Hearing loss in inherited peripheral neuropathies: Molecular diagnosis by NGS in a French series

Abstract

Background The most common inherited peripheral neuropathy is Charcot‐Marie‐Tooth disease (CMT), with a prevalence of 1/2500. Other symptoms can be associated to the condition, such as hearing loss. Currently, no global hearing impairment assessment has been determined, and the physiopathology is not well known. Methods The aim of the study was to analyze among a French series of 3,412 patients with inherited peripheral neuropathy (IPN), the ones who also suffer from hearing loss, to establish phenotype‐genotype correlations. An NGS strategy for IPN one side and nonsyndromic hearing loss (NSHL) on the other side, were performed. Results Hearing loss (HL) was present in only 44 patients (1.30%). The clinical data of 27 patients were usable. Demyelinating neuropathy was diagnosed in 15 cases and axonal neuropathy in 12 cases. HL varied from mild to profound. Five cases of auditory neuropathy were noticed. Diagnosis was made for 60% of these patients. Seven novel pathogenic variants were discovered in five different genes: PRPS1; MPZ; SH3TC2; NEFL; and ABHD12. Two patients with PMP22 variant, had also an additional variant in COCH and MYH14 respectively. No pathogenic variant was found at the DFNB1 locus. Genotype‐phenotype correlations do exist, especially with SH3TC2, PRPS1, ABHD12, NEFL, and TRPV4. Conclusion Involvement of PMP22 is not enough to explain hearing loss in patients suffering from IPN. HL can be due to cochlear impairment and/or auditory nerve dysfunction. HL is certainly underdiagnosed, and should be evaluated in every patient suffering from IPN.

Cohort Analysis of 67 Charcot-Marie-Tooth Italian Patients: Identification of New Mutations and Broadening of Phenotype Expression Produced by Rare Variants

“…To this aim, we conducted a systematic review of 23 cohort analysis studies consisting of Italian and European CMT patients in the period between 1997 and 2020. This data, summarized in Figure 2B and Supplementary data , identified a diagnostic yield of 71.7% in Italy ( Mostacciuolo et al, 2001 ; Manganelli et al, 2014 ; Gentile et al, 2020 ) and 26.7% in Europe ( Bort et al, 1997 ; Saporta et al, 2011 ; Murphy et al, 2012 ; Gess et al, 2013 ; Østern et al, 2013 ; Sivera et al, 2013 ; Høyer et al, 2014 ; Antoniadi et al, 2015 ; Laššuthová et al, 2016 ; Lupo et al, 2016 ; Dohrn et al, 2017 ; Marttila et al, 2017 ; Bacquet et al, 2018 ; Hoebeke et al, 2018 ; Milley et al, 2018 ; Nicolas et al, 2018 ; Lerat et al, 2019 ; Vaeth et al, 2019 ; Cortese et al, 2020 ; Figure 2B ). Therefore, the prevalence of genetic cases of CMT provided by the present data represents an average compared with the general prevalence measured in Italy and Europe.…”

Genetic spectrum of Charcot–Marie–Tooth disease associated with myelin protein zero gene variants in Japan

“…The frequency of hearing loss in 66 CMT patients with MPZ variants was reported as 3.33%, suggesting that the frequency of hearing loss is the same as that in the normal population. Thus, hearing loss may not be associated with MPZ variants 30 . However, in addition to hearing loss, pupillary abnormalities, trigeminal neuralgia, hemifacial spasm have been observed in CMT patients with MPZ variants 31‐33 .…”

Non-muscle myosin-2 contractility-dependent actin turnover limits the length of epithelial microvilli

“…NM2C exhibits specific expression to pituitary gland and glial cells, as well as inner ear sensory, intestinal, and kidney epithelia (32). Mutations in MYH14 have been linked to hearing loss, peripheral neuropathies, and developmental defects in the lower gastrointestinal tract (33)(34)(35)(36)(37)(38)(39)(40)(41). The parallel perturbation of both inner ear and intestinal epithelial systems by mutations in MYH14 is intriguing, as actin bundled-supported stereocilia found on the apical surface of hair cells are closely related to microvilli found on solute transporting epithelia, and may share mechanisms of assembly and maintenance (42,43).…”