Objectives: To assess the association between severity of neuropathy and disease stage, and estimate the rate of neuropathy progression in a retrospective cross-sectional analysis of a multinational population of patients with familial amyloidotic polyneuropathy (FAP).
Methods:We characterize neuropathy severity and rate of progression in available patients with FAP in France, the United States, Portugal, and Italy. Neuropathy Impairment Scores (NIS), time from symptom onset to NIS measurement, polyneuropathy disability (PND) scores, FAP disease stage, and manual grip strength data were collected. We estimated neuropathy progression using Loess Fit and Gompertz Fit models.Results: For the 283 patients studied (mean age, 56.4 years), intercountry genotypic variation in the transthyretin (TTR) mutation was observed, with the majority of patients in Portugal (92%) having early-onset Val30Met-FAP. There was also marked intercountry variation in PND score, FAP stage, and TTR stabilizer use. NIS was associated with PND score (NIS 10 and 99 for scores I and IV, respectively; p , 0.0001) and FAP stage (NIS 14 and 99 for stages 1 and 3, respectively; p , 0.0001). In addition, there was an association between NIS and TTR genotype. The estimated rate of NIS progression for a population with a median NIS of 32 was 14.3 points/year; the corresponding estimated rate for the modified NIS17 is 17.8 points/year.
Conclusions:In a multinational population of patients with FAP, rapid neuropathic progression is observed and the severity of neuropathy is associated with functional scales of locomotion. Familial amyloidotic polyneuropathy (FAP) is a progressive, fatal condition, with survival after diagnosis of 5 to 15 years.1 This rare, hereditary, autosomal dominant form of amyloidosis is caused by transthyretin (TTR) gene mutations, 2-4 which can result in misfolding and aggregation of the TTR protein and formation of insoluble amyloid fibrils.5 Tissue deposition of mutant and wild-type TTR fibrils results in intractable peripheral sensorimotor neuropathy, autonomic neuropathy, and/or cardiomyopathy. [6][7][8][9] Clinical manifestations of FAP are influenced by a patient's TTR genotype and geographic location.10 Val30Met (V30M) is the most common gene mutation in FAP, with the largest patient cluster reported in Portugal.10,11 Symptoms at presentation and clinical progression in patients with V30M-FAP differ among countries. Early-onset FAP is common in Portugal, 12 while late-onset cases of FAP are predominant in the United States and in France, with variation reported in the clinical presentation of neurologic phenotypes.
13In FAP clinical trials, change in neurologic function over time has been assessed using the Neuropathy Impairment Score (NIS), the NIS-lower limb, and the NIS plus 7 (NIS17) [14][15][16][17] From the National
