Neuropathy due to impaired axonal transport of non-fragmented mitochondria in MYH14 mutation carriers—Authors’ reply

We appreciate the interest in our work and the opportunity to discuss the diagnosis of peripheral neuropathy in the new family we describe [[1]Almutawa W. Smith C. Sabouny R. Smit R.B. Zhao T. Wong R. et al.The R941L mutation in MYH14 disrupts mitochondrial fission and associates with peripheral neuropathy.EBioMed. 2019; 45: 379-392Summary Full Text Full Text PDF PubMed Google Scholar]. While a nerve biopsy would have added to the evidence available regarding these cases, the hereditary neuropathy diagnosis was established based on the clinical picture, neurophysiology and family history (provided in detail in Supplemental Table 2 [[1]Almutawa W. Smith C. Sabouny R. Smit R.B. Zhao T. Wong R. et al.The R941L mutation in MYH14 disrupts mitochondrial fission and associates with peripheral neuropathy.EBioMed. 2019; 45: 379-392Summary Full Text Full Text PDF PubMed Google Scholar]). Subsequently, exome sequencing identified the MYH14 p.R941L mutation in all affected individuals. As the R941L mutation was previously associated with axonal neuropathy [[2]Choi B.O. Kang S.H. Hyun Y.S. Kanwal S. Park S.W. Koo H. et al.A complex phenotype of peripheral neuropathy, myopathy, hoarseness, and hearing loss is linked to an autosomal dominant mutation in MYH14.Hum Mutat. 2011; 32: 669-677Crossref PubMed Scopus (33) Google Scholar,[3]Iyadurai S. Arnold W.D. Kissel J.T. Ruhno C. McGovern V.L. Snyder P.J. et al.Variable phenotypic expression and onset in MYH14 distal hereditary motor neuropathy phenotype in a large, multigenerational North American family.Muscle Nerve. 2017; 56: 341-345Crossref PubMed Scopus (5) Google Scholar], it was not considered necessary to include a nerve biopsy for clinical purposes, especially as this procedure is invasive and frequently has unpleasant permanent side-effects [[4]Hilton D.A. Jacob J. Househam L. Tengah C. Complications following sural and peroneal nerve biopsies.J Neurol Neurosurg Psychiatry. 2007; 78: 1271-1272Crossref PubMed Scopus (38) Google Scholar]. The neuropathy was classified as axonal based upon the following: (a) predominantly small-fibre sensory loss, (b) absence of significant conduction velocity defect, (c) predominance of motor findings on neurophysiology, and (d) consistency with previously described cases with this mutation [[2]Choi B.O. Kang S.H. Hyun Y.S. Kanwal S. Park S.W. Koo H. et al.A complex phenotype of peripheral neuropathy, myopathy, hoarseness, and hearing loss is linked to an autosomal dominant mutation in MYH14.Hum Mutat. 2011; 32: 669-677Crossref PubMed Scopus (33) Google Scholar,[3]Iyadurai S. Arnold W.D. Kissel J.T. Ruhno C. McGovern V.L. Snyder P.J. et al.Variable phenotypic expression and onset in MYH14 distal hereditary motor neuropathy phenotype in a large, multigenerational North American family.Muscle Nerve. 2017; 56: 341-345Crossref PubMed Scopus (5) Google Scholar]. Since the publication of our work, we have obtained access to additional clinical records. Nerve conduction studies (NCS) performed in IV-1 at age 15 demonstrated CMAP reduction in distal legs with preserved conduction velocity, and normal sensory responses, indicating motor axonal polyneuropathy. Regarding the hearing loss, we agree that evoked potentials may have aided to further characterise these patients. Nonetheless, audiometric evaluations in IV-1 and IV-2 confirmed that hearing loss preceded clinical weakness in these participants, and likely represents phenotypic variability of MYH14-related disorders. It should be noted that several loss of function mutations in MYH14 are associated with non-syndromic sensorineural hearing loss without any peripheral neuropathy or reported mitochondrial dysfunction [[5]Donaudy F. Snoeckx R. Pfister M. Zenner H.P. Blin N. Di Stazio M. et al.Nonmuscle myosin heavy-chain gene MYH14 is expressed in cochlea and mutated in patients affected by autosomal dominant hearing impairment (DFNA4).Am J Hum Genet. 2004; 74: 770-776Summary Full Text Full Text PDF PubMed Scopus (115) Google Scholar]. Given that the NMIIC protein encoded by MYH14 has many cellular functions, it is possible that the mechanistic underpinnings of hearing loss are independent of the underlying cause of the peripheral neuropathy associated with the R941L mutation. The authors have nothing to disclose.

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