Importance of cardiology in the diagnosis of Fabry's disease

Introduction: Rare diseases are often diagnosed and treated with delay. In case of Fabry's disease (FD), a X-linked lysosomal storage disorder, the difficulty in correctly diagnosing the disease is implemented in a huge variety of symptoms caused by different genetic variants and individual manifestations. As patients sometimes have to wait suffering for years for the correct diagnosis, we sought to analyze the inidividual “way to diagnosis“  focusing on leading symtoms, medical disciplines and exploring where is need for further education.

Methods: A total of 403 patients with a confirmed genetic diagnosis of FD were screened. Altogether, 46 patients were excluded because of benigne genetic variants so that 357 patients were ultimately analyzed. Clinical data was obtained by reviewing medical record information and human genetic consultations. Main focus lay on family pedigrees and organ manifestation at the time of genetic diagnosis. Patients were assigned to one of ten diagnosis groups: ophthalmology, dermatology, cardiology, nephrology, neurology, paediatrics, rheumatology, general practice, family screening and self-diagnosis. In case of family screening, the medical discipline of the index patient was noted.

Results: The majority of patients were diagnosed via family screening (211/357, 59.1%). The most common medical discipline to initiate genetic testing was cardiology (42/357, 11.8%) with the leading symptoms hypertrophic cardiomyopathy (90.5%), late-gadolinium enhancement in a cardiac MRI (4.8%) and suspected NSTEMI (4.8%). The following disciplines to diagnose FD were nephrology ((29/357, 8.1%) due to chronic kidney disease (55.2%)) and neurology ((26/357, 7.3%) due to cerebral ischemia (50.0%)). In a subgroup analysis, it could be shown that 50.6% of patients with at least two vital organ manifestations (cardiac and/or renal and/or neurological) at time of diagnosis were identified via family screening. A closer look at the "index patients" revealed that cardiology in particular was the discipline to which most family screening patients were assigned (67/211, 31.8%).

Regarding gender differences, male patients with FD were significantly more likely to be diagnosed via cardiology (p<0.001), nephrology (p<0.001) and dermatology (p=0.001); female patients in particular via  family screening (p<0.001).

Over the last decades, there has been a shift in diagnostic processes depending on medical discipline, primarily from nephrology (until year 2005: n=9; years 2016-2020: n=4) and ophthalmology (until year 2005: n=13; years 2016-2020: n=4) to cardiology (until year 2005: n=1; years 2016-2020: n=13).

Conclusion: The ways in which Fabry's disease is diagnosed are multifaceted. The leading symptoms initiating genetic testing usually indicate advanced organ manifestations (left ventricular hypertrophy, chronic kidney disease, cerebral ischemia etc.), whereat cardiology plays a central role in diagnostic processes. Additionally, during the last decades a shift within the specialist disciplines in favour of cardiology could be detected showing that a growing number of suspected cardiac patients are tested for FD. This reflects not only a rising awareness among cardiologists for rare differential diagnoses but also the success of sharing profound knowledge and research. Simultaneously, the need for further education concerning rare diseases – also with regard to the next generations of physicians – is still evident.