In many patients, the diagnosis of Fabry disease is established rather late in the course of the disorder. Screening of newborns or case-finding studies among high-risk patient groups could, however, improve the clinical care of families with a hitherto unknown inherited trait. Hence, it is essential that awareness of this disease in the general population and among physicians is improved, so that early diagnosis and treatment can be achieved.

Introduction

The timely diagnosis of Fabry disease is difficult [1]. Early symptoms in childhood include acroparaesthesia and pain, which can be triggered by heat and fever, but these symptoms are often misinterpreted and only occasionally lead to the correct diagnosis [2]. The median age at diagnosis of Fabry disease was 28.6 years in a recent study from Australia [3]. Similarly, the median age at diagnosis was about 28 years among 688 patients recorded in FOS – the Fabry Outcome Survey – although the first symptoms occurred some 16 years earlier (Table 1).

Table 1

Onset of symptoms and age at diagnosis of female and male patients with Fabry disease.

Many patients with Fabry disease therefore have a long history of consultations with several different medical specialists and are often given the wrong diagnosis. Figure 1 shows the frequency of the most common erroneous diagnoses in patients included in the FOS database.

Figure 1

Frequency of erroneous diagnoses in patients with Fabry disease enrolled in FOS – the Fabry Outcome Survey.

Who makes the diagnosis?

For patients enrolled in FOS, the medical specialists who most often establish the diagnosis of Fabry disease are nephrologists, followed by geneticists, although many other specialists may be involved (Figure 2). The potential for bias in these data, however, should be acknowledged. For example, the number of cases diagnosed by paediatricians may be high in those large centres that also diagnose and treat adult patients. Also, diagnoses by nephrologists may be indirect, with renal biopsies resulting in a correct diagnosis in patients where the disease was not initially suspected. Furthermore, geneticists may confirm the diagnosis of Fabry disease, although they are often not the first to suspect the disease.

Figure 2

Among patients enrolled in FOS – the Fabry Outcome Survey – relatives, nephrologists and geneticists suspect and diagnose Fabry disease most frequently.

Once an index patient has been identified, family members often play a major role in suspecting and diagnosing Fabry disease among relatives (Figure 2). The clinician has an important role in performing a pedigree analysis and in offering non-directive genetic counselling, proper diagnosis and adequate therapy for affected relatives (see Chapter 35).

Screening and case-finding

In general, screening involves conducting tests in apparently healthy populations to identify individuals at increased risk of a disease or disorder. Those identified may be offered a subsequent diagnostic test or procedure and/or, where available, a treatment or preventive medication.

Looking for additional illnesses in those with medical problems is termed case-finding [4].

Case-finding studies

Fabry disease can affect a wide range of organs. Medical specialists caring for patients suffering from renal disease, heart disease or stroke, for example, are likely to encounter individuals with undiagnosed Fabry disease. Making a correct diagnosis in these cases has the potential to improve medical care in the affected individual, as well as perhaps leading to identification of the disease in relatives.

Importantly, case-finding studies in dialysis patients have revealed a more than tenfold higher prevalence of Fabry disease among those with end-stage renal disease, compared with historical data obtained from large renal registries in the USA [20] and Europe [21]. The prevalence of Fabry disease among male or female patients suffering from end-stage renal disease is shown in Table 2.

Table 2

Prevalence of Fabry disease among dialysis patients.

Similarly, cardiologists have shown a high prevalence of Fabry disease among patients with left ventricular hypertrophy or hypertrophic cardiomyopathy (Table 3).

Table 3

Prevalence of Fabry disease among patients with hypertrophic cardiomyopathy or left ventricular hypertrophy.

Among 721 young adults, aged 18–55 years, who presented with cryptogenic stroke, 21 out of 432 (4.9%) male patients, and 7 out of 289 (2.4%) female patients had Fabry disease, confirmed by mutational analysis of the α-galactosidase A gene [33]. By definition, this study excluded patients without typical risk factors for stroke, such as relevant nicotine abuse, significant carotid stenosis, severe obesity, cardiac emboli, patent foramen ovale, and coagulopathies, and also excluded those in whom there was no diagnosis made with regard to the aetiology of the stroke. Thus, based on an assumption that about 27% of juvenile strokes are of unknown aetiology, the authors estimated a prevalence of 1.2% for Fabry disease among all young patients with stroke.

Other patient populations that might harbour individuals with unknown Fabry disease include those who have multiple sclerosis or who present with chronic pain, rheumatic diseases or fever of unknown origin.

Conclusions

Diagnosis of Fabry disease is often delayed due to the rarity and variable nature of the disorder. This variability is reflected in the wide range of specialist physicians who diagnose the condition. Screening programmes and case-finding efforts may allow earlier diagnosis and hence earlier provision of effective enzyme replacement therapy.

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