Tafamidis in transthyretin amyloid cardiomyopathy

Transthyretin is primarily synthesized in the liver and transports thyroxine and vitamin A in the body. The transthyretin when dissociated into monomers can misfold and ultimately form amyloid fibrils. There are two types of ATTR amyloidosis: hereditary (caused by mutations in the TTR gene) and wild-type (also referred to as senile systemic amyloidosis). Amyloid cardiomyopathy can develop in patients with both types of ATTR amyloidosis, has a later onset and is characterized by progressive heart failure leading to death within a few years after diagnosis. Tafamidis is an oral-administered small molecule that binds to transthyretin and inhibits transthyretin tetramer dissociation, the rate-limiting step in the amyloidosis. Long-term efficacy and safety of tafamidis were shown in patients with transthyretin familial amyloid polyneuropathy. The objective of the phase 3 international, multicenter, double-blind, placebo-controlled, randomized ATTR-ACT study was to evaluate the efficacy, safety, and tolerability of tafamidis (20 or 80 mg orally QD) in comparison with placebo in 441 patients with hereditary and nonhereditary transthyretin cardiomyopathy (median age 75 years, 90% of males). At month 30, treatment with tafamidis was associated with a lower risk of all-cause mortality (by 30%) and a lower rate of cardiovascular related hospitalizations (by 32%) than placebo and resulted in a lower rate of decline in distance for the 6-minute walk test and a lower rate of decline in KCCQ-OS score. The data from extension study supports tafamidis 80 mg as the optimal dose (bioequivalent to tafamidis free acid 61 mg).

Nerve Ultrasound Comparison Between Transthyretin Familial Amyloid Polyneuropathy and Chronic Inflammatory Demyelinating Polyneuropathy

Backgrounds: Transthyretin familial amyloid polyneuropathy (TTR-FAP) is frequently misdiagnosed as chronic inflammatory demyelinating polyneuropathy (CIDP) because of similar phenotypes in the two diseases. This study was intended to identify the role of nerve ultrasonography in evaluating TTR-FAP and CIDP.Methods: Eighteen patients with TTR-FAP, 13 patients with CIDP, and 14 healthy controls (HC) were enrolled in this study. Consecutive ultrasonography scanning was performed in six pairs of nerves of bilateral limbs with 30 sites. The cross-sectional areas (CSAs) and CSA variability data of different groups were calculated and compared.Results: Both TTR-FAP and CIDP showed larger CSAs at most sites of both upper and lower limbs than in HC groups. CIDP patients had larger CSAs than TTR-FAP patients at 8/15 of these sites, especially at U1-3, Sci2 sites (p < 0.01). However, the CSAs at above sites were not a credible index to differentiate TTR-FAP from CIDP with a low area under the curve (<0.8). The CSA variability of median nerves was significantly higher in CIDP than in TTR-FAP and HC groups, with high sensitivity (0.692) and specificity (0.833) to differentiate CIDP from TTR-FAP. The CSA variability of ulnar nerves was not significantly different between the three groups. For the TTR-FAP group, mean CSAs at each site were not correlated with different Coutinho stages, modified polyneuropathy disability, course of sensory motor peripheral neuropathy, Neuropathy Impairment Score, or Norfolk Quality of life-diabetic neuropathy score. The mean compound muscle action potential of ulnar nerves was negatively correlated with the mean CSAs of ulnar nerves.Interpretation: TTR-FAP patients had milder nerve enlargement with less variability in CSAs of median nerves than those with CIDP, suggesting that nerve ultrasound can be a potential useful auxiliary tool to help differentiate the two neuropathies.

Poor Yield of Routine Transthyretin Screening in Patients with Idiopathic Neuropathy

ABSTRACT:Background and objectives:Transthyretin familial amyloid polyneuropathy (TTR-FAP) is caused by a mutation in the transthyretin (TTR) gene. Although classically described as rapidly progressive and life-threatening, recent studies on TTR-FAP show significant genetic and phenotypic heterogeneity depending on geographic localization. In light of new therapeutic advances and their implication for patient management, the aim of our study was to determine the prevalence of TTR-FAP within patients with idiopathic neuropathy in a North American population.Methods:We sequenced the TTR gene in a cohort of patients with idiopathic neuropathy. Genetic screening was performed in 110 patients from two neuromuscular clinics in Montreal, Canada.Results:No variants of unknown significance or pathogenic mutations were detected in the TTR gene.Conclusion:Our study confirms that TTR-FAP is a rare entity in our patient population, and that diagnostic yield of screening all patients with idiopathic neuropathy is very low.