.62% (174/28,165). In this analysis, high-risk populations include patients with hypertrophic cardiomyopathies, end-stage renal disease, stroke or small fibre neuropathy.14 Consequently, screening of patients for Fabry disease in these high-risk groups could increase the number of patients identified with the disease.15,16 Moreover, in a separate analysis, screening of patients in all clinical settings relevant to the signs and symptoms of Fabry disease revealed a prevalence of GLA gene variants of 1.8% (37/2034). In addition to cardiology, nephrology and neurology, this study also included ophthalmology, dermatology, gastroenterology, internal medicine, paediatrics and medical genetics. Of the patients identified with variants in the GLA gene, Fabry disease-related organ involvement was primarily attributed to the heart, peripheral nerves and kidney.17

Cardiac involvement is common in patients with Fabry disease and is a major cause of morbidity and mortality (see signs of symptoms of Fabry disease).18-20 The leading cause of death in both males and females with Fabry disease is cardiovascular disease.21 Data from FOS, published in 2004, revealed that 69% of 201 adult males and 65% of 165 adult females with Fabry disease reported cardiac symptoms, including angina, arrhythmias and dyspnoea.18 Although less common, paediatric patients with Fabry disease may also exhibit cardiovascular signs of the disease, suggesting there may be early onset of cardiac involvement even in childhood.6,22 Moreover, the disease manifestations of Fabry disease may be limited to the heart in some patients (see late-onset Fabry disease).23 Progressive thickening of the heart walls, which may be expressed as hypertrophic cardiomyopathy, is the primary manifestation of cardiac involvement in Fabry disease. Patients with cardiac symptoms may also exhibit atrioventricular conduction disturbances, arrhythmias, valvular involvement and coronary disease.24 In many patients with Fabry disease, dyspnoea and chest pain are related to left ventricular hypertrophy.20 This clinical manifestation is an early cardiac abnormality in Fabry disease and can be observed by echocardiography.25 Left ventricular hypertrophy is typically concentric in patients with Fabry disease but can also exhibit asymmetrical shapes on an echocardiogram.24 In a screening study of 4054 males with left ventricular hypertrophy or hypertrophic cardiomyopathy, the prevalence of variants in the GLA gene related to Fabry disease was 0.94%.26

In a Portuguese study of cardiologists’ awareness of the disease, exclusion of Fabry disease in patients presenting with unexplained left ventricular hypertrophy was not considered in 71% of patients (298/420) with ‘red flags’ for Fabry disease. In this study, ‘red flags’ included27:

  • Prespecified clinical conditions: cerebrovascular disease, neurological disease or renal disease
  • Other non-specific conditions: gastrointestinal symptoms, chronic fatigue, chronic limb pain, hearing impairment, and eye or skin problems
  • Specific electrocardiogram abnormalities: short or prolonged PR interval, intraventricular conduction abnormalities or need for permanent pacemaker implantation due to bradyarrhythmias
  • A pattern of concentric left ventricular hypertrophy on echocardiogram.


Cardiologists must therefore maintain an awareness of Fabry disease. A diagnosis of Fabry disease should be considered systematically in males aged ≥30 years and females aged ≥40 years presenting with unexplained left ventricular hypertrophy. Additional ‘red flags’ of Fabry disease for cardiologists may include28:

  • Extracardiac abnormalities such as kidney dysfunction, stroke or transient ischaemic attack, angiokeratomas and corneal verticillata
  • Evidence of a short PR interval, atrioventricular block or decreased heart rate variability using an electrocardiogram or 48-hour Holter; use of a pacemaker or presence of arrhythmias
  • Using echocardiography, evidence of concentric left ventricular hypertrophy (13‒22 mm), non-obstructive hypertrophic cardiomyopathy, abnormal infero-lateral longitudinal strain, right ventricular hypertrophy or thinning of the basal infero-lateral left ventricular wall
  • Using cardiac magnetic resonance imaging (MRI), evidence of postero-lateral late gadolinium enhancement, reduction in contrast T1 signal or elevated T2
  • Decreased glomerular filtration rate (GFR) and evidence of proteinuria or high-sensitivity troponin
  • Family history of Fabry disease, cryptogenic stroke or severe kidney failure.


Cardiologists are the first-line healthcare providers to diagnose left ventricular hypertrophy, and are therefore vital in the screening and diagnosis of Fabry disease.29 Although the Portuguese study outlined above suggested the need to improve cardiologists’ awareness of Fabry disease, the rarity and lack of physician knowledge of Fabry disease can explain delays in diagnosis and misdiagnoses.3,27 Targeted information on Fabry disease among general cardiologists may improve the screening and diagnosis of the disease in patients. A study performed in France demonstrated that provision of (1) an educational booklet on Fabry disease, (2) an oral presentation of the disease delivered by a cardiologist, and (3) screening tools for biochemical and genetic analysis of Fabry disease to cardiologists led to identification of two male patients with the disease within the following 12 months. Of the 42 cardiologists who participated in the study, 93% felt that more education on Fabry disease was required during their medical training, 93% found the targeted information to be appropriate in terms of structure and content and 86% found it helpful for their daily practice. No cardiologist had screened for or diagnosed Fabry disease in the 3 years before receiving the targeted information on Fabry disease. The findings from this study suggest that providing information on Fabry disease to cardiologists is viewed as valuable and can have a direct clinical impact for patients.29

The renal manifestations of Fabry disease, such as proteinuria or a decreased GFR, occur early in the disease course and affect many patients. End-stage renal disease in patients with Fabry disease can occur due to progression of these symptoms and deterioration of renal function over time.30 Data published in 2004 of adult patients enrolled in FOS indicated that 50% of 366 patients reported renal signs and symptoms of Fabry disease. Proteinuria was the most frequently reported sign, affecting 44% of 201 male patients and 33% of 165 female patients. In patients aged >18 years, end-stage renal failure was apparent in 17% of males but only 1% of females.18 Paediatric patients with Fabry disease may also present with renal signs such as abnormally low GFR values and proteinuria.22 In some patients with late-onset Fabry disease, development of progressive chronic kidney disease occurs in early adulthood, leading to end-stage renal disease when they are aged 40‒60 years, in the absence of the early-onset symptoms associated with classical Fabry disease.31,32 In a study of 23,954 males screened at haemodialysis clinics, the prevalence of variants of the GLA gene related to Fabry disease was 0.21%. Similarly, among 2031 screened males receiving a renal transplant, the prevalence of Fabry disease-related GLA gene variants was 0.24%.26 Although cardiovascular disease has been reported as the leading cause of death in patients with Fabry disease, renal events may be the first clinical event before cardiovascular events. For example, one study indicated that 63.3% of male patients (19/30) and 40% of female patients (2/5) with Fabry disease who died due to cardiovascular disease had also experienced a renal event during their lives.21 Consequently, nephrologists play an important role in the diagnosis of Fabry disease due to the renal manifestations associated with the disease.33

Chronic kidney disease may manifest as persistent albuminuria or proteinuria or estimated GFR <90 mL/min/1.73m2. Recommendations from the European Renal Best Practice guideline body of the European Renal Association/European Dialysis and Transplant Association state the screening of Fabry disease in patients with unexplained chronic kidney disease include34:

  • Screening male patients aged <50 years, even in the absence of a family history of Fabry disease
  • Screening female patients at any age as Fabry disease onset can occur later in females compared with males
  • Patient recollection of other non-renal signs of Fabry disease, such as hypohidrosis, heat or cold intolerance, acroparaesthesia and family history
  • Clinical examination (e.g. for the presence of angiokeratomas).


It is strongly recommended that patients with an uncertain diagnosis of Fabry disease-related nephropathy (any disease of the kidneys) are assessed by a nephrologist.35,36 For patients with variants in the GLA gene presenting with chronic kidney disease and no other characteristic features of Fabry disease, a kidney biopsy may be necessary to confirm nephropathy related to Fabry disease. For these patients, ‘red flags’ for Fabry disease diagnosis include high levels of globotriaosylceramide (Gb3) and ‘Maltese cross sign’ in the urine.36 In urinalysis, ‘Maltese cross signs’ are cholesterol-rich fat droplets, which have a cruciform appearance, in the urine of patients with Fabry disease due to aggregation of glycosphingolipids.37 Using electron microscopy, a diagnosis of Fabry disease-related nephropathy can be confirmed by the presence of characteristic lysosomal inclusions specific to Fabry disease in the kidney biopsy. The lysosomal inclusions must be present in the absence of medication use that may induce similar inclusion patterns. Correct diagnosis of Fabry disease-related nephropathy enables patients to be identified and treatment initiated as appropriate (see symptomatic management of Fabry disease).36

Neurologists have an important role to play in the early diagnosis of Fabry disease and identification of organ damage.38 In 366 adult patients enrolled in FOS, data published in 2004 suggested that the most frequently reported signs and symptoms of Fabry disease were neurological, affecting 84% of 201 males and 79% of 165 females. The most common neurological symptom was acroparaesthesia, which began at a mean age of 9.4 years in males and 16.9 years in females.18 Similarly, data from 82 paediatric patients included in FOS, published in 2006, indicated that the most commonly reported early clinical manifestations of Fabry disease were neurological symptoms (acroparaesthesia, generalised pain, altered temperature sensitivity and dyshidrosis), which affected approximately 80% of children.6 The neurological signs and symptoms of Fabry disease may also include cryptogenic strokes and cerebrovascular events leading to death in male and female patients.21,39 Patients with late-onset Fabry disease may specifically exhibit a cerebrovascular variant of the disease.26,39,40 Data published in 2009 from the ongoing international, multicentre, observational Fabry Registry study (sponsored by Sanofi Genzyme) showed that 138 of 2446 patients 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 male patients versus female patients (39.0 vs 45.7 years).41 In addition, screening of male patients with primarily cryptogenic or ischaemic strokes revealed a prevalence of GLA gene variants related to Fabry disease of 0.13%.26 The median age at death due to a cerebrovascular event in male and female patients with Fabry disease has been reported as 49.3 years and 56.7 years, respectively.21 Taken together, these data suggest that neurologists can aid early diagnosis of Fabry disease and document neurological involvement associated with the disease.38

Neurologists should be aware that acroparaesthesia could be an early indicator of Fabry disease. Fabry disease may also be an underlying cause of transient ischaemic attack or stroke, and should be considered in males and females aged 40‒50 years. Neurologists should also be mindful that these patients may also present with intolerance to extreme temperatures and hypohidrosis or anhidrosis, in addition to ≥1 of the following clinical features of Fabry disease: angiokeratoma, cornea verticillata, proteinuria and acroparaesthesia.38 Fabry disease should also be considered in all patients with cryptogenic stroke aged 18‒55 years.39

In some cases, Fabry disease can be misdiagnosed as multiple sclerosis, because patients with either disease can present with pain and white matter lesions on MRI.42 In one study, 11 of 187 patients initially diagnosed with multiple sclerosis were found to have Fabry disease. Mean (standard deviation) time to diagnosis of Fabry disease occurred 8.2 (9.8) years after diagnosis of multiple sclerosis and 12.8 (10.3) years after the onset of symptoms.43 To aid neurologists’ diagnosis of Fabry disease in patients initially diagnosed with multiple sclerosis42:

  • Clinical manifestations in different organs including the kidney, heart and eye should be evaluated to support the diagnosis of Fabry disease, particularly in males.
  • Fabry disease should be considered in all cases of presumptive multiple sclerosis with atypical clinical presentation and atypical MRI findings, and in the absence of oligoclonal bands in cerebrospinal fluid.
  • A family history of Fabry disease or its clinical manifestations should be determined, as this is critical in selecting the appropriate treatment.

 

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