Pedigree analysis in patients with Fabry disease: Evaluating changes in referral and diagnosis over successive generations

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CO RR EC TE D P RO OF 1.5%; all events were non-serious, mild, and did not result in dose reduction or discontinuation. Three were considered possibly related to eliglustat by the treating physician. Combined incidence of PN (n = 8) and polyneuropathy (n = 1) was 2.3%. No event was serious; most (7/9) were assessed as unrelated to eliglustat. All events of tremor and PN occurred only once in each patient; none resulted in eliglustat discontinuation or dose decrease. Six PN events occurred within 18 months of eliglustat initiation. Excluding the underlying Gaucher disease (itself a known cause of PN), review of the medical history showed that the vast majority of patients had additional risk factors for developing neurological symptoms or medical conditions associated with neuropathy including: hypothyroidism, Hashimoto's thyroiditis, diabetes mellitus, vitamin B12 deficiency, and monoclonal gammopathy. Most patients with PN had normal neurologic exams, non-progression of symptoms despite continuation of drug, anatomic locations inconsistent with druginduced neuropathy, and lack of supportive NCV findings. In the four patients reporting adverse events of PN in the ENCORE trial, three had NCV results available at baseline and 12 months; none had changes from baseline or findings of clinical significance on neurologic exams supporting a causal role of eliglustat. Notably, the patient who experienced both PN and paraesthesia had decompensated diabetes, hypothyroidism, and a history of paraesthesia. Evidence from the eliglustat safety database supports the claim that eliglustat does not promote tremor (1 event/100 person-years) or PN. The rate of PN adverse events noted after eliglustat treatment (2 events/100 person-years) is well within the rate of neuropathy that might be expected to develop spontaneously in the GD1 population (2.9 events/100 person-years); both rates are higher than that of the general population (between 0.0046 and 0.015/100 person-years) recently reported by Biegstraaten et al. (Brain 2010:133;2909).