Large International, Multicenter Studies are Needed to Determine the Prevalence of ATTRv Associated Polyneuropathy in Adults

With interest we read the article by Fisher et al. on a study on the prevalence of hereditary amyloid transthyretin variant (ATTRv) amyloidosis in an idiopathic polyneuropathy population by using genetic analysis by means of a panel test including 81 genes associated with neuromuscular disorders or by targeted gene sequencing of the TTR gene [1] .It was found that 38% of patients had at least one variant in 38 genes [1] .Four individuals were identified as having a single pathogenic alteration each in the NTRK1 gene (congenital insensitivity to pain with anhidrosis, the LRSAM1 gene (Charcot-Marie-Tooth disease type IIP, the SLC52A2 gene (Brown-Vialetto-Van Laere syndrome type II), and the IKBKAP gene (hereditary sensory and autonomic neuropathy type III).One patient had a variant of uncertain significance (VUS) (p.G103D) in TTR [1] .The study is impressive, but several points need to be discussed.Firstly, the success rate of genetic testing heavily depends on the molecular technique applied, whether the technique also identifies exonic or intronic repeat disorders, splice site variants, intronic point mutations, and mtDNA rearrangements.The success rate also depends on whether panel testing, whole exome sequencing, or while genome sequencing is applied.Since hereditary neuropathies are due to mutations in >100 genes [2] , the approach of the index study might have missed a number of causalities.Secondly, the number of genes tested via the panel approach.We should know why specifically 81 were chosen to be tested.Was no more comprehensive panel test available?Were the 81 genes regarded the most prevalent found in the included 134 patients?Thirdly, 2.2% of the 134 patients had a family history positive for ATTRv [1] .Surprisingly, in none of the included patients was a pathogenic variant in the TTR gene detected by panel testing or targeted TTR testing [1] .Since ATTRv is inherited via an autosomal dominant trait [3] , it can be expected that in half of the descendants the pathogenic variant can be detected.How do the authors explain that in none of patients with a positive family history for ATTRv an pathogenic TTR variant has been detected.The fourth point relates to the inclusion criteria [1] .In the first sentence of the method section it is stated that patients with an established polyneuropathy diagnosis were included [1] .In the second sentence, however, it is stated that no further exclusions were made regarding axonal neuropathy subtype.This statement suggests that only patients with axonal polyneuropathy were included, but this has not been explicitly stated as an inclusion criterion.This discrepancy should be explained.Finally, polyneuropathies are usually not detected or electrophysiologically confirmed by needle electromyography but by nerve conduction studies.This should be corrected in the article.In order to assess the prevalence of ATTRv associated polyneuropathy in adults, large international, multicenter studies are required.