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Open Access 01-12-2017 | Research

Novel neuro-audiological findings and further evidence for TWNK involvement in Perrault syndrome

Authors: Monika Ołdak, Dominika Oziębło, Agnieszka Pollak, Iwona Stępniak, Michal Lazniewski, Urszula Lechowicz, Krzysztof Kochanek, Mariusz Furmanek, Grażyna Tacikowska, Dariusz Plewczynski, Tomasz Wolak, Rafał Płoski, Henryk Skarżyński

Published in: Journal of Translational Medicine | Issue 1/2017

Abstract

Background

Hearing loss and ovarian dysfunction are key features of Perrault syndrome (PRLTS) but the clinical and pathophysiological features of hearing impairment in PRLTS individuals have not been addressed. Mutations in one of five different genes HSD17B4, HARS2, LARS2, CLPP or TWNK (previous symbol C10orf2) cause the autosomal recessive disorder but they are found only in about half of the patients.

Methods

We report on two siblings with a clinical picture resembling a severe, neurological type of PRLTS. For an exhaustive characterisation of the phenotype neuroimaging with volumetric measurements and objective measures of cochlear hair cell and auditory nerve function (otoacustic emissions and auditory brainstem responses) were used. Whole exome sequencing was applied to identify the genetic cause of the disorder. Co-segregation of the detected mutations with the phenotype was confirmed by Sanger sequencing. In silico analysis including 3D protein structure modelling was used to predict the deleterious effects of the detected variants on protein function.

Results

We found two rare biallelic mutations in TWNK, encoding Twinkle, an essential mitochondrial helicase. Mutation c.1196A>G (p.Asn399Ser) recurred for the first time in a patient with PRLTS and the second mutation c.1802G>A (p.Arg601Gln) was novel for the disorder. In both patients neuroimaging studies showed diminished cervical enlargement of the spinal cord and for the first time in PRLTS partial atrophy of the vestibulocochlear nerves and decreased grey and increased white matter volumes of the cerebellum. Morphological changes in the auditory nerves, their desynchronized activity and partial cochlear dysfunction underlay the complex mechanism of hearing impairment in the patients.

Conclusions

Our study unveils novel features on the phenotypic landscape of PRLTS and provides further evidence that the newly identified for PRLTS TWNK gene is involved in its pathogenesis.

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Title: Novel neuro-audiological findings and further evidence for TWNK involvement in Perrault syndrome
Authors: Monika Ołdak
Dominika Oziębło
Agnieszka Pollak
Iwona Stępniak
Michal Lazniewski
Urszula Lechowicz
Krzysztof Kochanek
Mariusz Furmanek
Grażyna Tacikowska
Dariusz Plewczynski
Tomasz Wolak
Rafał Płoski
Henryk Skarżyński
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Journal of Translational Medicine / Issue 1/2017
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-017-1129-4

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Novel neuro-audiological findings and further evidence for TWNK involvement in Perrault syndrome

Abstract

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Conclusions

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