The novel neurofilament light (NEFL) mutation Glu397Lys is associated with a clinically and morphologically heterogeneous type of Charcot-Marie-Tooth neuropathy

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

“…Linkage and haplotype analyses supported linkage of the mutation on the CMT2E locus and sequence analysis of the NFL gene revealed the corresponding mutations, as described by Georgiou et al (2002) and Zuchner et al (2004).…”

“…We studied two Slovenian families with an axonal autosomal dominant form of Charcot-Marie-Tooth disease caused by mutations in the NF-L gene. CMT2 in the family without AN is caused by the Pro22Ser (Georgiou et al, 2002) mutation and in NFL + AN family by the Glu397Lys (Zuchner et al, 2004) mutation. The genetic defects in these two families, occurring in the same gene, have different effects on auditory nerve, auditory brainstem, and central motor pathways.…”

“…Moreover, the integrity of both the myelin and axons is interdependent and clinical expression of CMT1A, where the genetic mutation impairs PMP22 function through a ''dosage effect'' (the alteration of a phenotype by an increased dosage, or amount, of the product of the gene), occurs only after the pathogenic processes affect also axons (Krajewski et al, 2000). It may also be important to note that different mutations in same genes (e.g., NF-L, MPZ, Cx32) may cause features of either demyelinative or axonal type of polyneuropathy (Senderek et al, 2000;Hattori et al, 2003;Zuchner et al, 2004). Even the demyelination, that has been considered ''secondary'' to axonal loss in different degenerative and metabolic axonal disorders, is probably an essential feature of the pathology (Dyck, 1975).…”

“…Both families were identified as having dominantly inherited disease genetically localized to 8p21 locus (Georgiou et al, 2002). 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. Both families have comparable peripheral nerve involvement but only one family had an asymptomatic involvement of auditory nerve.…”

“…For objective measures of auditory nerve and brainstem functions we used ABRs; for cochlear outer hair cell functions we used OAEs; and for vestibular function we used ENGs. Our study was motivated by a recent account of ''deafness'' occurring in a single member of a family with an NF-L mutation (Zuchner et al, 2004) but did not define whether the deafness was related to a particular variation in the NF-L gene affecting auditory nerve, or a non-specific sensorineural hearing loss. The second rationale for the study was based on findings of asymptomatic abnormalities of peripheral nerve function in several forms of CMT (Dubourg et al, 2001;Infante et al, 2001) and cranial neuropathies (Ceranic and Luxon, 2004).…”