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Ear Hear. 2016 Jan-Feb;37(1):112-20. doi: 10.1097/AUD.0000000000000198.

Nonmuscle Myosin Heavy Chain IIA Mutation Predicts Severity and Progression of Sensorineural Hearing Loss in Patients With MYH9-Related Disease.

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1Department of Otorhinolaryngology and Head and Neck Surgery, University Medical Center Utrecht, Utrecht, The Netherlands; 2Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands; 3Department of Otorhinolaryngology, Head and Neck Surgery, Radboud University Medical Centre, Nijmegen, The Netherlands; 4Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Centre, Nijmegen, The Netherlands; 5Department of Hematology Research, Instituto de Investigaciones Médicas Alfredo Lanari, UE IDIM-CONICET, University of Buenos Aires, Buenos Aires, Argentina; 6Institut d'Investigació Biomèdica Sant Pau, Universitat Aut∫noma de Barcelona, Barcelona, Spain; 7Institute for Maternal and Child Health, IRCCS "Burlo Garofolo," and University of Trieste, Trieste, Italy; 8Department of Otorhinolaryngology, IRCCS Policlinico San Matteo Foundation, Pavia, Italy; 9Department of Internal Medicine, Section of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy; and 10Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation and University of Pavia, Piazzale Golgi, Pavia, Italy.



MYH9-related disease (MYH9-RD) is an autosomal- dominant disorder deriving from mutations in MYH9, the gene for the nonmuscle myosin heavy chain (NMMHC)-IIA. MYH9-RD has a complex phenotype including congenital features, such as thrombocytopenia, and noncongenital manifestations, namely sensorineural hearing loss (SNHL), nephropathy, cataract, and liver abnormalities. The disease is caused by a limited number of mutations affecting different regions of the NMMHC-IIA protein. SNHL is the most frequent noncongenital manifestation of MYH9-RD. However, only scarce and anecdotal information is currently available about the clinical and audiometric features of SNHL of MYH9-RD subjects. The objective of this study was to investigate the severity and propensity for progression of SNHL in a large series of MYH9-RD patients in relation to the causative NMMHC-IIA mutations.


This study included the consecutive patients diagnosed with MYH9-RD between July 2007 and March 2012 at four participating institutions. A total of 115 audiograms were analyzed from 63 patients belonging to 45 unrelated families with different NMMHC-IIA mutations. Cross-sectional analyses of audiograms were performed. Regression analysis was performed, and age-related typical audiograms (ARTAs) were derived to characterize the type of SNHL associated with different mutations.


Severity of SNHL appeared to depend on the specific NMMHC-IIA mutation. Patients carrying substitutions at the residue R702 located in the short functional SH1 helix had the most severe degree of SNHL, whereas patients with the p.E1841K substitution in the coiled-coil region or mutations at the nonhelical tailpiece presented a mild degree of SNHL even at advanced age. The authors also disclosed the effects of different amino acid changes at the same residue: for instance, individuals with the p.R702C mutation had more severe SNHL than those with the p.R702H mutation, and the p.R1165L substitution was associated with a higher degree of hearing loss than the p.R1165C. In general, mild SNHL was associated with a fairly flat audiogram configuration, whereas severe SNHL correlated with downsloping configurations. ARTA plots showed that the most progressive type of SNHL was associated with the p.R702C, the p.R702H, and the p.R1165L substitutions, whereas the p.R1165C mutation correlated with a milder, nonprogressive type of SNHL than the p.R1165L. ARTA for the p.E1841K mutation demonstrated a mild degree of SNHL with only mild progression, whereas the ARTA for the mutations at the nonhelical tailpiece did not show any substantial progression.


These data provide useful tools to predict the progression and the expected degree of severity of SNHL in individual MYH9-RD patients, which is especially relevant in young patients. Consequences in clinical practice are important not only for appropriate patient counseling but also for development of customized, genotype-driven clinical management. The authors recently reported that cochlear implantation has a good outcome in MYH9-RD patients; thus, stricter follow-up and earlier intervention are recommended for patients with unfavorable genotypes.

[Indexed for MEDLINE]

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