Sensory Hearing Loss Research Articles

The impact of degree of hearing loss on auditory brainstem response predictions of behavioral thresholds.

Diagnosis of hearing loss and prescription of amplification for infants and young children require accurate estimates of ear- and frequency-specific behavioral thresholds based on auditory brainstem response (ABR) measurements. Although the overall relationship between ABR and behavioral thresholds has been demonstrated, the agreement is imperfect, and the accuracy of predictions of behavioral threshold based on ABR may depend on degree of hearing loss. Behavioral thresholds are lower than ABR thresholds, at least in part due to differences in calibration interacting with the effects of temporal integration, which are manifest in behavioral measurements but not ABR measurements and depend on behavioral threshold. Listeners with sensory hearing loss exhibit reduced or absent temporal integration, which could impact the relationship between ABR and behavioral thresholds as degree of hearing loss increases. The present study evaluated the relationship between ABR and behavioral thresholds in infants and children over a range of hearing thresholds, and tested an approach for adjusting the correction factor based on degree of hearing loss as estimated by ABR measurements. A retrospective review of clinical records was completed for 309 ears of 177 children with hearing thresholds ranging from normal to profound hearing loss and for whom both ABR and behavioral thresholds were available. Children were required to have the same middle ear status at both evaluations. The relationship between ABR and behavioral thresholds was examined. Factors that potentially could affect the relationship between ABR and behavioral thresholds were analyzed, including degree of hearing loss observed on the ABR, behavioral test method (visual reinforcement, conditioned play, or conventional audiometry), the length of time between ABR and behavioral assessments, and clinician-reported reliability of the behavioral assessment. Predictive accuracy of a correction factor based on the difference between ABR and behavioral thresholds as a function of ABR threshold was compared to the predictive accuracy achieved by two other correction approaches in current clinical use. As expected, ABR threshold was a significant predictor of behavioral threshold. The agreement between ABR and behavioral thresholds varied as a function of degree of hearing loss. The test method, length of time between assessments, and reported reliability of the behavioral test results were not related to the differences between ABR and behavioral thresholds. A correction factor based on the linear relationship between the differences in ABR and behavioral thresholds as a function of ABR threshold resulted in more accurately predicted behavioral thresholds than other correction factors in clinical use. ABR is a valid predictor of behavioral threshold in infants and children. A correction factor that accounts for the effect of degree of hearing loss on the differences between ABR and behavioral thresholds resulted in more accurate predictions of behavioral thresholds than methods that used a constant correction factor regardless of degree of hearing loss. These results are consistent with predictions based on previous research on temporal integration for listeners with hearing loss.

De novo interstitial deletion of 15q22q23 with global developmental delay and hypotonia: the first Korean case.

Interstitial deletions involving the chromosome band 15q22q24 are very rare and only nine cases have been previously reported. Here, we report on a 12-day-old patient with a de novo 15q22q23 interstitial deletion. He was born by elective cesarean section with a birth weight of 3,120 g at 41.3-week gestation. He presented with hypotonia, sensory and neural hearing loss, dysmorphism with frontal bossing, flat nasal bridge, microretrognathia with normal palate and uvula, thin upper lip in an inverted V-shape, a midline sacral dimple, severe calcanovalgus at admission, and severe global developmental delay at 18 months of age. Fluorescence in situ hybridization findings confirmed that the deleted regions contained at least 15q22. The chromosome analysis revealed a karyotype of 46,XY,del(15) (q22q23). Parental chromosome analysis was performed and results were normal. After reviewing the limited literature on interstitial 15q deletions, we believe that the presented case is the first description of mapping of an interstitial deletion involving the chromosome 15q22q23 segment in Korea. This report adds to the knowledge of the clinical phenotype associated with the 15q22q23 deletion.

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The Relationship between Severe Hyperbilirubinemia and Abnormal Auditory Brainstem Response in children

Introduction: Hyperbilirubinemia is one of the most common cause of congenital sensory neuronal hearing loss. These patients are screened by auditory brainstem response (ABR) test at bilirubin levels higher than 1% of gestational weight. Aim of this study is to determine whether hyperbilirubinemia less than 1% of gestational weight could induce hearing loss and abnormal auditory brainstem response (ABR). Materials and Methods: In this case control study the outcome of ABR test in children younger than 3 years old with a history of term delivery and hyperbilirubinemia (bilirubin level less than 1% of gestational weight) were compared with the control group without hyperbilirubinemia matched for age and gender. Results: Mean ABR amplitude (wave I, V) were significantly prolonged in neonates with jaundice compared with controls (P 0.6% gestational weight was 2.25 with 95% confidence intervals (CI) (1.44-3.89 and p=0.02). Conclusion: Our study showed a relevant association between bilirubin levels less than 20 mg/dl and abnormal ABR.

Reinnervation of hair cells by neural stem cell-derived neurons

Background Replacement of spiral ganglion neurons would be one prioritized step in an attempt to restore sensory neuronal hearing loss. However, the possibility that transplanted neurons could regenerate new synaptic connections to hair cells has not been explored. The objective of this study was to test whether neural stem cell (NSC)-derived neurons can form synaptic connections with hair cells in vitro. Methods NSCs were mechanically separated from the hippocampus in SD rat embryos (E12-E14) and cultured in a serum-free medium containing basic fibroblast growth factor and epidermal growth factor. Rat NSCs were co-cultured with explants of cochlea sensory epithelia obtained from postnatal Day 3 rats under transway filter membrane. Results At Day 3, the NSCs began to show chemotactic differentiation and grew toward cochlea sensory epithelia. After 9-day co-culture, neurites of NSC-derived neurons predominantly elongated toward hair cells. Immunohistochemical analyses revealed the fibers overlapped with synapsin and hair cells, indicating the formation of new synaptic connections. After 14-day culture, triple staining revealed the fibers overlapped with PSD95 (postsynaptic density) which is juxtaposed with CtBP2 (presynaptic vesicle), indicating the formation of new ribbon synapse. Conclusions NSC-derived neurons can make synaptic connections with hair cells and provide a model for studying synaptic plasticity and regeneration. Whether the newly forming synapse is functional merits further electrophysiological study.

How difficult is difficult? Speech perception in noise in the elderly hearing impaired.

Perception of speech in the presence of competing multitalker noise is difficult for most individuals with sensory hearing loss, and in particular, for the elderly hearing impaired. Elderly people frequently report that these difficulties are poorly compensated for by hearing aids, albeit the algorithms and technologies aiming to improve speech perception in noise. The aim of the current study was therefore to assess competing speech signals processing by measuring the amount of signal to noise ratio (SNR) loss experienced by elderly hearing impaired individuals and their performance in dichotic listening tests. Speech in multitalker babble noise and dichotic listening were assessed in older hearing impaired individuals and in young normal-hearing adults. The average dichotic scores in the elderly group were substantially and significantly lower compared with the scores of the younger group with a significant right ear advantage (higher accuracy in reporting words arriving at the right ear than words arriving at the left ear) in the elderly group. Speech identification in noise in the older group was significantly poorer than in the younger group (SNR loss: 10 dB). The poor performance in the elderly hearing impaired group highlights the difficulties faced by hearing impaired older adults in demanding listening environments. Our results suggest that it may be unreasonable to expect that elderly hearing impaired individuals may fully understand speech in multitalker environments even when hearing aids are used.

The outcome of our modified double-flap technique for cochlear implantation: A case series of 342 consecutive patients

ObjectivesA lazy S-shaped postauricular incision with a modified double-flap technique has been used for cochlear implant surgery at our institution for the past 10 years. The postoperative surgical complications, morbidity, and outcome of this technique were evaluated.MethodsA retrospective case review was conducted in a tertiary referral teaching center. A total of 342 patients with profound sensory hearing loss (173 female and 169 male subjects; age range, 11 months to 52 years) who underwent cochlear implantation using the double-flap postauricular transmastoid surgical approach during a 5-year period (2005 through 2009) with at least 5 years' follow-up were retrospectively evaluated. Postoperative wound complications were identified. Major complications included flap necrosis, wound infection requiring surgical intervention, and wound dehiscence with or without implant exposure. Swelling over the implant and superficial wound infections treated medically were considered minor complications. Other non-wound-related complications, surgical time, and number of electrodes inserted were also recorded.ResultsThe surgical approach was accomplished in all the patients with four minor wound complications. The mean surgical time was 1.4 hours, and the mean time between surgery and the programming process was 2 weeks.ConclusionThis modified double-flap technique was easy to perform and appeared to reduce the incidence of wound complications in cochlear implant surgery. It allowed programming of the implant after a shorter period of time.

Loudness perception affected by high doses of salicylate—A behavioral model of hyperacusis

The major side-effects of high doses of salicylate include sensorial hearing loss and tinnitus. Although salicylate decreases cochlear output, it enhances the evoked potentials recorded from the central auditory system (CAS), suggesting an increase to sound sensitivity. However, the loudness change after salicylate administration has not yet been directly measured. In this study, we established an operant conditioning based behavioral task in rats and measured their loudness perception changes before and after high doses of salicylate injection (250mg/kg, i.p.). We found that high doses of salicylate induced a significant increase to loudness response in 40% of the rats (out of 20 rats), suggesting a hyperacusis behavior. In another 40% of rats, a rapid increase of loudness response was detected, suggesting loudness recruitment. The reaction time of the rats was also measured during the loudness tests before and after salicylate exposure. The reaction time level functions are highly correlated to the loudness response functions. Our studies confirmed that increased sound sensitivity, which is commonly seen in patients with tinnitus and hyperacusis, can be induced by high doses of salicylate. This loudness change induced by salicylate may be related with hypersensitivity in the CAS.

A Comparison of Auditory Brain Stem Responses Elicited by Click and Chirp Stimuli in Adults With Normal Hearing and Sensory Hearing Loss

The aim of this study was to compare the human auditory brain stem response (ABR) elicited by clicks and chirps with overall behavioral hearing thresholds in participants with normal hearing and with sensory hearing loss. The authors hypothesized that ABRs to chirps would be more robust and that thresholds would be more similar to overall behavioral hearing thresholds compared with ABRs to clicks. Twenty-five adults with normal hearing and 25 adults with sensory hearing loss were recruited. Subjects were without middle ear or neurological pathologies at the time of testing. Subjects with sensory hearing loss were separated into mild to moderate hearing loss and mild to severe hearing loss groups. Behavioral hearing thresholds for pure tones were obtained at nine octave and interoctave frequencies ranging from 250 to 8000 Hz; an average of these nine frequencies was calculated for each participant. Evoked potential thresholds were measured by ABRs to click and chirp stimuli. Analyses included wave V absolute latencies and wave V peak-to-peak amplitudes. Thresholds for ABRs to clicks and chirps were compared with each other and with overall behavioral hearing thresholds. ABR thresholds to chirp and click stimuli did not differ significantly for either the normal-hearing or the hearing loss groups. Wave V peak-to-peak amplitude was higher for chirps than clicks, particularly at lower intensities, for all groups. ABR thresholds to chirps were closer to overall behavioral thresholds than clicks in all groups. Moreover, ABR thresholds to chirps did not differ significantly from behavioral thresholds in the two hearing loss groups. ABRs obtained with chirp stimuli provide an efficient method for estimating hearing thresholds in individuals with normal hearing and sensory hearing loss where broadband signals are selected for testing. ABRs to chirps display higher peak-to-peak amplitudes than those obtained with clicks and may provide responses closer to behavioral thresholds. This information could result in improved accuracy in identifying hearing loss and estimating hearing sensitivity for broadband signals in infants, children, and difficult-to-test older populations.

Fatores que interferem no desempenho de usuários de implante coclear em testes de percepção de fala

Objetivo : analisar os fatores que interferem no desempenho de usuários de implante coclear em testes de percepção de fala.Métodos : foram aplicados questionários e testes de percepção de fala em 25 indivíduos, de ambos os sexos, portadores de perda auditiva neurossensorial e usuários de IC unilateral.Resultados : - 48% dos participantes atingiram bom desempenho nos resultados dos testes de percepção de fala, apresentando porcentagens maiores ou iguais a 50 % de acertos. - Os participantes que obtiveram melhores resultados não são necessariamente os que possuem maior idade auditiva. - Dos 12 participantes que atingiram desempenho acima de 50%, 10 (83,3%) foram implantados mais precocemente (até 5 anos). - O uso do AASI na orelha contralateral influenciou significantemente nos índices de reconhecimento das palavras ou sentenças. - Os participantes que iniciaram o uso de AASI mais cedo não foram necessariamente os que apresentaram melhores resultados nos testes.Conclusão : a ativação mais precoce dos IC mostrou-se uma variável importante no desempenho dos testes. - O uso do AASI na orelha contralateral influenciou significantemente nos índices de reconhecimento das palavras ou sentenças.

ANCA関連血管炎性中耳炎の臨床像と診断基準（案）

Chronic otitis media or deep sensorineural deafness often develops due to ANCA (antineutrophil cytoplasmic antibody)-associated vasculitis such as granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), and similar diseases of the ear has recently been termed otitis media with ANCA-associated vasculitis (OMAAV). The OMAAV-working group was subsequently organized in the Japan Otological Society and studied 90 cases with OMAAV. All patients complained initially of ear symptoms such as hearing loss, ear pain and/or otorrhea, which were not improved by treatments with antibiotics and tympanic tube insertion. At the initial visit, granulomatous lesions in the tympanic cavity and/or mastoid cavity were seen in 74 (89.2%). Serum PR3- or MPO-ANCAs were detected in 66 (78%) patients. Eighty three (92%) patients had sensory hearing loss. Facial nerve palsy, hypertrophic pachymeningitis, lung lesions and kidney lesions developed in 25 (28%), 18 (21%), 8 (9%) and 6 (7%) patients, respectively. Three (3%) patients died because of subarachnoid hemorrhage due to vasculitis of the basilar artery. When a lesion progresses, it is easy for concomitant complications to occur alongside OMAAV such as facial paralysis and hyperplastic pachymeningitis. The current diagnostic criteria of ANCA-related vasculitis cannot be used to diagnose cases of OMAAV. Even if a diagnosis is not made of an intractable upper respiratory tract lesion including the ear, it is necessary to bear OMAAV in mind when thinking about the AAV (ANCA-associated vasculitis)-related lesions. OMAAV cases are being accumulated by the OMAAV working group, and pathologic elucidation currently anticipated.

手術治療したサーファーズ・イア7 耳の検討

When the ear canal often gets exposed to cold water, it leads to the formation of a state called external auditory canal exostoses. This condition is known as surfer’s ear because it is commonly seen among surfers. We experienced seven cases of surfer’s ear from March 2008 to October 2012. All these patients were males with more than 15 years’ experience of surfing. These patients consistently complained of having ear-fullness and hearing loss. In all of these cases, a surgical approach was adopted and performed. The posterior ear incision with a trans-canal approach was chosen for all the cases.It might appear to be difficult to approach an anterior elevated exostoses in the wall of the external auditory canal via this approach, but drilling the external auditory canal in a conical shape from the posterior wall could enlarge the access very appropriately.The method provides a wide field of view and enough space for surgical techniques; therefore it could decrease the risk of sensory hearing loss due to surgical damage. The post surgical results of the canal formation demonstrated successful enlargement with a good shape in all the cases we have experienced.

A case of neurosarcoidosis with labyrinthine involvement.

Sarcoidosis is a chronic granulomatous disease of unknown aetiology, which may involve any organ system. It most commonly occurs in adults with childhood involvement being rare. Central nervous system involvement is seen in up to 25% and typically involves meningeal disease resulting in multiple cranial neuropathies. Other common clinical findings include seizures, headache, dementia, and pituitary dysfunction. Imaging plays a central role in the diagnosis with typical findings including pachymeningeal and leptomeningeal enhancing lesions. Other imaging findings include lacunar and major territory infarcts, hypothalamic and infundibular thickening, hydrocephalus, and cranial nerve enhancement. We present a case of an eight-year-old male patient with progressive headache, visual disturbance, unilateral sensory hearing loss, and multiple cranial neuropathies. Imaging findings demonstrated the classic pachymeningeal and leptomeningeal enhancement along much of the skull base, as well as enhancement of the right and left second and eighth cranial nerves. Extensive inflammatory changes were noted in the temporal bones and paranasal sinuses. There was also enhancement of the right and left labyrinths. Sinus biopsy confirmed sarcoidosis. We present the first case to our knowledge of sarcoid labyrinthitis.

Round window closure affects cochlear responses to suprathreshold stimuli

The round window acts as a vent for releasing inner ear pressure and facilitating basilar membrane vibration. Loss of this venting function affects cochlear function, which leads to hearing impairment. In an effort to identify functional changes that might be used in clinical diagnosis of round window atresia, the current investigation was designed to examine how the cochlea responds to suprathreshold stimuli following round window closure. Prospective, controlled, animal study. A rat model of round window occlusion (RWO) was established. With this model, the thresholds of auditory brainstem responses (ABR) and the input/output (IO) functions of distortion product otoacoustic emissions (DPOAEs) and acoustic startle responses were examined. Round window closure caused a mild shift in the thresholds of the auditory brainstem response (13.5 ± 9.1 dB). It also reduced the amplitudes of the distortion product otoacoustic emissions and the slope of the input/output functions. This peripheral change was accompanied by a significant reduction in the amplitude, but not the threshold, of the acoustic startle reflex, a motor response to suprathreshold sounds. In addition to causing mild increase in the threshold of the auditory brainstem response, round window occlusion reduced the slopes of both distortion product otoacoustic emissions and startle reflex input/output functions. These changes differ from those observed for typical conductive or sensory hearing loss, and could be present in patients with round window atresia. However, future clinical observations in patients are needed to confirm these findings.

In Vivo Gene Transfer into Neonatal Mice Cochlea Using Adeno‐ Associated Viral Vectors

Objectives: Although sensory hearing loss is the most common sensory disorder, with more than 75% of genetic origin, there are no curative treatments available. A promising approach to restore inherited hearing loss consists of introducing a functional copy of the deficient gene using gene therapy. The present study develops a non-invasive surgical approach using adeno-associated viruses (AAV) vector to introduce reporter genes into neonatal mice cochleae, without affecting the normal development of hearing. Methods: AAV2, AAV2/8, AAV2/1, and AAV8, carrying green fluorescent protein (GFP) reporter gene, were tested using 150 neonatal mice. Two microliters of vectors, with titer of 1013 vg/ml, were injected into the scala tympani through the round window. Two weeks after viral injection, evoked auditory brain-stem responses (ABR) were recorded; cellular expression and distribution of GFP were analyzed by immunohistochemistry and confocal imaging. Results: AAV2/8 vector transduced cochlear inner hair cells with high efficiency (80%) and to a lesser degree supporting cells (40%). Serotype 8 transduced mostly neurons (30%). The efficiency of serotypes 2/1, 1, and 2 varied from 5% to 80% of the inner hair cells and from 35% to 80% of supporting cells. The recording of the evoked ABR responses of the injected mice at P16 showed that cochlear function is not affected. Conclusions: We have developed a surgical procedure that might be useful for AAV gene transfer into the cochlea to treat genetic deafness. As a next step, a therapeutic gene will be transferred into a mouse model for human deafness to correct hearing loss.

3D‐FIESTA Screening for Unilateral Auditory Dysfunction

Objectives: In patients with unilateral auditory dysfunctions such as tinnitus and hearing loss, differential diagnosis of cochlear, retrocochlear, or vascular problems is important. Because unilateral hearing loss and tinnitus patients are increasing recently, screening tools are required. There are many diagnostic tests for differential diagnosis about patients with unilateral auditory dysfunction, but there is no efficient screening tool which can confirm all lesions. The purpose of this work is to assess the clinical usefulness of 3D fast imaging employing steady state acquisition (3D-FIESTA) sequence in unilateral hearing loss or tinnitus. Methods: Two hundred and sixty patients with unilateral tinnitus and hearing loss who underwent 3D-FIESTA temporal bone imaging were retrospectively analyzed, looking atmedical charts and radiologic reports. Otologic symptoms, which were measured based on pure tone audiometry results, were reviewed. We evaluated radiologic pathologic finding in the cochlear and retrochoclear areas. Results: Of the hearing symptoms, tinnitus comprised 49.6%, sudden sensory hearing loss, 31.9%, and unilateral hearing disturbance, 15.7%. Twelve patients were diagnosed with acoustic neuromas, four with enlarged vestibular aqueduct syndrome, two with posterior inferior cerebellar artery aneurysms, inner ear anormaly and vestibular cochlear nerve palsy each by 3D-FIESTA MR. Conclusions: 3D-FIESTA MR is highly sensitive and a cost effective method for differential diagnosis of hearing loss and tinnitus. 3D-FIESTA MR image is a useful diagnostic tool as screening for cochlear and retrocochlear lesions.

Establishment of Mouse Model of MYH9 Disorders: Heterozygous R702C Mutation Provokes Macrothrombocytopenia with Leukocyte Inclusion Bodies, Renal Glomerulosclerosis and Hearing Disability

Nonmuscle myosin heavy chain IIA (NMMHCIIA) encoded by MYH9 is associated with autosomal dominantly inherited diseases called MYH9 disorders. MYH9 disorders are characterized by macrothrombocytopenia and very characteristic inclusion bodies in granulocytes. MYH9 disorders frequently cause nephritis, sensorineural hearing disability and cataracts. One of the most common and deleterious mutations causing these disorders is the R702C missense mutation.We generated knock-in mice expressing the Myh9 R702C mutation. R702C knock-in hetero mice (R702C+/− mice) showed macrothrombocytopenia. We studied megakaryopoiesis of cultured fetal liver cells of R702C+/− mice and found that proplatelet formation was impaired: the number of proplatelet tips was decreased, proplatelet size was increased, and proplatelet shafts were short and enlarged. Although granulocyte inclusion bodies were not visible by May–Grünwald Giemsa staining, immunofluorescence analysis indicated that NMMHCIIA proteins aggregated and accumulated in the granulocyte cytoplasm.In other organs, R702C+/− mice displayed albuminuria which increased with age. Renal pathology examination revealed glomerulosclerosis. Sensory hearing loss was indicated by lowered auditory brainstem response.These findings indicate that Myh9 R702C knock-in mice mirror features of human MYH9 disorders arising from the R702C mutation.

Audiological outcomes of cochlear implantation in Waardenburg Syndrome.

Summary Introduction: The most relevant clinical symptom in Waardenburg syndrome is profound bilateral sensorioneural hearing loss. Aim: To characterize and describe hearing outcomes after cochlear implantation in patients with Waardenburg syndrome to improve preoperative expectations. Method: This was an observational and retrospective study of a series of cases. Children who were diagnosed with Waardenburg syndrome and who received a multichannel cochlear implant between March 1999 and July 2012 were included in the study. Intraoperative neural response telemetry, hearing evaluation, speech perception, and speech production data before and after surgery were assessed. Results: During this period, 806 patients received a cochlear implant and 10 of these (1.2%) were diagnosed with Waardenburg syndrome. Eight of the children received a Nucleus 24® implant and 1 child and 1 adult received a DigiSonic SP implant. The mean age at implantation was 44 months among the children. The average duration of use of a cochlear implant at the time of the study was 43 months. Intraoperative neural responses were present in all cases. Patients who could use the speech processor effectively had a pure tone average of 31 dB in free-field conditions. In addition, the MUSS and MAIS questionnaires revealed improvements in speech perception and production. Four patients did not have a good outcome, which might have been associated with ineffective use of the speech processor. Conclusion: Despite the heterogeneity of the group, patients with Waardenburg syndrome who received cochlear implants were found to have hearing thresholds that allowed access to speech sounds. However, patients who received early intervention and rehabilitation showed better evolution of auditory perception.

The anatomical classification of AICA/PICA branching and configurations in the cerebellopontine angle area on 3D-drive thin slice T2WI MRI

BackgroundWith the technical advance of magnetic resonance imaging (MRI), we have been able to observe not only the small cranial nerves arising from the brain stem but also the branches of vertebrobasilar artery in the cerebellopontine angle (CPA) cistern. PurposeThe purpose was to demonstrate the courses and configurations of the anterior inferior cerebellar artery (AICA) or posterior inferior cerebellar artery (PICA) branch including the internal auditory artery in the CPA cistern and evaluate the relationship between the facial–vestibulocochlear (VIIth–VIIIth) nerves and AICA/PICA on high-resolution, thin-slice, three-dimensional T2-weighted MRI using driven equilibrium pulse. Material and methodsThirty-three men and 27 women aged 8–85 years old with sensory hearing loss or vertigo, and/or tinnitus were evaluated by thin-slice (0.75 mm) T2-weighted MRI. Five subjects (3 men, 2 women) without any auditory symptoms were also examined. ResultsThin-slice T2WI drive MRI revealed several variations of the AICA/PICA coursing, such as a loop formation (n=30, 48 sides) or the IAC extension (n=19, 30 sides). Contact with the vestibulocochlear nerve was seen in 31.7% subjects (n=19, 27 sides). The AICA/PICA branching and shape patterns relative to the CPA and IAC were classified into four major types: type 1A, nonloop AICA/PICA in the CPA cistern; type 1 B, nonloop AICA/PICA (internal auditory artery) entering the IAC; type 2A, loop-type AICA/PICA in the CPA cistern; and type 2B, loop-type AICA/PICA entering the IAC. ConclusionThere was statistically significant association between types 1A and 2A (P<.01) regarding the existence of any auditory 3 symptoms. The results of our study suggest that this classification is simple and very useful for the elucidation of the mechanism of auditory symptoms and deciding the therapeutic strategies.

DNMT1 mutation hot spot causes varied phenotypes of HSAN1 with dementia and hearing loss

Mutations in DNA methyltransferase 1 (DNMT1) have been identified in 2 autosomal dominant syndromes: 1) hereditary sensory autonomic neuropathy with dementia and hearing loss (HSAN1E); and 2) cerebellar ataxia, deafness, and narcolepsy. Both syndromes have mutations in targeting sequence (TS) domain (exons 20-21), which is important in mediating DNA substrate binding to the DNMT1 catalytic domain. Frontal lobe hypometabolism has been documented in an HSAN1E family, but memory loss has been the primary cognitive complaint. The chromosomal location of the DNMT1 gene at 19p13.2 has been linked to familial late-onset Alzheimer disease. We sequenced 41 exons of DNMT1 and their flanking regions in 1) 2 kindreds with HSAN1E; 2) 48 patients with HSAN1 alone without dementia and hearing loss; and 3) 5 probands of familial frontotemporal dementia (FTD) kindreds. We also sequenced exon 20 and 21 in 364 autopsy-confirmed late-onset Alzheimer disease cases. Mutations in DNMT1 were specific to 2 HSAN1E kindreds with dementia and hearing loss (no narcolepsy). One family carried previously identified mutation Tyr495Cys; the other carried a novel Tyr495His, both in the TS domain. The symptoms of these patients include prominent personality, psychiatric manifestations, and seizures in one and the onset time is later than the previously reported cases. Clinicians should consider DNMT1 mutations in patients presenting with FTD or primary memory decline who also have sensory neuropathy and hearing loss. Amino acid Tyr495 is a hot spot for HSAN1E, distinct from exon 21 mutations associated with narcolepsy.