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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.

Usher syndrome is an autosomal recessive disorder characterized by congenital hearing impairment, progressive visual loss owing to retinitis pigmentosa and in some cases vestibular dysfunction. Usher syndrome is divided into three subtypes, USH1, USH2 and USH3. Twelve loci and eleven genes have so far been identified. Duplications and deletions in PCDH15 and USH2A that lead to USH1 and USH2, respectively, have previously been identified in patients from United Kingdom, Spain and Italy. In this study, we investigate the proportion of exon deletions and duplications in PCDH15 and USH2A in 20 USH1 and 30 USH2 patients from Denmark using multiplex ligation-dependent probe amplification (MLPA). Two heterozygous deletions were identified in USH2A, but no deletions or duplications were identified in PCDH15. Next-generation mate-pair sequencing was used to identify the exact breakpoints of the two deletions identified in USH2A. Our results suggest that USH2 is caused by USH2A exon deletions in a small fraction of the patients, whereas deletions or duplications in PCDH15 might be rare in Danish Usher patients.

CHARGE (coloboma of the eye, heart defects, choanal atresia, retarded growth and development, genital hypoplasia and ear anomalies and/or hearing loss) syndrome is a rare genetic, multiple-malformation syndrome. About 80% of patients with a clinical diagnose, have a mutation or a deletion in the gene encoding chromodomain helicase DNA-binding protein 7 (CHD7). Genotype-phenotype correlation is only partly known. In this nationwide study, phenotypic characteristics of 18 Danish CHD7 mutation positive CHARGE individuals (N = 18) are presented. We studied patient records, clinical photographs, computed tomography, and magnetic resonance imaging (MRI). Information was not available for all traits in all subjects. Therefore, the results are presented as fractions. The following prevalence of cardinal symptoms were found: coloboma, 16/17; heart defects, 14/18; choanal atresia, 7/17; retarded growth and development, 11/13; genital abnormalities, 5/18; ear anomalies, 15/17 and sensorineural hearing loss, 14/15. Vestibular dysfunction (10/13) and swallowing problems (12/15) were other frequent cranial nerve dysfunctions. Three-dimensional reconstructions of MRI scans showed temporal bone abnormalities in >85%. CHARGE syndrome present a broad phenotypic spectrum, although some clinical features are more frequently occurring than others. Here, we suggest that genetic testing for CHD7 mutation should be considered in neonates with a specific combination of several clinical symptoms., (© 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.)

Autosomal dominant inheritance is described in about 20% of all nonsyndromic hearing loss with currently 54 distinct loci (DFNA1-54), and >20 different genes identified. Seven different unconventional myosin genes are involved in ten different types of syndromic and nonsyndromic hearing loss with different patterns of inheritance: MYO7A in DFNA11/DFNB2/USH1B, MYH9 in DFNA17, MYH14 in DFNA4, MYO6 in DFNA22/DFNB37, MYO3A in DFNB30, MYO1A in DFNA48, and MYO15A in DFNB3. Two missense mutations in MYO6 (p.C442Y and p.H246R) have been characterized in families of Italian and American Caucasian extraction with autosomal dominant hearing loss, respectively, and the latter was associated with cardiomyopathy in some patients. Three Pakistani families had homozygosity for three MYO6 mutations (c.36insT, p.R1166X, and p.E216V, respectively), and was in one instance associated with retinal degeneration. In the present study, we linked autosomal dominant hearing loss in a large Danish family to a 38.9 Mb interval overlapping with the DFNA22/DFNB37 locus on chromosome 6q13. A novel nonsense mutation in MYO6 exon 25 (c.2545C > T; p.R849X) was identified in the family. The mutation co-segregated with the disease and the mutant allele is predicted to encode a truncated protein lacking the coiled-coil and globular tail domains. These domains are hypothesized to be essential for targeting myosin VI to its cellular compartments. No other system was involved indicating nonsyndromic loss. In conclusion, a novel nonsense MYO6 mutation causes post-lingual, slowly progressive autosomal dominant nonsyndromic moderate to severe hearing loss in a Danish family., (Copyright 2008 Wiley-Liss, Inc.)

Wolfram syndrome (WS) is a neuro-degenerative autosomal recessive (AR) disorder (OMIM #222300) caused by mutations in the WFS1 gene on 4p16.1. More than 120 mutations have been identified in WFS1 associated with AR WS, as well as autosomal dominant nonsyndromic low-frequency sensorineural hearing loss (LFSNHL). WFS1 variants were identified in eight subjects from seven families with WS, leading to the identification of four novel mutations, Q194X (nonsense), H313Y (missense), L313fsX360 (duplication frame shift) and F883fsX951 (deletion frame shift), and four previously reported mutations, A133T and L543R (missense), V415del (in frame triple deletion) and F883fsX950 (deletion frame shift). A mutation was found in 11/14 disease chromosomes, two subjects were homozygous for one mutation, one subject was compound heterozygous for two nucleotide substitutions (missense), one subject was compound heterozygous for a duplication and a deletion (frame shift), and in three families only one mutation was detected (Q194X and H313Y). All affected individuals shared clinically early-onset diabetes mellitus and progressive optic atrophy with onset in the first and second decades, respectively. In contrast, diabetes insipidus was present in two subjects only. Various degrees and types of hearing impairment were diagnosed in six individuals and cataract was observed in five subjects.

Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by variable clinical manifestations including branchial fistulae, preauricular pits, ear malformations, hearing impairment, and renal anomalies. BOR is caused by mutations in the genes EYA1 and SIX1. A Danish BOR family with five affected individuals in three generations was analyzed for mutations in all 17 exons of EYA1 using direct sequencing of polymerase chain reaction (PCR) amplified genomic DNA. A novel splice-site mutation (IVS9+1 G>C) was detected in all affected family members but not in unaffected family members or in 96 controls. We conclude that this mutation is causing BOR in the family, most likely as a result of haploinsufficiency or an abnormal protein product caused by aberrant splicing of EYA1 mRNA.

Population based cytogenetic fra(X) surveys have not previously been reported from Denmark. In the present study we present an estimate of fra(X) based on 1) information from the Danish Central Cytogenetic Registry of diagnosed fra(X) males of all age groups in all Denmark in the period 1980-1992 and 2) a systematic cytogenetic fra(X) survey of 175 of 8-10-year-old children with special educational needs resident in a defined, demographically representative area of Denmark (the county of Funen). The study was performed in 1988-90 before the cloning of the FMR-1 gene. In the county of Funen there were 7,837 male children in the age group of 8-10 years. In the cytogenetic survey of learning disabled children, no fra(X) positive was diagnosed. There were 99 registered males with fra(X) in all Denmark, equivalent to a prevalence of 0.04 per 1,000 males (confidence interval 0.032:1,000-0.048:1,000). Molecular fra(X) surveys of different, large populations are needed in order to estimate the frequency of fra(X) and clarify whether significant differences in prevalence exist in different populations.

In a Danish county (the island of Funen) cytogenetic screening for fragile X [fra(X)] of 32 autistic individuals aged 0-23 years showed a prevalence of 2/20 among boys and 0/12 among girls. In both cases additional fra(X) positive relatives were found. In 3 patients other chromosome aberrations were demonstrated and in one female Rett syndrome was diagnosed, initially suspected from observations of her behavior on videotapes. The presence of an underlying cause of autism in 6/32, of the patient group encourages an active search for a specific diagnosis among autistic males and females. Future screening of autistic individuals should include 1) fra(X) search also in females, 2) search for other chromosomal disorders, and 3) observation of behavior, in order to diagnose, i.e., Rett syndrome.