Analysis Of Clinical And Genetic Features And Assessment Of Aetiology Of Infants And Young Children With Auditory Neuropathy Spectrum Disorder

Auditory neuropathy spectrum disorder(ANSD), also known as auditory neuropathy(AN), describe a special kind of auditory disorders due to dysfunction of the synapse of the inner hair cells and auditory nerve, and/or the auditory nerve itself. It is one of the most common diseases leading to hearing and speech communication barriers in infants and young children with the prevalence of 0.23% in infants with risk factors, and it accounts for approximately 8% of the newly diagnosed cases of hearing loss in children each year. But, the etiologies, the exact sites of lesions and the pathogenesis of ANSD are still not well understood, which results in the difficulties of clinical interventions for these patients. The key to break the bottleneck lies in the identification of the etiology and pathogenesis of different patients and the clinical classification of ANSD, which is very important to personalized intervention.The period in infant and young children is an important stage for hearing and language development, so early diagnosis and intervention of ANSD in infant and young children would be vital to their growth. So, in the present study, we analysised the clinical features of ANSD in infant and young children and explored the etiological characteristics from the the viewpoint of genetic and environmental factors. And then we analysised the clinical characteristics of different causes and discussed the strategies and methods of clinical classification.The thesis is divided into four parts:PART 1:Clinical characters of infants and young Children with auditory neuropathy spectrum disorderWe enrolled 85 unrelated infants and young children with ANSD, and analysed the clinical and audiological characteristics of them. Except the special kind of ANSD like temperature sensitivity ANSD and unilateral ANSD, most of the infants and young children showed severe to profound hearing loss, accounting for 93.62%. In the 85 cases, only 1 was identified with retinopathy, the rest was not found with accompanying symptoms. Most of the hearing impairment was found in the age of 7 months to 2 years old, accounting for 75.3%; while only 16.5% were identified before 3 months and 24.7% before 6 months. Besides, in 20 cases accepted newborn hearing screening,15 cases were passed with bilateral ears (75%).PART 2:High frequency of OTOF mutations in Chinese infants and young Children with auditory neuropathy spectrum disorderHere, we investigated the contribution of OTOF mutations to congenital ANSD patients in China.37 subjects with congenital ANSD were screened for all the exons of OTOF gene. We identified a total of 25 probable pathogenic mutations, of them,18 were novel and 7 were previously reported mutations. In the 37 cases,14 were shown to carry two or three mutant alleles of OTOF with the high frequency of 37.8%. Our results confirmed that mutations in the OTOF gene were a major cause of congenital ANSD in China.PART 3:Risk factors investigation and etiology analysis in infants and young Children with auditory neuropathy spectrum disorderIn this study, a retrospective analysis of risk factors in 78 infants and young Children with ANSD was performed. Of them,12 were identified with significant risk factors, accounted for 15.38%. The main risk factors include:hyperbilirubinemia encephalopathy, hypoxic ischemic encephalopathy, premature birth, low birth weight, anoxia/asphyxia. Besides, we alos found that most of the cases had more than one risk factor. In the 12 cases with significant risk factors,5 were screened for OTOF gene, and none was identified with OTOF mutations. But, in the cases without risk factors,26 cases were screened for OTOF gene and 50% were identified with OTOF mutations.PART 4:Follow up observision and clinical investigation of patients with temperature sensitive auditory neuropathyIn the present study, we reported four 2-6 years old children who were diagnosed with ANSD complained of severe hearing loss when they had fever. Their hearing thresholds varied from the morning to the afternoon, before and after a workout or taking a shower. Three of these patients’hearing improved with age. Genetic analysis revealed that these patients were otoferlin (OTOF) homozygotes or compound heterozygotes mutations. Our study suggests that these gene mutations may be the cause of temperature sensitive auditory neuropathy. The long term follow up study suggests that the hearing loss in this type of auditory neuropathy may recover with age. Our study has provided important information for clinical management of this disease.