A novel pathogenic variant of NEFL responsible for deafness associated with peripheral neuropathy discovered through next‐generation sequencing and review of the literature

Abstract

Neurofilaments are neuron‐specific intermediate filaments essential for the radial growth of axons during development and the maintenance of axonal diameter. Pathogenic variants of Neurofilament Light (NEFL) are associated with CMT1F, CMT2E, and CMTDIG and have been observed in less than 1% of Charcot‐Marie‐Tooth (CMT) cases, resulting in the reporting of 35 variants in 173 CMT patients to date. However, only six variants have been reported in 17 patients with impaired hearing. No genotype‐phenotype correlations have yet been established. Here, we report an additional case: a 69‐year‐old female, who originally presented with axonal sensory and motor neuropathy at the age of 45, associated with moderate sensorineural hearing loss, with a slight slope at high frequencies. Next‐generation sequencing identified a novel pathogenic variant: c.269A > G, p.(Glu90Gly). Hearing impairment is often linked to CMT due to pathogenic variants of NEFL, especially p.(Glu90Lys) and p.(Asn98Ser), and in our case p.(Glu90Gly). These pathogenic variants are all located at hot spots, in the head domain and the two ends of the rod domain of the protein.

Charcot–Marie–Tooth disease Type 2E/1F mutant neurofilament proteins assemble into neurofilaments

“…Source . Data from Abe et al (), Agrawal et al (), Baets et al (), Benedetti et al (), Berciano et al (, ), Bhagavati et al (), Butinar et al (), Choi et al (, ), De Jonghe et al (), DiVincenzo et al (), Doppler et al (), Drew et al (), Elbracht et al (), Fabrizi et al (), Fabrizi et al (), Fu and Yuan (), Georgiou et al (), Hashiguchi et al (), Horga et al (), Jordanova et al (), Lerat et al (), Leung et al (), Lin et al (), Luigetti et al (), Manganelli et al (), Mersiyanova et al (), Miltenberger‐Miltenyi et al (), Noto et al (), Pisciotta et al (), Sainio et al (), Shin et al (), Sivera et al (), Werheid et al (), Yang et al (), Yoshihara et al (), Yum et al (), Züchner et al () [Color figure can be viewed at wileyonlinelibrary.com]…”

“…There are 34 reported CMT2E/1F NFL mutations in human patients ( Figure 1) (Doppler et al, 2017;Fu & Yuan, 2018;Horga et al, 2017;Lerat et al, 2019;Sainio et al, 2018). These are primarily missense mutations, but there are also frameshift, deletion, and nonsense F I G U R E 1 Schematic of the known CMT2E/1F NFL mutations.…”

Charcot-Marie-Tooth: From Molecules to Therapy

“…The slowly progressive nature of the condition (as opposed to an immune-mediated etiology) and noticeable length-dependent weakness/atrophy (rather than a predominantly stocking glove sensory loss with minimal to no weakness more typical of common metabolic-toxic neuropathies) are clinical clues to CMT in addition to uncovering any suggestive family history. The majority of patients also have pes cavus as a hallmark feature with smaller percentages having scoliosis, hip dysplasia, restless legs syndrome, tremor, or hearing loss [9,10,11,12,13,14,15,16,17].…”

A review and analysis of the clinical literature on Charcot–Marie–Tooth disease caused by mutations in neurofilament protein L

“…Please note that the name “severe, early‐onset axonal neuropathy” has been proposed for the E210X mutation (Yum et al, 2009) to reflect the severity of the condition and to avoid the confusing CMT2B nomenclature for recessive CMT, but we have chosen to group it with other type 2E mutations for the purposes of this figure. Data from: Abe et al (2009), Agrawal et al (2014), Baets et al (2011), Benedetti et al (2010), Berciano et al (2015), Berciano et al (2016), Bhagavati, Maccabee, and Xu (2009), Butinar, Starr, Zidar, Koutsou, and Christodoulou (2008), Choi et al (2004), Choi et al (2012), De Jonghe et al (2001), DiVincenzo et al (2014), Doppler et al (2017), Drew et al (2015), Elbracht et al (2014), Fabrizi et al (2004), Fabrizi et al (2007), Fu and Yuan (2018), Georgiou et al (2002), Hashiguchi et al (2014), Horga et al (2017), Jordanova et al (2003), Lerat et al (2019), Leung, Nagan, Graham, and Liem (2006), Lin et al (2011), Luigetti et al (2016), Manganelli et al (2014), Mersiyanova et al (2000), Miltenberger‐Miltenyi et al (2007), Noto et al (2015), Pisciotta et al (2015), Sainio et al (2018), Shin et al (2008), Sivera et al (2013), Werheid et al (2016), Yang, Gu, Burnette, and Li (2016), Yoshihara et al (2002), Yum et al (2009) and Zuchner et al (2004) [Color figure can be viewed at wileyonlinelibrary.com]…”