Difficulties and barriers in diagnosing Fabry disease: what can be learnt from the literature?

Fabry disease (FD) is an X-linked disorder of glycosphingolipid metabolism caused by deficiency of the lysosomal enzyme alpha galactosidase A. Clinical features include neuropathic pain, rash, proteinuria renal failure, stroke and cardiomyopathy accompanied by a reduced life expectancy. Patients report an average delay of > 10 years between symptom onset and diagnosis. Newborn screening studies suggest a much higher prevalence than that found on population studies supporting the notion that FD is under-diagnosed.

Four key challenges in the diagnosis of FD and strategies to overcome them are discussed. The clinical features of FD are highly heterogeneous resulting in patients presenting to many different specialists, often with non-specific symptoms with a wide differential diagnosis. The pathophysiological mechanisms underlying this are poorly understood and the prediction of pathogenicity on the basis of gene mutation analysis can be problematic. While the availability of treatment adds an impetus to make the correct diagnosis, our understanding of when and if treatment may be required in a specific individual is incomplete.

Improving diagnostic rates of FD requires a greater awareness of the disorder among physicians to whom patients may present, new strategies to determine the pathogenicity of novel mutations and a greater understanding of the natural history of FD across the phenotypic spectrum. Collaborative clinical and laboratory research is vital in furthering knowledge of the underlying mechanisms of this disorder and how they may be impacted by current or future therapies.