Enzyme replacement therapy for Fabry disease: proving the clinical benefit.

Fabry disease is an X-linked lysosomal storage disorder that results from a deficiency of the enzyme a-galactosidase A (a-Gal A). The lack of a-Gal A leads to incomplete metabolism and progressive lysosomal accumulation of glycosphingolipids, particularly globotriaosylceramide (GL3). This process causes damage to endothelial, perithelial and smooth-muscle cells of the vascular system, glomerular and tubular cells of the kidney, myocardial cells and valvular fibrocytes, epithelial cells of the cornea and ganglion cells of the dorsal root and autonomic nervous system, as well as cortical and brain-stem structures [1]. Therefore, the disease presents as a multi-system disorder, clinical features being typical but highly variable in affected individuals. One of the earliest and most debilitating symptoms is the onset of acroparaesthesias in childhood. Other common manifestations are lenticular and corneal opacities, angiokeratomas, hypohidrosis, oedema and abdominal pain. During the third and fourth decade of life, the disease is characterized by a progressive course and severe morbidity due to cardiac, renal and cerebrovascular involvement [1,2]. One of the most severely affected organs in Fabry disease is the kidney. Renal involvement can be detected in early adulthood as mild to heavy proteinuria and microhaematuria. The majority of patients show progressive renal failure and eventually develop end-stage renal disease (ESRD) [3]. The leading cardiac manifestation in Fabry disease is concentric left ventricular hypertrophy (LVH) [4,5]. Some studies report constrictive cardiomyopathy [6] and congestive heart failure [7,8] as well as disturbances in the conduction system with reduced PR interval [9]. Late cardiac manifestations are hypertrophic cardiomyopathy [10], myocardial ischaemia, heart failure and ventricular arrhythmias associated with sudden cardiac death [11]. The average age of onset of cerebrovascular symptoms in hemizygous individuals is 33 years. It includes hemiparesis, vertigoudizziness, diplopia, dysarthria, nauseauvomiting, headache and hemiataxia [12]. There is an elevated risk for transient ischaemic attacks, premature stroke and dementia [13].