Guillemette Beaudonnet

TTR kinetic stabilizers and TTR gene silencing: a new era in therapy for familial amyloidotic polyneuropathies

ABSTRACT Introduction: Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP) is a rare disease with autosomal dominant transmission due to a point mutation of the TTR gene. By removing the main source of systemic mutant TTR, liver transplantation (LT) has become the reference therapy of this severe and fatal polyneuropathy of adult-onset, stopping disease progression in subgroup of patients. Recently, new therapeutic strategies have emerged, which intend to stabilize TTR or to silence the TTR gene. Amongst them, the TTR kinetic stabilizer tafamidis is the first drug approved in the EU. Areas covered: We shall review the natural history of TTR-FAP and the best indications for LT. Data on the efficacy, safety and tolerability of the TTR kinetic stabilizers, tafamidis and diflunisal, have been reviewed, from the pivotal Phase III clinical trials published in PubMed medical journals or presented at international meetings. We will review the ongoing phase III clinical trials of TTR gene silencing with RNAi therapeutics and ASO published in clinicaltrialgov. Expert opinion: Due to the data on efficacy, tolerability, safety, tafamidis and diflunisal became the first line anti-amyloid treatment in stage 1 TTR-FAP. Both drugs slow progression of the disease. Only tafamidis got marketing authorization. We are waiting for results of the 2 phase III clinical trials of TTR gene silencing in varied stages of the disease.

Transthyretin amyloid polyneuropathies mimicking a demyelinating polyneuropathy

Objective To clearly define transthyretin familial amyloid polyneuropathies (TTR-FAPs) fulfilling definite clinical and electrophysiologic European Federation of Neurological Societies/Peripheral Nerve Society criteria for chronic inflammatory demyelinating polyneuropathy (CIDP). Methods From a cohort of 194 patients with FAP, 13 of 84 patients (15%) of French ancestry had late-onset demyelinating TTR-FAP. We compared clinical presentation and electrophysiology to a cohort with CIDP and POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndrome. We assessed nerve histology and the correlation between motor/sensory amplitudes/velocities. Predictors of demyelinating TTR-FAP were identified from clinical and electrophysiologic data. Results Pain, dysautonomia, small fiber sensory loss above the wrists, upper limb weakness, and absence of ataxia were predictors of demyelinating TTR-FAP (p < 0.01). The most frequent demyelinating features were prolonged distal motor latency of the median nerve and reduced sensory conduction velocity of the median and ulnar nerves. Motor axonal loss was severe and frequent in the median, ulnar, and tibial nerves (p < 0.05) in demyelinating FAP. Ulnar nerve motor amplitude <5.4 mV and sural nerve amplitude <3.95 μV were distinguishing characteristics of demyelinating TTR-FAP. Nerve biopsy showed severe axonal loss and occasional segmental demyelination-remyelination. Conclusion Misleading features of TTR-FAP fulfilling criteria for CIDP are not uncommon in sporadic late-onset TTR-FAP, which highlights the limits of European Federation of Neurological Societies/Peripheral Nerve Society criteria. Specific clinical aspects and marked electrophysiologic axonal loss are red flag symptoms that should alert to this diagnosis and prompt TTR gene sequencing.

Management of stage 1 TTR FAP: French experience

Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP) is a worldwide autosomal dominant disease due to point mutation of TTR gene. The main endemic area is Portugal, associated with V30M variant and an early onset (EO) (mean age 30 yo). Phenotype is a progressive length dependent small fiber polyneuropathy with autonomic dysfunction and cardiac conduction disorders; the median survival is 12 years. France is a prototypic non endemic country, characterized by sporadic cases in 50%, a late onset (LO>50 yo) in 75%, a genetic heterogeneity (41 variants ; V30M in 55%). Liver transplantation (LT) is the gold standard treatment allows to stop progression of the neuropathy in EO V30M patients and to prolonge significantly the survival. Tafamidis, a TTR kinetic stabilizer, received marketing authorization in Europe for stage 1 FAP (walking unaided) allowing to slow progression of the neuropathy. Aims of the study was to assess the place of tafamidis in the management of TTR-FAP.

Teachings from the French database of TTR familial amyloidotic polyneuropathy (TTR-FAP): large genetic and phenotypic heterogeneity, usefulness of TTR gene testing.

TTR-FAP is progressive, disabling, irreversible and life-threatening neuropathy due to a point mutation of TTR gene with autosomal dominant transmission. France is a non endemic European country. To study the impact of labeling French reference center for FAP (NNERF) and building of a national network CORNAMYL.