伴周围神经病变听神经病患者的临床特征分析
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摘要
目的分析一组伴周围神经病变听神经病患者的临床症状特点和听力学特征,总结综合征型听神经病的遗传学和表型特征。方法对课题组2003年至2018年间收集的听神经病患者采用统一问卷调查,记录发病年龄和临床症状特点,并进行标准化的听力学评估:包括纯音测听、听性脑干反应(ABR)、声导抗、畸变产物耳声发射(DPOAE)、耳蜗电图(ECochG)、言语识别率测试。结果 2003-2018年共收集听神经病患者531例,伴周围神经病变者69例,占12.99%;其中男性32例,女性37例,男女比例为1:1.16;发病年龄在0-26岁,平均14.85±5.23岁,其中婴幼儿期(≤3岁)发病4例,占5.79%;儿童期(3-12岁)发病10例,占14.49%;青少年期(12-18岁)发病36例,占52.17%;成人(≥18岁)发病19例,占27.54%。44例(63.77%)患者首发为听神经病,另25例(36.23%)首发为视力下降、四肢麻木、走路不稳等周围神经病变的表现;54例(78.26%)伴有耳鸣,7例(10.14%)伴有眩晕或前庭功能障碍。纯音听力图以低频上升型听力曲线为主,占66.92%;听力损失程度主要表现为轻、中度听力损失,占68.46%。结论听神经病可伴发多种神经系统疾病,多表现为周围神经病变,如四肢麻木、肌张力低下、共济失调、视力下降等。综合征型听神经病患者的首发症状可以是听神经病,也可以是其他神经系统疾病,其听力学评估结果符合听神经病的听力学特征。
Objective To describe clinical symptoms and audiological characteristics of patients with auditory neuropathy and comorbid peripheral neuropathy, and to summarize genetic and phenotypic characteristics of syndromic auditory neuropathy. Methods A questionnaire was used to record the age of onset and clinical symptoms in patients with auditory neuropathy, in addition to standardized hearing assessment including pure tone audiometry, auditory brainstem responses(ABR), acoustic immittance, distorted product otoacoustic emissions(DPOAE), electrocochleogram(ECochG) and speech-discrimination scores(SDS). Results A total of 531 patients with auditory neuropathy were evaluated from 2003 to 2018, with 69(12.99%) having peripheral neuropathy at the same time, of whom 32 were male and37 were female(men to women ratio = 1:1.16). The age of onset was 0 to 26 years(mean = 14.85±5.23 years). The onset occurred in infancy(≤ 3 years) in 4 cases(5.79%), in childhood(3-12 years) in 10 cases(14.49%), in adolescence(12-18 years) in 36 cases(52.17%) and in adulthood(≥18 years) in 19 cases(27.54%). Hearing loss and poor speech recognition were the initial symptoms in 44 patients(63.77%), while the rest of patients presented with features of peripheral neuropathy such as vision loss, numbness in limbs and balance difficulties. Tinnitus was reported in 54 cases(78.26%) and vertigo or vestibular dysfunction in 7 cases(10.14%). Pure tone audiograms were dominated by low frequency rising hearing loss(66.92%) of mainly mild and moderate severities(68.46%). Conclusion Auditory neuropathy can be accompanied by a variety of neurological diseases, dominated by peripheral neuropathy, manifesting as numbness in limbs, dysmyotonia, ataxia, vision loss, etc. The initial symptoms in patients with syndromic auditory neuropathy can be those of auditory neuropathy or other neurological diseases, although results of hearing evaluation are typically in line with the audiological characteristics of auditory neuropathy.
Objective To describe clinical symptoms and audiological characteristics of patients with auditory neuropathy and comorbid peripheral neuropathy, and to summarize genetic and phenotypic characteristics of syndromic auditory neuropathy. Methods A questionnaire was used to record the age of onset and clinical symptoms in patients with auditory neuropathy, in addition to standardized hearing assessment including pure tone audiometry, auditory brainstem responses(ABR), acoustic immittance, distorted product otoacoustic emissions(DPOAE), electrocochleogram(ECochG) and speech-discrimination scores(SDS). Results A total of 531 patients with auditory neuropathy were evaluated from 2003 to 2018, with 69(12.99%) having peripheral neuropathy at the same time, of whom 32 were male and37 were female(men to women ratio = 1:1.16). The age of onset was 0 to 26 years(mean = 14.85±5.23 years). The onset occurred in infancy(≤ 3 years) in 4 cases(5.79%), in childhood(3-12 years) in 10 cases(14.49%), in adolescence(12-18 years) in 36 cases(52.17%) and in adulthood(≥18 years) in 19 cases(27.54%). Hearing loss and poor speech recognition were the initial symptoms in 44 patients(63.77%), while the rest of patients presented with features of peripheral neuropathy such as vision loss, numbness in limbs and balance difficulties. Tinnitus was reported in 54 cases(78.26%) and vertigo or vestibular dysfunction in 7 cases(10.14%). Pure tone audiograms were dominated by low frequency rising hearing loss(66.92%) of mainly mild and moderate severities(68.46%). Conclusion Auditory neuropathy can be accompanied by a variety of neurological diseases, dominated by peripheral neuropathy, manifesting as numbness in limbs, dysmyotonia, ataxia, vision loss, etc. The initial symptoms in patients with syndromic auditory neuropathy can be those of auditory neuropathy or other neurological diseases, although results of hearing evaluation are typically in line with the audiological characteristics of auditory neuropathy.
引文
1 Santarelli R.Information from cochlear potentials and genetic mutations helps localize the lesion site in auditory neuropathy[J].Genome Med,2010,2(12):91.
2 Starr A,Picton TW,Sininger Y,et al.Auditory neuropathy[J].Brain,1996,119(Pt 3)741-753.
3王锦玲,王剑,石力,等.伴发神经系统疾病的听神经病36例临床分析[J].听力学及言语疾病杂志,2011,3(19):197-202.Wang JL,Shi J,Shi L,et al.A clinical analysis of 36 nervous System Disease Patients Acompanying Auditory Neuropathy[J].Journal of Audiology and Speech Pathology,2011,3(19):197-202.
4王秋菊.听神经病:从发现到渐入精准[J].中华耳鼻咽喉头颈外科杂志,2018,53(3):161-171.Wang QJ,Starr A.Hereditary auditory neuropathies:stepping into precision management from the discovery[J].Chin J Otorhinolaryngol Head Neck Surg,2018,53(3):161-171.
5 Who.Report of the Informal Working Group on Prevention of Deafness and Hearing Impairment Programme Planning[J].Geneva,1991,2.
6 Katz J,Medwetsky L,Burkard R.Handbook of clinical audiology.sixth edition.[J].Lippincott:Williams&Wilkins,2009,41.
7朱庆文,朱丽娜,单春光.听神经病的综合研究[J].河北医科大学学报,2011,4(32):493-496.Zhu QW,Zhu LN,Shan ChG.A comprehensive study of auditory neuropathy[J].Journal of Hebei Medical University,2011,4(32):493-496.
8齐悦,兰兰,史伟,等.225例听神经病患者的耳鸣发生特点及临床特征分析[J].中华耳科学杂志,2013,11(01):59-62.Qi Y,Lan L,Shi W,et al.Analysis of Clinical features and tinnitus characteristics in 225 patients with auditory neuropathy[J].Chinese Journal of Otology,2013,11(01):59-62.
9 Ramdharry G.Peripheral nerve disease[J].Handb Clin Neurol,2018,159(403-415.
10 Moser T,Starr A.Auditory neuropathy--neural and synaptic mechanisms[J].Nat Rev Neurol,2016,12(3):135-149.
11 Rance G,Kearns LS,Tan J,et al.Auditory function in individuals within Leber's hereditary optic neuropathy pedigrees[J].JNeurol,2012,259(3):542-550.
12杜卫,刘辉.Wolfram综合征的临床表现、影像学特征、诊断及治疗[J].中国临床神经科学,2018,26(01):104-107.Du W,Liu H.Wolfram Syndrome:Clinical Presentations,Imaging Feature,Diagnosis and Treatment[J].Chin J Clin Neurosci,2018,26(01):104-107.
13 Ha AD,Parratt KL,Rendtorff ND,et al.The phenotypic spectrum of dystonia in Mohr-Tranebjaerg syndrome[J].Movement disorders:official journal of the Movement Disorder Society,2012,27(8):1034-1040.
14 Bamiou DE,Spraggs PR,Gibberd FB,et al.Hearing loss in adult Refsum's disease[J].Clinical otolaryngology and allied sciences,2003,28(3):227-230.
15 Starr A,Rance G.Auditory neuropathy[J].Handb Clin Neurol,2015,129(495-508.
16 Manchaiah VK,Zhao F,Danesh AA,et al.The genetic basis of auditory neuropathy spectrum disorder(ANSD)[J].Int J Pediatr Otorhinolaryngol,2011,75(2):151-158.
17 Starr A,Isaacson B,Michalewski HJ,et al.A dominantly inherited progressive deafness affecting distal auditory nerve and hair cells[J].J Assoc Res Otolaryngol,2004,5(4):411-426.
18齐悦,兰兰,史伟,等.以听神经病为首发病伴周围神经病家系的听力学及遗传学特征分析[J].听力学及言语疾病杂志,2012,20(6):523-527.Qi Y,Lan L,Shi W,et al.Clinical and Genetic Characteristics Analysis of Auditory Neuropathy Acompanying Peripheral Nervous System Disease[J].Journal of Audiology and Speech Pathology,2012,20(6):523-527.
19 Kovach MJ,Campbell KC,Herman K,et al.Anticipation in a unique family with Charcot-Marie-Tooth syndrome and deafness:delineation of the clinical features and review of the literature[J].Am J Med Genet,2002,108(4):295-303.
20 Starr A,Michalewski HJ,Zeng FG,et al.Pathology and physiology of auditory neuropathy with a novel mutation in the MPZgene(Tyr145->Ser)[J].Brain,2003,126(Pt 7):1604-1619.
21 Bahr M,Andres F,Timmerman V,et al.Central visual,acoustic,and motor pathway involvement in a Charcot-Marie-Tooth family with an Asn205Ser mutation in the connexin 32 gene[J].Journal of neurology,neurosurgery,and psychiatry,1999,66(2):202-206.
22 Butinar D,Starr A,Zidar J,et al.Auditory nerve is affected in one of two different point mutations of the neurofilament light gene[J].Clinical neurophysiology:official journal of the International Federation of Clinical Neurophysiology,2008,119(2):367-375.
23 Kalaydjieva L,Gresham D,Gooding R,et al.N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom[J].American journal of human genetics,2000,67(1):47-58.
24 Rance G,Fava R,Baldock H,et al.Speech perception ability in individuals with Friedreich ataxia[J].Brain,2008,131(Pt 8):2002-2012.
25 Koeppen AH.Friedreich's ataxia:pathology,pathogenesis,and molecular genetics[J].Journal of the neurological sciences,2011,303(1-2):1-12.
26 Yu-Wai-Man P,Griffiths PG,Gorman GS,et al.Multi-system neurological disease is common in patients with OPA1 mutations[J].Brain,2010,133(Pt 3):771-786.
27 Chun BY,Rizzo JF,3rd.Dominant optic atrophy:updates on the pathophysiology and clinical manifestations of the optic atrophy
1 mutation[J].Curr Opin Ophthalmol,2016,27(6):475-480.
28 Meyer E,Michaelides M,Tee LJ,et al.Nonsense mutation in TMEM126A causing autosomal recessive optic atrophy and auditory neuropathy[J].Molecular vision,2010,16(650-664.
29 Wang QJ,Li QZ,Rao SQ,et al.AUNX1,a novel locus responsible for X linked recessive auditory and peripheral neuropathy,maps to Xq23-27.3[J].J Med Genet,2006,43(7):e33.
30 Zong L,Guan J,Ealy M,et al.Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder[J].J Med Genet,2015,52(8):523-531.
31 Hansen L,Eiberg H,Barrett T,et al.Mutation analysis of the WFS1 gene in seven Danish Wolfram syndrome families;four new mutations identified[J].Eur J Hum Genet,2005,13(12):1275-1284.
32 Bahmad F,Jr.,Merchant SN,Nadol JB,Jr.,et al.Otopathology in Mohr-Tranebjaerg syndrome[J].The Laryngoscope,2007,117(7):1202-1208.
33 Liaqat K,Schrauwen I,Raza SI,et al.Identification of CAC-NA1D variants associated with sinoatrial node dysfunction and deafness in additional Pakistani families reveals a clinical significance[J].Journal of human genetics,2018
34 Oysu C,Aslan I,Basaran B,et al.The site of the hearing loss in Refsum's disease[J].Int J Pediatr Otorhinolaryngol,2001,61(2):129-134.
2 Starr A,Picton TW,Sininger Y,et al.Auditory neuropathy[J].Brain,1996,119(Pt 3)741-753.
3王锦玲,王剑,石力,等.伴发神经系统疾病的听神经病36例临床分析[J].听力学及言语疾病杂志,2011,3(19):197-202.Wang JL,Shi J,Shi L,et al.A clinical analysis of 36 nervous System Disease Patients Acompanying Auditory Neuropathy[J].Journal of Audiology and Speech Pathology,2011,3(19):197-202.
4王秋菊.听神经病:从发现到渐入精准[J].中华耳鼻咽喉头颈外科杂志,2018,53(3):161-171.Wang QJ,Starr A.Hereditary auditory neuropathies:stepping into precision management from the discovery[J].Chin J Otorhinolaryngol Head Neck Surg,2018,53(3):161-171.
5 Who.Report of the Informal Working Group on Prevention of Deafness and Hearing Impairment Programme Planning[J].Geneva,1991,2.
6 Katz J,Medwetsky L,Burkard R.Handbook of clinical audiology.sixth edition.[J].Lippincott:Williams&Wilkins,2009,41.
7朱庆文,朱丽娜,单春光.听神经病的综合研究[J].河北医科大学学报,2011,4(32):493-496.Zhu QW,Zhu LN,Shan ChG.A comprehensive study of auditory neuropathy[J].Journal of Hebei Medical University,2011,4(32):493-496.
8齐悦,兰兰,史伟,等.225例听神经病患者的耳鸣发生特点及临床特征分析[J].中华耳科学杂志,2013,11(01):59-62.Qi Y,Lan L,Shi W,et al.Analysis of Clinical features and tinnitus characteristics in 225 patients with auditory neuropathy[J].Chinese Journal of Otology,2013,11(01):59-62.
9 Ramdharry G.Peripheral nerve disease[J].Handb Clin Neurol,2018,159(403-415.
10 Moser T,Starr A.Auditory neuropathy--neural and synaptic mechanisms[J].Nat Rev Neurol,2016,12(3):135-149.
11 Rance G,Kearns LS,Tan J,et al.Auditory function in individuals within Leber's hereditary optic neuropathy pedigrees[J].JNeurol,2012,259(3):542-550.
12杜卫,刘辉.Wolfram综合征的临床表现、影像学特征、诊断及治疗[J].中国临床神经科学,2018,26(01):104-107.Du W,Liu H.Wolfram Syndrome:Clinical Presentations,Imaging Feature,Diagnosis and Treatment[J].Chin J Clin Neurosci,2018,26(01):104-107.
13 Ha AD,Parratt KL,Rendtorff ND,et al.The phenotypic spectrum of dystonia in Mohr-Tranebjaerg syndrome[J].Movement disorders:official journal of the Movement Disorder Society,2012,27(8):1034-1040.
14 Bamiou DE,Spraggs PR,Gibberd FB,et al.Hearing loss in adult Refsum's disease[J].Clinical otolaryngology and allied sciences,2003,28(3):227-230.
15 Starr A,Rance G.Auditory neuropathy[J].Handb Clin Neurol,2015,129(495-508.
16 Manchaiah VK,Zhao F,Danesh AA,et al.The genetic basis of auditory neuropathy spectrum disorder(ANSD)[J].Int J Pediatr Otorhinolaryngol,2011,75(2):151-158.
17 Starr A,Isaacson B,Michalewski HJ,et al.A dominantly inherited progressive deafness affecting distal auditory nerve and hair cells[J].J Assoc Res Otolaryngol,2004,5(4):411-426.
18齐悦,兰兰,史伟,等.以听神经病为首发病伴周围神经病家系的听力学及遗传学特征分析[J].听力学及言语疾病杂志,2012,20(6):523-527.Qi Y,Lan L,Shi W,et al.Clinical and Genetic Characteristics Analysis of Auditory Neuropathy Acompanying Peripheral Nervous System Disease[J].Journal of Audiology and Speech Pathology,2012,20(6):523-527.
19 Kovach MJ,Campbell KC,Herman K,et al.Anticipation in a unique family with Charcot-Marie-Tooth syndrome and deafness:delineation of the clinical features and review of the literature[J].Am J Med Genet,2002,108(4):295-303.
20 Starr A,Michalewski HJ,Zeng FG,et al.Pathology and physiology of auditory neuropathy with a novel mutation in the MPZgene(Tyr145->Ser)[J].Brain,2003,126(Pt 7):1604-1619.
21 Bahr M,Andres F,Timmerman V,et al.Central visual,acoustic,and motor pathway involvement in a Charcot-Marie-Tooth family with an Asn205Ser mutation in the connexin 32 gene[J].Journal of neurology,neurosurgery,and psychiatry,1999,66(2):202-206.
22 Butinar D,Starr A,Zidar J,et al.Auditory nerve is affected in one of two different point mutations of the neurofilament light gene[J].Clinical neurophysiology:official journal of the International Federation of Clinical Neurophysiology,2008,119(2):367-375.
23 Kalaydjieva L,Gresham D,Gooding R,et al.N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom[J].American journal of human genetics,2000,67(1):47-58.
24 Rance G,Fava R,Baldock H,et al.Speech perception ability in individuals with Friedreich ataxia[J].Brain,2008,131(Pt 8):2002-2012.
25 Koeppen AH.Friedreich's ataxia:pathology,pathogenesis,and molecular genetics[J].Journal of the neurological sciences,2011,303(1-2):1-12.
26 Yu-Wai-Man P,Griffiths PG,Gorman GS,et al.Multi-system neurological disease is common in patients with OPA1 mutations[J].Brain,2010,133(Pt 3):771-786.
27 Chun BY,Rizzo JF,3rd.Dominant optic atrophy:updates on the pathophysiology and clinical manifestations of the optic atrophy
1 mutation[J].Curr Opin Ophthalmol,2016,27(6):475-480.
28 Meyer E,Michaelides M,Tee LJ,et al.Nonsense mutation in TMEM126A causing autosomal recessive optic atrophy and auditory neuropathy[J].Molecular vision,2010,16(650-664.
29 Wang QJ,Li QZ,Rao SQ,et al.AUNX1,a novel locus responsible for X linked recessive auditory and peripheral neuropathy,maps to Xq23-27.3[J].J Med Genet,2006,43(7):e33.
30 Zong L,Guan J,Ealy M,et al.Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder[J].J Med Genet,2015,52(8):523-531.
31 Hansen L,Eiberg H,Barrett T,et al.Mutation analysis of the WFS1 gene in seven Danish Wolfram syndrome families;four new mutations identified[J].Eur J Hum Genet,2005,13(12):1275-1284.
32 Bahmad F,Jr.,Merchant SN,Nadol JB,Jr.,et al.Otopathology in Mohr-Tranebjaerg syndrome[J].The Laryngoscope,2007,117(7):1202-1208.
33 Liaqat K,Schrauwen I,Raza SI,et al.Identification of CAC-NA1D variants associated with sinoatrial node dysfunction and deafness in additional Pakistani families reveals a clinical significance[J].Journal of human genetics,2018
34 Oysu C,Aslan I,Basaran B,et al.The site of the hearing loss in Refsum's disease[J].Int J Pediatr Otorhinolaryngol,2001,61(2):129-134.