Genotype–phenotype correlation and course of transthyretin familial amyloid polyneuropathies in France

Abstract

ObjectiveTo compare the natural history of familial transthyretin amyloid polyneuropathies (FAP) due to the Val30Met, Ser77Tyr, and Ile107Val mutations in France with the classical Portuguese Val30Met FAP.MethodsWe compared 84 French patients with a control group of 110 Portuguese patients carrying the Val30Met mutation also living in France, all referred to and followed at the French National FAP Reference Center from 1988 to 2010. Clinical examination, functional and walking disability scores, nerve conduction studies, and muscle biopsies are reported. We also conducted a comprehensive literature review to further determine the range of phenotypic expression.ResultsBy comparison with Portuguese Val30Met FAP, French Ile107Val, Ser77Tyr, and LateVal30Met FAP showed more rapid and severe disease progression; onset of gait disorders was 3 times more rapid (p < 0.0001) and the rate of modified Norris test decline was up to 40 times faster in Ile107Val patients (p < 0.0001). Median survival was much shorter in Ile107Val and in Val30Met mutation with late onset (>50 years; LateMet30) FAP (p = 0.0005). Other distinctive features relative to the Portuguese patients included atypical clinical presentations, demyelination on nerve conduction studies (p = 0.0005), and difficult identification of amyloid deposits in nerve and muscle biopsies.InterpretationIle107Val and LateMet30 mutations are associated with the most debilitating and severe FAP ever described, with rapid onset of tetraparesis and shorter median survival. It could be explained by frequent large‐fiber involvement and associated demyelination and more severe axonal loss. These findings have major implications for genetic counseling and patient management as new therapeutic options are being assessed in clinical trials (TTR gene silencing). Ann Neurol 2015;78:901–916

Hereditary and inflammatory neuropathies: a review of reported associations, mimics and misdiagnoses

“…More recently, Mariani et al ,67 in a large genotype-phenotype correlation study, demonstrated predominant early large fibre involvement in non-Met30 cases with frequent electrophysiological demyelination and raised CSF protein. The European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) clinical and electrodiagnostic criteria for CIDP68 were met in no less than 40% of Val107 cases and 24% in late Met30 cases and histopathological signs of segmental demyelination/remyelination found in nearly a third.…”

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].…”

Transthyretin amyloid neuropathy has earlier neural involvement but better prognosis than primary amyloid counterpart: an answer to the paradox?

“…As has been reported in past retrospective studies, we found the prevailing pattern of neuropathic involvement to be similar for AL and TTR amyloid - most commonly distal, symmetric, sensory predominant neuropathy with paresthesias and/or numbness and autonomic involvement, followed by progression and development of motor neuronal and systemic non-neuronal involvement. 5, 12, 15, 21, 45–47 However, through evaluating chronologic time of onset of clinical features, we find that pan-neuronal involvement occurs earlier and more often in TTR cases than in AL cases, in particular motor nerve involvement. Conversely, non-neuronal organ involvement in the first year after onset was more often seen in AL cases than TTR cases.…”