Diagnosing Fabry disease—delays and difficulties within discordant siblings

Extract

Introduction

Fabry disease, or Anderson-Fabry disease, was first described in 1898 by two separate physicians, William Anderson (London) and Johannes Fabry (Germany).^1,2 They independently described patients with ‘angiokeratoma corporis diffusum’, the now well-recognized characteristic dermatological manifestations of this condition. It is perhaps more commonly known as Fabry disease since Johannes Fabry suggested a systemic disorder was responsible. We now know that Fabry disease is a multi-system progressive X-linked lysosomal storage disorder due to alpha-galactosidase deficiency, which can present in numerous ways to different clinicians.^3,4 As a result the diagnosis is often delayed for many years or even decades.⁵

Fabry disease is often only clinically recognized in the classical form of the disorder, associated with undetectable alpha-galactosidase activity, resulting in impaired degradation of neutral glycosphingolipids, particularly globotriaosylceramide (GL-3).³ Progressive accumulation of these substances in various tissues and body fluids produces end organ damage, which subsequently leads to presentations that include severe debilitating chronic acroparasthesias, episodes of excruciating or lightening pain, hypohidrosis, chest or abdominal pain, diarrhoea, rashes (isolated or diffuse) and so on. Many other presentations are possible and diagnosis is eventually made by specialist referral for neurological, dermatological, ophthalmological, gastrointestinal, renal (e.g. proteinuria, unexplained renal impairment), cardiac [e.g. unexplained left ventricular hypertrophy (LVH), cardiomyopathy] or cerebrovascular (e.g. early stroke without obvious risk factors), signs or symptoms, in combination or isolation, from the first decade of life onwards.³