Auditory nerve is affected in one of two different point mutations of the neurofilament light gene

Dušan Butinar,Arnold Starr,Janez Zidar,Pantelitsa Koutsou,Kyproula Christodoulou

doi:10.1016/j.clinph.2007.10.004

Abstract

Objective To define auditory nerve and cochlear functions in two families with autosomal dominant axonal Charcot-Marie-Tooth (CMT). Methods Affected members in two families with different point mutations of NF- L gene were screened with auditory brainstem responses (ABRs). Those with abnormal ABRs were further investigated with clinical, neurophysiological and audiological procedures. The point mutations of NF- L gene involved were Glu397Lys in 8 affected members of the family with AN, and Pro22Ser in 9 affected members of the family without AN. Results ABRs and stapedial muscle reflexes were absent or abnormal in affected members of only one family consistent with auditory neuropathy (AN). In them, audiograms, otoacoustic emissions, and speech comprehension were normal. Absent or abnormal ABRs were consistent with slowing of conduction along auditory nerve and/or brainstem auditory pathway. Wave I when present was of normal latency. Conclusions Auditory nerve involvement in the presence of normal cochlear outer hair cell activity is asymptomatic in one of two families with CMT disorder with different point mutations of the NF- L gene. The nerve disorder is consistent with altered synchrony and slowed conduction. Significance The absence of “deafness” may reflect the ability of central mechanisms to compensate for the slowly developing auditory nerve abnormalities.

Highlights

Hearing loss and deafness is an uncommon phenotypic variant in Charcot-Marie-Tooth (CMT) (Satya-Murti q Sources of support: DC-02168 from the National Institutes of Health (Starr), 3311-01-838072, Slovenian Ministry of Education, Science and Sport (Butinar), and Muscular Dystrophy Association of the United States (Christodoulou).et al, 1980; Raglan et al, 1987)
We found that the disease in one family is associated with the neurofilament light (NF-L) Pro22Ser (Georgiou et al, 2002) mutation and in the other family with the (NF-L) Glu397Lys (Zuchner et al, 2004) mutation
We identified members of NFL family who were affected with a peripheral neuropathy and identified by nerve conduction studies performed under standardized conditions (Stalberg and Falck, 1993)

Summary

Introduction

Hearing loss and deafness is an uncommon phenotypic variant in Charcot-Marie-Tooth (CMT) (Satya-Murti q Sources of support: DC-02168 from the National Institutes of Health (Starr), 3311-01-838072, Slovenian Ministry of Education, Science and Sport (Butinar), and Muscular Dystrophy Association of the United States (Christodoulou).et al, 1980; Raglan et al, 1987). At least three of these studies (Butinar et al, 1999; Kovach et al, 2002; Starr et al, 2003) demonstrated that affected individuals showed normal physiological measures of cochlear outer hair cell activity (otoacoustic emissions, OAEs) but abnormal auditory nerve activity (auditory brainstem responses, ABRs), localizing the hearing loss to dysfunction of the auditory nerve. Deafness in CMT can be attributed to an accompanying neuropathy of the auditory nerve sparing the inner hair cells. A similar conclusion was drawn by both Spoendlin (Spoendlin, 1974) and Hallpike et al (Hallpike et al, 1980) based on cochlear histopathology in subjects with CMT and deafness without the availability of physiological tests used to define auditory neuropathy (AN)

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