今日の臨床サポート

先天性難聴(遺伝子変異による難聴など)

著者: 宇佐美真一 信州大学医学部附属病院 耳鼻咽喉科

監修: 森山寛 東京慈恵会医科大学附属病院

著者校正/監修レビュー済:2016/11/30
患者向け説明資料

概要・推奨   

疾患のポイント:
  1. 先天性難聴は、難聴以外の症状を伴う症候群性難聴と、難聴以外の症状を伴わない非症候群性難聴に大別される。
  1. 遺伝子変異、先天性ウイルス感染などが原因となっており、原因に応じた対応が必要である。
 
診断:
  1. 純音聴力検査を行い、難聴の程度、難聴の型(聴力像)を明らかにする。特に伝音難聴、混合性難聴、感音難聴の鑑別はその後の治療方針決定に必須である。
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  1. 耳音響放射(otoacoustic emission、OAE)を実施しAuditory Neuropathy Spectrum Disorder (ANSD)との鑑別を行う。ANSDが疑われた場合は候補遺伝子のスクリーニングを実施する(OTOF遺伝子、OPA1遺伝子、PJVK遺伝子)。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
宇佐美真一 : 未申告[2021年]
監修:森山寛 : 特に申告事項無し[2021年]

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 先天性難聴とは生下時より難聴を呈する疾患の総称であり、新出生児1,000人に1人に認められる比較的頻度の高い先天性障害の1つである。
  1. 新生児聴覚スクリーニングの普及に伴い難聴の早期発見が可能となってきたため、早期診断および早期療育により音声言語コミュニケーションの発達が可能となってきている。
  1. 先天性難聴あるいは小児期発症の難聴の60~70%は遺伝子の関与によるものと推測されている。遺伝子以外の原因では先天性サイトメガロウイルス感染症によるものが多い(わが国では約10%)。
  1. 遺伝性難聴は、難聴以外の症状を伴う症候群性難聴と、難聴以外の症状を伴わない非症候群性難聴に大別される。
  1. 症候群性難聴は全体の30%程度、非症候群性難聴は全体の70%程度を占める。
  1. 症候群性難聴は400種類を超える疾患群があり、さまざまな随伴症状を伴う症候群が報告されている。
  1. 障害部位が外耳~中耳の場合は伝音難聴、内耳~聴神経の場合は感音難聴となる。また、両方を併せた混合性難聴となる場合もある。
  1. 遺伝子変異の種類により障害部位や程度が異なるため、難聴の程度や予後などの臨床像が異なる。2012年からは保険診療として遺伝子診断を実施することが可能となった。
  1. 原因診断を行うことでサブタイプ分類が可能となり、最適な治療法、介入法を提案する個別化医療が可能となる。
問診・診察のポイント  
問診:
  1. 新生児聴覚スクリーニング検査受検の有無とその結果

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文献 

著者: Cynthia C Morton, Walter E Nance
雑誌名: N Engl J Med. 2006 May 18;354(20):2151-64. doi: 10.1056/NEJMra050700.
Abstract/Text
PMID 16707752  N Engl J Med. 2006 May 18;354(20):2151-64. doi: 10.1056・・・
著者: Shin-ichi Usami, Shin-ya Nishio, Makoto Nagano, Satoko Abe, Toshikazu Yamaguchi, Deafness Gene Study Consortium
雑誌名: PLoS One. 2012;7(2):e31276. doi: 10.1371/journal.pone.0031276. Epub 2012 Feb 24.
Abstract/Text Although etiological studies have shown genetic disorders to be a common cause of congenital/early-onset sensorineural hearing loss, there have been no detailed multicenter studies based on genetic testing. In the present report, 264 Japanese patients with bilateral sensorineural hearing loss from 33 ENT departments nationwide participated. For these patients, we first applied the Invader assay for screening 47 known mutations of 13 known deafness genes, followed by direct sequencing as necessary. A total of 78 (29.5%) subjects had at least one deafness gene mutation. Mutations were more frequently found in the patients with congenital or early-onset hearing loss, i.e., in those with an awareness age of 0-6 years, mutations were significantly higher (41.8%) than in patients with an older age of awareness (16.0%). Among the 13 genes, mutations in GJB2 and SLC26A4 were mainly found in congenital or early-onset patients, in contrast with mitochondrial mutations (12S rRNA m.1555A>G, tRNA(Leu(UUR)) m.3243A>G), which were predominantly found in older-onset patients. The present method of simultaneous screening of multiple deafness mutations by Invader assay followed by direct sequencing will enable us to detect deafness mutations in an efficient and practical manner for clinical use.

PMID 22384008  PLoS One. 2012;7(2):e31276. doi: 10.1371/journal.pone.0・・・
著者: Hidekane Yoshimura, Satoshi Iwasaki, Yukihiko Kanda, Hiroshi Nakanishi, Toshinori Murata, Yoh-ichiro Iwasa, Shin-ya Nishio, Yutaka Takumi, Shin-ichi Usami
雑誌名: Int J Pediatr Otorhinolaryngol. 2013 Feb;77(2):298-302. doi: 10.1016/j.ijporl.2012.11.007. Epub 2012 Dec 11.
Abstract/Text Usher syndrome type 1 (USH1) appears to have only profound non-syndromic hearing loss in childhood and retinitis pigmentosa develops in later years. This study examined the frequency of USH1 before the appearance of visual symptoms in Japanese deaf children by MYO7A mutation analysis. We report the case of 6-year-old male with profound hearing loss, who did not have visual symptoms. The frequency of MYO7A mutations in profound hearing loss children is also discussed. We sequenced all exons of the MYO7A gene in 80 Japanese children with severe to profound non-syndromic HL not due to mutations of the GJB2 gene (ages 0-14 years). A total of nine DNA variants were found and six of them were presumed to be non-pathogenic variants. In addition, three variants of them were found in two patients (2.5%) with deafness and were classified as possible pathogenic variants. Among them, at least one nonsense mutation and one missense mutation from the patient were confirmed to be responsible for deafness. After MYO7A mutation analysis, the patient was diagnosed with RP, and therefore, also diagnosed with USH1. This is the first case report to show the advantage of MYO7A mutation analysis to diagnose USH1 before the appearance of visual symptoms. We believed that MYO7A mutation analysis is valid for the early diagnosis of USH1.

Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
PMID 23237960  Int J Pediatr Otorhinolaryngol. 2013 Feb;77(2):298-302.・・・
著者: Maiko Miyagawa, Shin-ya Nishio, Shin-ichi Usami
雑誌名: PLoS One. 2012;7(8):e40366. doi: 10.1371/journal.pone.0040366. Epub 2012 Aug 10.
Abstract/Text Screening for gene mutations in CDH23, which has many exons, has lagged even though it is likely to be an important cause for hearing loss patients. To assess the importance of CDH23 mutations in non-syndromic hearing loss, two-step screening was applied and clinical characteristics of the patients with CDH23 mutations were examined in this study. As a first screening, we performed Sanger sequencing using 304 probands compatible with recessive inheritance to find the pathologic mutations. Twenty-six possible mutations were detected to be pathologic in the first screening. For the second screening, using the probes for these 26 mutations, a large cohort of probands (n = 1396) was screened using Taqman amplification-based mutation analysis followed by Sanger sequencing. The hearing loss in a total of 52 families (10 homozygous, 13 compound heterogygous, and 29 heterozygous) was found to be caused by the CDH23 mutations. The majority of the patients showed congenital, high frequency involved, progressive hearing loss. Interestingly, some particular mutations cause late onset moderate hearing loss. The present study is the first to demonstrate the prevalence of CDH23 mutations among non-syndromic hearing loss patients and indicated that mutations of the CDH23 gene are an important cause of non-syndromic hearing loss.

PMID 22899989  PLoS One. 2012;7(8):e40366. doi: 10.1371/journal.pone.0・・・
著者: Hideaki Moteki, Shin-ya Nishio, Shigenari Hashimoto, Yutaka Takumi, Satoshi Iwasaki, Norihito Takeichi, Satoshi Fukuda, Shin-ichi Usami
雑誌名: J Hum Genet. 2012 Sep;57(9):587-92. doi: 10.1038/jhg.2012.73. Epub 2012 Jun 21.
Abstract/Text TECTA gene encodes α-tectorin, the major component of noncollagenous glycoprotein of the tectorial membrane, and has a role in intracochlear sound transmission. The TECTA mutations are one of the most frequent causes of autosomal dominant (AD) hearing loss and genotype-phenotype correlations are associated with mutations of TECTA in exons according to α-tectorin domains. In this study, we investigated the prevalence of hearing loss caused by TECTA mutations in Japanese AD hearing loss families, and confirmed genotype-phenotype correlation, as well as the intracellular localization of missense mutations in the α-tectorin domain. TECTA mutations were detected in 2.9% (4/139) of our Japanese AD hearing loss families, with the prevalence in moderate hearing loss being 7.7% (4/52), and all patients showed typical genotype-phenotype correlations as previously described. The present in vitro study showed differences of localization patterns between wild type and mutants, and suggested that each missense mutation may lead to a lack of assembly of secretion, and may reduce the incorporation of α-tectorin into the tectorial membrane.

PMID 22718023  J Hum Genet. 2012 Sep;57(9):587-92. doi: 10.1038/jhg.20・・・
著者: Sakiko Furutate, Satoshi Iwasaki, Shin-ya Nishio, Hideaki Moteki, Shin-ichi Usami
雑誌名: Acta Otolaryngol. 2011 Sep;131(9):976-82. doi: 10.3109/00016489.2011.583268. Epub 2011 May 26.
Abstract/Text CONCLUSIONS: Congenital cytomegalovirus (CMV) infection is a major cause of bilateral and unilateral sensorineural hearing loss (SNHL) in children, accounting for 9.0% of SNHL cases. The diagnostic rate using combined genetic deafness test and CMV DNA detection test was determined to be 46.4% in bilateral profound SNHL.
OBJECTIVES: The present study investigated the prevalence of congenital CMV infection diagnosed retrospectively by detection of CMV DNA in dried umbilical cord specimens from children with unilateral or bilateral SNHL up to the age of 12 years.
METHODS: Preserved dried umbilical cords were collected from 134 children with bilateral (46 children) or unilateral (88 children) SNHL. DNA was extracted from the dried umbilical cords and CMV DNA was detected by quantitative PCR. Genetic deafness tests based on the invader assay were performed in children with bilateral SNHL.
RESULTS: CMV DNA from the dried umbilical cords was detected in 8.7% of the bilateral SNHL and 9.1% of unilateral SNHL. Deafness gene mutations were identified in 21.7% (10/46) of children with bilateral SNHL.

PMID 21612560  Acta Otolaryngol. 2011 Sep;131(9):976-82. doi: 10.3109/・・・
著者: K Tsukada, S Nishio, S Usami, Deafness Gene Study Consortium
雑誌名: Clin Genet. 2010 Nov;78(5):464-70. doi: 10.1111/j.1399-0004.2010.01407.x.
Abstract/Text GJB2 is the gene most frequently associated with hereditary hearing loss, and the GJB2 mutation spectrums vary among different ethnic groups. In this study, the mutation spectrum as well as clinical features of patients with GJB2 mutations as found in more than 1000 Japanese hearing loss families are summarized. The present results show that the frequency of GJB2 mutations in the Japanese population with hearing loss is 14.2% overall and 25.2% in patients with congenital hearing loss. c.235delC was the most frequent allele (49.8%), was associated with a more severe phenotype, and was mainly found in patients who were diagnosed by the age of 3. In contrast, the second most frequent was p.V37I (16.5%), which has a milder phenotype and was mainly found in patients diagnosed at a higher age. Additional clinical features in hearing loss patients with GJB2 mutations in this study were the near absence of tinnitus, vestibular dysfunction and inner ear malformations.

© 2010 John Wiley & Sons A/S.
PMID 20497192  Clin Genet. 2010 Nov;78(5):464-70. doi: 10.1111/j.1399-・・・
著者: S Y Lu, S Nishio, K Tsukada, T Oguchi, K Kobayashi, S Abe, S Usami
雑誌名: Clin Genet. 2009 May;75(5):480-4.
Abstract/Text The mitochondrial 1555A>G mutation is one of the most common mutations responsible for hearing loss in Asians. Although the association with aminoglycoside exposure is well known, there is great variation in the severity of hearing loss. We analyzed hearing levels in 221 Japanese individuals with this mutation and attempted to identify relevant covariants including (i) age, (ii) aminoglycoside exposure, (iii) heteroplasmy ratio, and (iv) other gene mutations. At every age, average hearing levels were worse than those in normal subjects, suggesting that mitochondrial function itself may affect the severity of hearing loss. Although the hearing loss in individuals with the 1555A>G mutation progressed with age, the rate did not differ from that of the normal subjects. Those who had reported aminoglycoside exposure had moderate-to-severe hearing impairment regardless of age, confirming that such exposure is the most important environmental variable. We also confirmed the presence of heteroplasmy, which is known to modify the expression of other mitochondrial diseases, but found no evidence for a significant correlation with hearing impairment. A high prevalence of GJB2 heterozygous mutations was noted, indicating that these mutations may exhibit epistatic interaction with the 1555A>G mutation.

PMID 19475720  Clin Genet. 2009 May;75(5):480-4.
著者: Hiroaki Suzuki, Aki Oshima, Koji Tsukamoto, Satoko Abe, Kozo Kumakawa, Kyoko Nagai, Hitoshi Satoh, Yukihiko Kanda, Satoshi Iwasaki, Shin-ichi Usami
雑誌名: Acta Otolaryngol. 2007 Dec;127(12):1292-7. doi: 10.1080/00016480701258739.
Abstract/Text CONCLUSIONS: The present study confirmed the clinical characteristics of patients with SLC26A4 mutations: congenital, fluctuating, and progressive hearing loss usually associated with vertigo and/or goiter during long-term follow-up. This clarification should help to facilitate appropriate genetic counseling and proper medical management for patients with these mutations, but there was no particular genotype-phenotype correlation among them, suggesting that other factors may contribute to such variability.
OBJECTIVES: Due to the wide range of phenotypes caused by SLC26A4 mutations, there is controversy with regard to genotype-phenotype correlation. The present study was performed: (1) to determine phenotypic range in patients with biallelic SLC26A4 mutations, and (2) to evaluate whether possible genotype-phenotype correlation exists.
SUBJECTS AND METHODS: Phenotypes in 39 hearing loss patients with SLC26A4 mutations were summarized and genotype-phenotype correlation was analyzed.
RESULTS: Hearing level varied in the individuals from mild to profound severity. Most of the patients had fluctuating and progressive hearing loss that may have been of prelingual onset. Twenty-four (70.6%) patients had episodes of vertigo, and 10 (27.8%) patients had goiter, which had appeared at age 12 or older. In contrast to such phenotypic variabilities, no apparent correlation was found between these phenotypes and their genotypes.

PMID 17851929  Acta Otolaryngol. 2007 Dec;127(12):1292-7. doi: 10.1080・・・
著者: Hisakuni Fukuoka, Yukihiko Kanda, Shuji Ohta, Shin-ichi Usami
雑誌名: J Hum Genet. 2007;52(6):510-5. doi: 10.1007/s10038-007-0144-3. Epub 2007 May 11.
Abstract/Text Mutations in WFS1 are reported to be responsible for two conditions with distinct phenotypes; DFNA6/14/38 and autosomal recessive Wolfram syndrome. They differ in their associated symptoms and inheritance mode, and although their most common clinical symptom is hearing loss, it is of different types. While DNFA6/14/38 is characterized by low frequency sensorineural hearing loss (LFSNHL), in contrast, Wolfram syndrome is associated with various hearing severities ranging from normal to profound hearing loss that is dissimilar to LFSNHL (Pennings et al. 2002). To confirm whether within non-syndromic hearing loss patients WFS1 mutations are found restrictively in patients with LFSNHL and to summarize the mutation spectrum of WFS1 found in Japanese, we screened 206 Japanese autosomal dominant and 64 autosomal recessive (sporadic) non-syndromic hearing loss probands with various severities of hearing loss. We found three independent autosomal dominant families associated with two different WFS1 mutations, A716T and E864K, previously detected in families with European ancestry. Identification of the same mutations in independent families with different racial backgrounds suggests that both sites are likely to be mutational hot spots. All three families with WFS1 mutations in this study showed a similar phenotype, LFSNHL, as in previous reports. In this study, one-third (three out of nine) autosomal dominant LFSNHL families had mutations in the WFS1 gene, indicating that in non-syndromic hearing loss WFS1 is restrictively and commonly found within autosomal dominant LFSNHL families.

PMID 17492394  J Hum Genet. 2007;52(6):510-5. doi: 10.1007/s10038-007-・・・

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