Rapid progression of familial amyloidotic polyneuropathy

Abstract

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

Long-term safety and efficacy of tafamidis for the treatment of hereditary transthyretin amyloid polyneuropathy: results up to 6 years

“…Presenting symptoms and disease course of ATTR-FAP are influenced by the underlying TTR mutation and by geographic location [3][4][5]. The most common and widely studied TTR mutation worldwide is ATTRV30M (p.TTRV50M) [1,6]; non-ATTRV30M mutations are increasingly reported and often associated with a higher incidence of mixed phenotypes (neuropathy, cardiomyopathy and leptomeningeal complications) and with a more rapid and severe disease course [5].…”

Cutaneous nerve biomarkers in transthyretin familial amyloid polyneuropathy

“…1 TTR is a 55kD protein that transports thyroxine and retinol-binding protein in the blood and cerebrospinal fluid (CSF) and normally exists as a tetramer. 5 Classical symptoms of TTR-FAP occur symmetrically in the distal lower extremities with tingling and prickly burning sensations of pain, suggesting early injury of small nerve fibers. [2][3][4] TTR-FAP is a progressive, disabling neuropathy affecting the autonomic, sensory, and motor components of the peripheral nerve system.…”

Assessing mNIS+7Ionis and international neurologists' proficiency in a familial amyloidotic polyneuropathy trial

“…In a recently published multinational study, rapid progression of FAP was demonstrated using the Neuropathy Impairment Score (NIS), and its severity was correlated with functional scales of locomotion …”