Marfanoid habitus is a nonspecific feature of Perrault syndrome.

Marfanoid habitus is a nonspecific feature of Perrault syndrome.

Clin Dysmorphol. 2017 Aug 21;:

Authors: Zerkaoui M, Demain LAM, Cherkaoui Jaouad I, Ratbi I, Amjoud K, Urquhart JE, O'Sullivan J, Newman WG, Sefiani A

Abstract
The objective of this study was to report the clinical and biological characteristics of two Perrault syndrome cases in a Moroccan family with homozygous variant c.1565C>A in the LARS2 gene and to establish genotype-phenotype correlation of patients with the same mutation by review of the literature. Whole-exome sequencing was performed. Data analysis was carried out and confirmed by Sanger sequencing and segregation. The affected siblings were diagnosed as having Perrault syndrome with sensorineural hearing loss at low frequencies; the female proband had primary amenorrhea and ovarian dysgenesis. Both affected individuals had a marfanoid habitus and no neurological features. Both patients carried the homozygous variant c.1565C>A; p.Thr522Asn in exon 13 of the LARS2 gene. This variant has already been reported as a homozygous variant in three other Perrault syndrome families. Both affected siblings of a Moroccan consanguineous family with LARS2 variants had low-frequency sensorineural hearing loss, marfanoid habitus, and primary ovarian insufficiency in the affected girl. According to the literature, this variant, c.1565C>A; p.Thr522Asn, can be correlated with low-frequency hearing loss. However, marfanoid habitus was been considered a nonspecific feature in Perrault syndrome, but we believe that it may be more specific than considered previously. This diagnosis allowed us to provide appropriate management to the patients and to provide more accurate genetic counseling to this family.

PMID: 28832386 [PubMed - as supplied by publisher]

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A homozygous missense variant in HSD17B4 identified in a consanguineous Chinese Han family with type II Perrault syndrome.

Related Articles

A homozygous missense variant in HSD17B4 identified in a consanguineous Chinese Han family with type II Perrault syndrome.

BMC Med Genet. 2017 Aug 23;18(1):91

Authors: Chen K, Yang K, Luo SS, Chen C, Wang Y, Wang YX, Li DK, Yang YJ, Tang YL, Liu FT, Wang J, Wu JJ, Sun YM

Abstract
BACKGROUND: Perrault syndrome is a rare multisystem disorder that manifests with sensorineural hearing loss in both sexes, primary ovarian insufficiency in females and neurological features. The syndrome is heterogeneous both genetically and phenotypically.
CASE PRESENTATION: We reported a consanguineous family (two affected sisters) with Perrault syndrome. The proband had the characteristics of Perrault syndrome: ovarian dysgenesis, bilateral hearing loss and obvious neurological signs. Target genetic sequencing and triplet repeat primed PCR (TP-PCR) plus capillary electrophoresis was conducted to detect causative mutations in the proband. The detected variant was further confirmed in the proband and tested in other family members by Sanger sequencing. Both the proband and her sister were found homozygous for the novel variant HSD17B4 c.298G > T (p.A100S) with their parents heterozygous. Detected by western blot, the protein expression of HSD17B4 mutant was much lower than that of the wild type in SH-SY5Y cells transfected by HSD17B4 wild type or mutant plasmid, which indicated the pathogenicity of the HSD17B4 mutation.
CONCLUSIONS: Our findings supported that HSD17B4 was one of the genes contributing to Perrault syndrome with the likely pathogenic variant c.298G > T (p.A100S). Special manifestations of cerebellar impairment were found in cases caused by HSD17B4 mutations. Besides, attention should be paid to distinguish Perrault syndrome from D-bifunctional protein deficiency and hereditary ataxia.

PMID: 28830375 [PubMed - in process]

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A novel splice site mutation of myosin VI in mice leads to stereociliary fusion caused by disruption of actin networks in the apical region of inner ear hair cells.

A novel splice site mutation of myosin VI in mice leads to stereociliary fusion caused by disruption of actin networks in the apical region of inner ear hair cells.

PLoS One. 2017;12(8):e0183477

Authors: Seki Y, Miyasaka Y, Suzuki S, Wada K, Yasuda SP, Matsuoka K, Ohshiba Y, Endo K, Ishii R, Shitara H, Kitajiri SI, Nakagata N, Takebayashi H, Kikkawa Y

Abstract
An unconventional myosin encoded by the myosin VI gene (MYO6) contributes to hearing loss in humans. Homozygous mutations of MYO6 result in nonsyndromic profound congenital hearing loss, DFNB37. Kumamoto shaker/waltzer (ksv) mice harbor spontaneous mutations, and homozygous mutants exhibit congenital defects in balance and hearing caused by fusion of the stereocilia. We identified a Myo6c.1381G>A mutation that was found to be a p.E461K mutation leading to alternative splicing errors in Myo6 mRNA in ksv mutants. An analysis of the mRNA and protein expression in animals harboring this mutation suggested that most of the abnormal alternatively spliced isoforms of MYO6 are degraded in ksv mice. In the hair cells of ksv/ksv homozygotes, the MYO6 protein levels were significantly decreased in the cytoplasm, including in the cuticular plates. MYO6 and stereociliary taper-specific proteins were mislocalized along the entire length of the stereocilia of ksv/ksv mice, thus suggesting that MYO6 attached to taper-specific proteins at the stereociliary base. Histological analysis of the cochlear hair cells showed that the stereociliary fusion in the ksv/ksv mutants, developed through fusion between stereociliary bundles, raised cuticular plate membranes in the cochlear hair cells and resulted in incorporation of the bundles into the sheaths of the cuticular plates. Interestingly, the expression of the stereociliary rootlet-specific TRIO and F-actin binding protein (TRIOBP) was altered in ksv/ksv mice. The abnormal expression of TRIOBP suggested that the rootlets in the hair cells of ksv/ksv mice had excessive growth. Hence, these data indicated that decreased MYO6 levels in ksv/ksv mutants disrupt actin networks in the apical region of hair cells, thereby maintaining the normal structure of the cuticular plates and rootlets, and additionally provided a cellular basis for stereociliary fusion in Myo6 mutants.

PMID: 28832620 [PubMed - in process]

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A novel splice site mutation of myosin VI in mice leads to stereociliary fusion caused by disruption of actin networks in the apical region of inner ear hair cells.

A novel splice site mutation of myosin VI in mice leads to stereociliary fusion caused by disruption of actin networks in the apical region of inner ear hair cells.

PLoS One. 2017;12(8):e0183477

Authors: Seki Y, Miyasaka Y, Suzuki S, Wada K, Yasuda SP, Matsuoka K, Ohshiba Y, Endo K, Ishii R, Shitara H, Kitajiri SI, Nakagata N, Takebayashi H, Kikkawa Y

Abstract
An unconventional myosin encoded by the myosin VI gene (MYO6) contributes to hearing loss in humans. Homozygous mutations of MYO6 result in nonsyndromic profound congenital hearing loss, DFNB37. Kumamoto shaker/waltzer (ksv) mice harbor spontaneous mutations, and homozygous mutants exhibit congenital defects in balance and hearing caused by fusion of the stereocilia. We identified a Myo6c.1381G>A mutation that was found to be a p.E461K mutation leading to alternative splicing errors in Myo6 mRNA in ksv mutants. An analysis of the mRNA and protein expression in animals harboring this mutation suggested that most of the abnormal alternatively spliced isoforms of MYO6 are degraded in ksv mice. In the hair cells of ksv/ksv homozygotes, the MYO6 protein levels were significantly decreased in the cytoplasm, including in the cuticular plates. MYO6 and stereociliary taper-specific proteins were mislocalized along the entire length of the stereocilia of ksv/ksv mice, thus suggesting that MYO6 attached to taper-specific proteins at the stereociliary base. Histological analysis of the cochlear hair cells showed that the stereociliary fusion in the ksv/ksv mutants, developed through fusion between stereociliary bundles, raised cuticular plate membranes in the cochlear hair cells and resulted in incorporation of the bundles into the sheaths of the cuticular plates. Interestingly, the expression of the stereociliary rootlet-specific TRIO and F-actin binding protein (TRIOBP) was altered in ksv/ksv mice. The abnormal expression of TRIOBP suggested that the rootlets in the hair cells of ksv/ksv mice had excessive growth. Hence, these data indicated that decreased MYO6 levels in ksv/ksv mutants disrupt actin networks in the apical region of hair cells, thereby maintaining the normal structure of the cuticular plates and rootlets, and additionally provided a cellular basis for stereociliary fusion in Myo6 mutants.

PMID: 28832620 [PubMed - in process]

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Using Electrically-evoked Compound Action Potentials to Estimate Perceptive Levels in Experienced Adult Cochlear Implant Users.

Hypothesis: The cochlear implant (CI) fitting level prediction accuracy of electrically-evoked compound action potential (ECAP) should be enhanced by the addition of demographic data in models. Introduction: No accurate automated fitting of CI based on ECAP has yet been proposed. Methods: We recorded ECAP in 45 adults who had been using MED-EL CIs for more than 11 months and collected the most comfortable loudness level (MCL) used for CI fitting (prog-MCL), perception thresholds (meas-THR), and MCL (meas-MCL) measured with the stimulation used for ECAP recording. Linear mixed models taking into account cochlear site factors were computed to explain prog-MCL, meas-MCL, and meas-THR. Results: Cochlear region and ECAP threshold were predictors of the three levels. In addition, significant predictors were the ECAP amplitude for the prog-MCL and the duration of deafness for the prog-MCL and the meas-THR. Estimations were more accurate for the meas-THR, then the meas-MCL, and finally the prog-MCL. Conclusion: These results show that 1) ECAP thresholds are more closely related to perception threshold than to comfort level, 2) predictions are more accurate when the inter-subject and cochlear regions variations are considered, and 3) differences between the stimulations used for ECAP recording and for CI fitting make it difficult to accurately predict the prog-MCL from the ECAP recording. Predicted prog-MCL could be used as bases for fitting but should be used with care to avoid any uncomfortable or painful stimulation. Copyright (C) 2017 by Otology & Neurotology, Inc. Image copyright (C) 2010 Wolters Kluwer Health/Anatomical Chart Company

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Clinical Characteristics of Benign Recurrent Vestibulopathy: Clearly Distinctive From Vestibular Migraine and Meniere's Disease?.

Objective: We aimed to systematically investigate the clinical characteristics of benign recurrent vestibulopathy (BRV), vestibular migraine (VM), and Meniere's disease (MD) and to assess whether clinical symptoms exist that are unique to BRV. Study Design: Prospective cohort study. Setting: Tertiary referral center. Methods: Between January 2015 and November 2016, patients were prospectively recruited at a specialized dizziness clinic. Patients were included if they met the diagnostic criteria for BRV, VM, or MD which was evaluated by simultaneous consultation of an otorhinolaryngologist and neurologist. All patients received a comprehensive clinical examination that included vestibular tests and pure-tone audiometry. A questionnaire was designed to systematically document symptoms of the three vestibular disorders. Results: A total of 122 patients were included in our study, 65 (53%) were females in whom 29 (24%) were postmenopausal. The mean age was 55.5 +/- 13.7 years and the mean age of onset of vertigo attacks was 49.2 +/- 14.8 years (n = 119). Forty-five (37%) patients had a clinical diagnosis of BRV, 34 (28%) of VM, and 43 (35%) of MD. No symptom could be identified which was specifically linked to BRV. In patients with BRV, similar to those with VM, we found a female preponderance (p = 0.05 in BRV, p = 0.001 in VM). Patients with VM reported significantly more often a positive history of motion sickness (p = 0.01). In addition, canal paresis was most profound in patients with MD (p = 0.001). Conclusion: We found no clinical characteristics that were distinctive for BRV. However, we did find several distinctive clinical features for VM and MD which may assist the physician in their history taking. Copyright (C) 2017 by Otology & Neurotology, Inc. Image copyright (C) 2010 Wolters Kluwer Health/Anatomical Chart Company

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Selective Stimulation of Facial Muscles Following Chronic Intraneural Electrode Array Implantation and Facial Nerve Injury in the Feline Model.

Background: Our group has previously shown that activation of specific facial nerve (FN) fiber populations and selective activation of facial musculature can be achieved through acute intraneural multichannel microelectrode array (MEA) implantation in the feline model. Hypothesis: Selective stimulation of facial muscles will be maintained in the setting of 1) chronic and 2) acute MEA implantation after FN injury and subsequent recovery. Methods: This study included seven cats. In three cats with normal facial function, 4-channel penetrating MEAs were implanted chronically in the FN and tested biweekly for 6 months. Electrical current pulses were delivered to each channel individually, and elicited electromyographic (EMG) voltage outputs were recorded for each of several facial muscles. For FN injury experiments, two cats received a standardized hemostat-crush injury, and two cats received a transection-reapproximation injury to the FN main trunk. These four underwent acute implantation of MEA and EMG recording in terminal experiments 4 months postinjury. Results: Stimulation through individual channels selectively activated restricted nerve populations, resulting in activation of individual muscles in cats with chronic MEA implantation and after nerve injury. Increasing stimulation current levels resulted in increasing EMG voltage responses in all patients. Nerve histology showed only minor neural tissue reaction to the implant. Conclusion: We have established in the animal model the ability of a chronically implanted MEA to selectively stimulate restricted FN fiber populations and elicit activations in specific facial muscles. Likewise, after FN injury, selective stimulation of restricted FN fiber populations and subsequent activation of discrete facial muscles can be achieved after acute MEA implantation. Copyright (C) 2017 by Otology & Neurotology, Inc. Image copyright (C) 2010 Wolters Kluwer Health/Anatomical Chart Company

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