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Genetic Disorders Early Detection of Fabry Disease – The Important Role of Ophthalmology Colin Willoughby Professor of Molecular Ophthalmology, Department of Eye and Vision Science, Institute of Ageing and Chronic Disease, Faculty of Health & Life Sciences, University of Liverpool, UK Abstract The diagnosis of Fabry disease (FD; MIM #301500), a rare genetic disorder, is often missed or delayed as the systemic symptoms of FD show similarities to several other common medical conditions. Delayed diagnosis has significant clinical implications for the patient as FD can result in end-stage renal disease and life-threatening cardiovascular or cerebrovascular complications. Early diagnosis is preferable in achieving the best clinical outcomes for patients. FD demonstrates several classic ocular features, which are asymptomatic and observable through a routine eye examination. These features usually present early in the course of the disease and the identification of the ocular signs of FD offer a vital opportunity to diagnose FD, maximising the chance to improve patient outcomes. Keywords Fabry disease, cornea verticillata, lens opacities, vascular tortuosity, genetics Disclosure: Colin Willoughby has no conflicts of interest to declare. Received: 22 September 2014 Accepted: 30 October 2014 Citation: European Ophthalmic Review, 2014;8(2):127–31 Correspondence: Colin Willoughby, Professor of Molecular Ophthalmology, Department of Eye and Vision Science, Institute of Ageing and Chronic Disease, Faculty of Health & Life Sciences, University of Liverpool, Liverpool, L69 3GA, UK. E: C.Willoughby@liverpool.ac.uk. Support: Shire commissioned the writing of this article and paid the agency and journal a publication fee. No fee has been paid to Professor Willoughby. Fabry disease (FD) is a rare, X-linked, lysosomal storage disorder with a reported incidence of 1:117,000 live births. 1 However, due to the pan-ethnic nature of FD, reported incidence rates of 1:117,000 may underestimate the true prevalence of the disease, which have been recorded as high as 1:3,100 live births. 2,3 FD is caused by mutations in the gene encoding the enzyme alpha- galactosidase A (α-Gal A), resulting in an absence or deficiency of this lysosomal enzyme. Complete or partial enzymatic insufficiency of α-Gal  A leads to the accumulation of the plasma membrane component glycosphingolipids, predominantly globotriaosylceramide (Gb3; also known as ceramidetrihexoside [CTH]). 2 Gb3 accumulates in the lysosomes of multiple cell types including the endothelial and smooth muscle cells of the vascular system, as well as renal, cardiac and nerve cells. FD is therefore a multisystem disease affecting the brain, heart, eyes, kidneys and other organs, which can result in end-stage renal disease and life-threatening cardiovascular or cerebrovascular complications. 4,5 The phenotype in affected males reflects the level of α-Gal A activity. 6 Classic FD is a term reserved for males having absolutely no α-Gal  A activity. Individuals with this phenotype will develop the full complement of clinical signs and symptoms with onset usually in childhood. Males with atypical manifestations of FD have partial α-Gal A activity. These patients may experience symptoms in childhood, but they do not manifest the full clinical spectrum of classic FD. Typically these patients develop late- onset cardiac and renal abnormalities, which are non-specific and are often indistinguishable from those occurring in the general population. These adult-onset cardiac and renal variants seem to be much more prevalent than the classic phenotype and may explain many cases of © To u ch MEd ica l MEdia 201 4 midlife-cardiac and renal disease. Female carriers of FD can manifest clinical features depending on the level of X-inactivation or Lyonisation and can be considered affected clinically with variable penetrance. 7 Data from disease registries demonstrate that, in fact, female FD gene carriers have a significant risk for major organ involvement and should be regularly monitored for signs and symptoms of FD. Ophthalmological Opportunities for Diagnosis The diagnosis of FD is often missed or delayed as FD shows similarities to several other common medical conditions, 8,9 in particular those patients with ‘cardiac’ and ‘renal’ variants, and the symptoms are non-specific. A delay in diagnosis has significant implications for the patient as early diagnosis is vitally important for achieving best outcomes for patients. 10 Detecting the ocular features of FD, which are asymptomatic, offers a vital opportunity to diagnose FD at any early stage and can be detected by a routine eye examination. 11 Much of the pain, suffering and adverse impact of FD can be avoided if an alert eye care professional sees the patient at an early age, identifies the condition and makes the appropriate referral. 12,13 There are several distinctive and unusual ophthalmic manifestations of FD, which appear early in the disease’s course. 14 These ocular signs can be detected by examination procedures that are non‐invasive, inexpensive and non-time-consuming. However, as eyesight does not tend to be impaired by FD, 15 diagnosis is almost always opportunistic, e.g. during a routine eye check by an optometrist or ophthalmologist. Ocular Manifestations of Fabry Disease Corneal Verticillata The accumulation of Gb3 in the cornea causes a typical but not pathognomonic FD lesion called cornea verticillata, which is considered 127