Three New Mutations and Mild, Asymmetrical Phenotype in the Highly Distinctive LAMM Syndrome: A Report of Eight Further Cases.

Labyrinthine aplasia, microtia, and microdontia (LAMM) is an autosomal recessive condition causing profound congenital deafness, complete absence of inner ear structures (usually Michel's aplasia), microtia (usually type 1) and microdontia. To date, several families have been described with this condition and a number of mutations has been reported. We report on eight further cases of LAMM syndrome including three novel mutations, c. 173T>C p.L58P; c. 284G>A p.(Arg95Gln) and c.325_327delinsA p.(Glu109Thrfs*18). Congenital deafness was the primary presenting feature in all affected individuals and consanguinity in all but two families. We compare the features in our patients to those previously reported in LAMM, and describe a milder, asymmetrical phenotype associated with FGF3 mutations.

Correction to: The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management.

The following information was inadvertently omitted in the original publication.

The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management.

Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS) is a rare clinically distinct syndrome caused by a single dominant missense mutation, c.2452G>A, p.Glu818Lys, in ATP1A3, encoding the neuron-specific alpha subunit of the Na+/K+-ATPase α3. Allelic mutations cause the neurological diseases rapid dystonia Parkinsonism and alternating hemiplegia of childhood, disorders which do not encompass hearing or visual impairment. We present detailed clinical phenotypic information in 18 genetically confirmed patients from 11 families (10 previously unreported) from Denmark, Sweden, UK and Germany indicating a specific type of hearing impairment-auditory neuropathy (AN). All patients were clinically suspected of CAPOS and had hearing problems. In this retrospective analysis of audiological data, we show for the first time that cochlear outer hair cell activity was preserved as shown by the presence of otoacoustic emissions and cochlear microphonic potentials, but the auditory brainstem responses were grossly abnormal, likely reflecting neural dyssynchrony. Poor speech perception was observed, especially in noise, which was beyond the hearing level obtained in the pure tone audiograms in several of the patients presented here. Molecular modelling and in vitro electrophysiological studies of the specific CAPOS mutation were performed. Heterologous expression studies of α3 with the p.Glu818Lys mutation affects sodium binding to, and release from, the sodium-specific site in the pump, the third ion-binding site. Molecular dynamics simulations confirm that the structure of the C-terminal region is affected. In conclusion, we demonstrate for the first time evidence for auditory neuropathy in CAPOS syndrome, which may reflect impaired propagation of electrical impulses along the spiral ganglion neurons. This has implications for diagnosis and patient management. Auditory neuropathy is difficult to treat with conventional hearing aids, but preliminary improvement in speech perception in some patients suggests that cochlear implantation may be effective in CAPOS patients.

Long-term follow-up of hearing loss in children and young adults with enlarged vestibular aqueducts: relationship to radiologic findings and Pendred syndrome diagnosis.

OBJECTIVE: To describe the long-term audiologic findings in pediatric patients with enlarged vestibular aqueducts (EVAs). The relationship between the hearing loss (HL) and the dimensions of the EVA, enlarged endolymphatic duct (EED), or enlarged endolymphatic sac (EES) was also investigated. The influence of a Pendred syndrome (PS) diagnosis on the audiologic phenotype was also examined. STUDY DESIGN: Retrospective analysis of case notes and imaging records, including measurement of the dimensions of the EVA, EED, and EES. SETTING: Tertiary referral center. PATIENTS: Twenty-seven patients (21 female, 6 male) had an EVA in at least one ear. Eighty-five percent had bilateral enlargements. Median age at onset of follow-up was 5.0 years, and median follow-up was 9.7 years. MAIN OUTCOME MEASURES: Hearing thresholds at the start and end of follow-up, rate of progression of HL, history of sudden drops in hearing. RESULTS: : All ears with an EVA had HL. Average HL at the start and end of follow-up was severe. Thirty-seven percent of patients had progressive HL, and 33% reported sudden drops in hearing. Progression was significantly associated with a history of sudden drops. PS patients had worse hearing at the end of follow-up as compared with nonsyndromic patients. There was no evidence of a relationship between the dimensions of the EVA, EED, or EES and the severity or progression of HL. CONCLUSIONS: Patients with EVAs should be advised to avoid known trigger factors for sudden drops in hearing (e.g., minor head trauma). A diagnosis of PS may be associated with a worse audiologic prognosis.