Fabry disease in a geriatric population

To the Editor, Fabry disease (FD, OMIM 301 500) is an X-linked lysosomal storage disorder caused by an α-galactosidase A enzyme deficiency leading to accumulation of glycosphingolipids. The classical phenotype (no residual enzymatic activity) emerges during childhood and adolescence and includes acroparesthesia, angiokeratoma, hypohidrosis, and gastrointestinal problems. In adults, disease progression results in cerebrovascular and cardiovascular manifestations, and chronic kidney disease (CKD), leading to premature death (1). A mutation-dependent atypical phenotype (low residual enzymatic activity) with a prominent cardiac involvement has also been described (2). Enzyme replacement therapy (ERT; agalsidase-alfa, Shire HGT and agalsidase-beta, Sanofi-Genzyme) is the only specific approved treatment for FD, although the use of this expensive therapy in a geriatric population (≥75 years) has not yet been evaluated. The clinical characteristics of six elderly (one male/five females) with FD are presented in Table 1. The male patient was diagnosed at the age of 73 based on left ventricular hypertrophy (LVH), and the mutation c.352C>T conferred the atypical phenotype. Because of a moderate disease severity, ERT was introduced at a low dose. Three of the five females were diagnosed after 70 years of age based on a positive familial history and a classical phenotype. Nervous system manifestations included transient ischemic attack (TIA) and/or stroke (2/5), diffuse and supra-normal white-matter lesions (2/5), and bilateral hearing loss (4/5). A moderate or severe LVH was systematically observed, associated with conduction anomalies (4/5), history of coronaropathy (2/5) and/or significant valvular anomalies (3/5). Microalbuminuria/proteinuria was detected in all females. One female was on hemodialysis and three others had CKD. Each female patient showed a severe level of involvement of the brain, heart, and/or kidney. The clinical impact of their disease was therefore as severe as that observed in younger hemizygous male patients. Males with the classical form of FD do not normally reach old age, but our male patient with the atypical form, had a moderate LVH at the age of 75 years, but normal renal function and no history of TIA/stroke. In fact, patients with the atypical form do not have glycosphingolipid deposits in their endothelial and vascular smooth muscle cells in contrast to the classical phenotype (2). The preservation of the vascular conduits in these patients may explain their better long-term prognosis. Life expectancy is reduced in FD, with a mean of 58.2 years for males and 75.4 years for females (1). Recent studies using long-term ERT in male adults affected with the classical form showed that once cardiovascular remodeling is well established, ERT did not prevent disease progression i.e. a decline in renal function, increase in cardiac mass and/or fibrosis, sudden death, and new TIA/strokes (3, 4). However, the risk of developing a first or second renal, cardiac or cerebral complication declined with increasing treatment duration (3). In long-term treated females, renal function was usually normal and cardiac mass remained stable or even decreased slightly, but ERT did not prevent new TIA/stroke occurrence (3, 4). Two of three of our untreated females, with a severe LVH, died of sudden death at the age of 77 and 87 years, respectively, i.e. within a normal life expectancy range. The two treated women, with comparable disease severity, received ERT at the age of 65 and 73 years, respectively. However, the effectiveness of ERT in severe FD is considered to be limited (3, 4), particularly in patients with CKD (5). The use of ERT in newly diagnosed elderly males with a moderate atypical form of FD is also questionable. Before considering ERT treatment in geriatric patients with FD, nephroprotection strategies and the prevention of severe arrhythmia with pace-makers or defibrillators should also be considered. Addressing quality of life, care of co-morbidities, as well as these alternative interventions is crucial in patients where ERT treatment is not recommended. The introduction of ERT in geriatric patients (≥75 years) with classical and atypical forms of FD appears to be of poor benefit in terms of life expectancy and cost effectiveness. This strengthens the importance of early diagnosis for more effective therapy.