| Low frequency hearing loss is a sensorineural hearing loss involving frequencies below 1000 Hz.The pathogenesis and clinical outcome are not clear,and it can be the external manifestations of a large class of clinical disease:such as hereditary deafness,auditory neuropathy,Meniere’s disease,migraine,acute low-frequency sensorineural deafness,etc.These diseases are sometimes intertwined and difficult to distinguish,and this complex etiology is increased.The diagnosis and treatment difficulty of low-frequency sensorineural deafness is worthy of in-depth exploration and research.This study is based on the national deafness gene pool and China’s rich clinical deafness resources,including the following two contentsPart Ⅰ Identification and new phenotypic study of DIAPH1 gene mutation in low frequency sensorineural hearing lossObjectiveTo explore the clinical phenotypic characteristics and molecular genetic mechanism of low-frequency related autosomal dominant deafness family,enrich the hereditary deafness gene pool,and provide evidence for genetic counseling and pre-pregnancy diagnosis.MethodsThrough the form of questionnaires,the history of 1507327 families collected in the previous period was collected,using pure audiometry,speech recognition rate detection,auditory brainstem response,distortion otoacoustic emission and other audiological examination methods and imaging examination methods.The deafness phenotype was analyzed in depth,the genetic map was drawn,the genetic model was determined,and the pathogenicity analysis of the family was carried out by means of the classic deafness gene linkage analysis and a new generation of all exome sequencing technology.Results1.A total of 51 people were investigated in 1507327,and 20 people were found to have hearing loss.Among them,15 were relatives of sensorineural deafness,2 were conductive deafness,1 were mixed deafness,and 2 were spouse sensorineural deafness.Among the immediate family members of the sensorineural deafness:6 males and 9 females;the age of onset was 8 to 49 years old,with an average of 31.7 years;4 cases of low-frequency hearing loss,11 cases of full-frequency hearing loss;and mild hearing loss 2 For example,moderate in 4 cases,moderate to severe in 3 cases,severe in 5 cases,and profound in 1 case;the mean hearing threshold（y）increased gradually with age（x）（y=1.180x+4.886,R2=0.618,P=0.001）Each generation of continuous disease,each generation of men and women can be sick;among the family members who have undergone hearing tests,the prevalence of the second generation is 100%（1/1）,and the prevalence of the third generation is 61.11%（11/18）.The prevalence of IV was 13.04%（3/23）;the average age of onset of Ⅱ was 35.00 years,the average age of onset of Ⅲ was 32.45 years,and the average age of onset of IV was 27.67 years.The deafness family is an autosomal dominant inheritance model.2.Linkage analysis locked the linkage region of the deafness phenotype to the range of chromosome 138.845～149.509cM（physical position chr5:137876920～146572145）,the LOD value of this region was>4;the whole exome analysis found that it was located in the known deafness The frameshift variation of the related gene DIAPH1 c.3551 3552del was separated in the core family of the test,and the frequency was 0 in the database of multiple populations.Many predictive software predicted disease,and the surrounding area was highly conserved.The mutation led to the advance of protein translation.Upon termination,Sanger sequencing verified that the variant did not completely separate the phenotype in other members of the family,and that 3 earriers who did not reach the age of onset had no phenotype.The gene is located in the above-mentioned linkage region,and no other suspected pathogenic mutations were found in the second-generation sequencing in this region.3.4 of the 3 generations of the family branch showed a poor phenotype of auditory nerve synchronization,which can be heard cannot understand the language,ABR abnormalities,DPOAE or CM waves can be induced,acoustic reflection cannot lead or Delay,-SP/AP>1;but the speech recognition rate is better,with the increase of hearing decline,the ABR waveform anomaly gradually increases and DPOAE gradually loses.The eldest patients in this group had extremely severe hearing loss,ABR could not be drawn,and DPOAE and CM waves could not be drawn.The phenotype of dyssynchrony of the auditory nerve was first reported in the DIAPH1 gene-related family.ConclusionsThe 1507327 family is a family of autosomal dominant hereditary deafness with a low frequency onset and gradually affecting the full frequency,and the degree of hearing loss is gradually increased.DIAPH1 c.35513552del is the causative gene of this family.The dyssynchrony of auditory nerve is the new gene of this gene.Part Ⅱ Clinical research of recurrent low-frequency sensorineural deafnessObjectiveExploring the clinical characteristics,outcomes and diagnosis of recurrent low-frequency sensorineural deafness,understanding the process and outcome of the disease to develop a feasible and practical clinical early warning program and identify the differential membrane hydrops,migraine,etc.Provide a theoretical basis for different causes and use of drugs.MethodsRetrospective analysis of 47 cases（53 ears）of recurrent low-frequency sensorineural deafness in patients with medical history,clinical manifestations,audiological examination,auxiliary examination and other data,telephone return to some patients,fill out the follow-up questionnaire,draw a pure tone audiometry curve.Results1.General conditions:A total of 47 cases（53 ears）were brought into the study,the duration of hearing examination ranged from 1 to 124 months,with a median of 8 months.The duration of the disease ranged from 3 to 320 months,with an average duration of 29 months.The incidence of tinnitus was 93.6%,the incidence of ear tightness was 83.0%,and 38.3%of patients presented vestibular symptoms in the course of disease development.2.During the observation period,27 cases（57.4%）were diagnosed with related diseases:7 cases（14.9%）Meniere’s disease,6 cases（12.8%）vestibular migraine,2 cases（4.3%）with Meniere’s disease and migraine,and 1 case（2.1%）with idiopathic intracranial hypotension 11 cases（23.4%）were possible cochlear migraine;Migraine-related RLFD had a younger onset age,more common in women.3.83.0%of patients had stable or improved low-frequency hearing during the observation period,17.0%The patient experienced low-frequency hearing;18.9%of patients had high-frequency hearing loss;RLFD had 6 types of audiological outcomes:low-frequency improvement/high-frequency stability;low-frequency stability/high-frequency stability;low frequency progress/high frequency stability type;low frequency improvement/high frequency progress type;low frequency stability/high frequency progress type;low frequency progress/high frequency progress type;The low frequency hearing prognosis of Rising Type hearing curve is good,Mountain Type and Descending are poor.4.Auxiliary examination results:the positive rate of all patients receiving cochlear electrogram or glycerol test was 27.3%,and the positive rate of migraine related patients was 21.4%;the diagnosis of Meniere’s disease The positive rate of patients was 37.5%;the positive rate of patients who received vestibular function tests was 35.0%,the positive rate of migraine-related cases was 22.2%,and the positive rate of Meniere cases was 42.9%;15.0%of patients had high and low stimulating ABR and positive ears The side is consistent;40.0%of MRV inferior lateral venous return is consistent with the affected side.ConclusionsTinnitus and ear suffocation are early symptoms and most plagued the symptoms of RLFD patients.Migraine-related mechanisms may play an important role in the pathogenesis of RLFD,and the age of onset is small,and women are more common.Rare causes such as low intracranial pressure syndrome cannot be ignored.After long-term fluctuation of RLFD,the hearing is mostly stable or improved,but some patients may have low frequency and high frequency hearing.The initial hearing curve type is the influencing factor of prognosis.Long-term hearing follow-up can help to evaluate prognosis. |
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