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Background: Kabuki syndrome (KS) is an autosomal dominant inherited syndrome that involves multiple organs and systems. Gene mutation is the main cause of KS. The reported mutations in X-linked histone H3 lysine 4 methylase (KMT2D) and KDM6A genes are 2 relatively clear pathogenic pathways. In this paper, we report a case of KS with neonatal hypoglycemia and special features caused by KMT2D gene mutation confirmed by whole exome sequencing, it enriched the clinical phenotype spectrum and gene mutation spectrum of KS, which helps to improve the understanding of the disease., Case Report: Through whole exome sequencing, we performed gene diagnosis of a newborn child with special facial features and multiple malformations, which revealed heterozygous mutation of NM_003482.3:c.755dupA(p.His252Glnfs*21) in KMT2D gene. It is consistent with the pathogenesis of KS, an autosomal dominat genetic disease caused by KMT2D gene mutation. This pathogenic mutation has not been prebiously reported., Discussion: KS has strong clinical characteristics and biological heterogeneity. Genetic diagnosis can help identify mutant gene types. However, the relationship between genotype and phenotype has not been fully clarified. The molecular etiological mechanism still needs to be further explored and elucidated., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background and Objectives: Bilateral vestibulopathy (BVP) is a chronic debilitating neurologic disorder with no monogenic cause established so far despite familiar presentations. We hypothesized that replication factor complex subunit 1 (RFC1) repeat expansions might present a recurrent monogenic cause of BVP., Methods: The study involved RFC1 screening and in-depth neurologic, vestibulo-oculomotor, and disease evolution phenotyping of 168 consecutive patients with idiopathic at least "probable BVP" from a tertiary referral center for balance disorders, with127 of them meeting current diagnostic criteria of BVP (Bárány Society Classification)., Results: Biallelic AAGGG repeat expansions in RFC1 were identified in 10/127 patients (8%) with BVP and 1/41 with probable BVP. Heterozygous expansions in 10/127 patients were enriched compared with those in reference populations. RFC1-related BVP manifested at a median age of 60 years (range 34-72 years) and co-occurred predominantly with mild polyneuropathy (10/11). Additional cerebellar involvement (7/11) was subtle and limited to oculomotor signs in early stages, below recognition of classic cerebellar ataxia, neuropathy, and vestibular areflexia syndrome. Clear dysarthria, appendicular ataxia, or cerebellar atrophy developed 6-8 years after onset. Dysarthria, absent patellar reflexes, and downbeat nystagmus best discriminated RFC1-positive BVP from RFC1-negative BVP, but neither sensory symptoms nor fine motor problems. Video head impulse gains of patients with RFC1-positive BVP were lower relative to those of patients with RFC1-negative BVP and decreased until 10 years disease duration, indicating a potential progression and outcome marker for RFC1-disease., Discussion: This study identifies RFC1 as the first-and frequent-monogenic cause of BVP. It characterizes RFC1-related BVP as part of the multisystemic evolution of RFC1 spectrum disease, with implications for designing natural history studies and future treatment trials., Classification of Evidence: This study provides Class II evidence that RFC1 repeat expansions cause BVP., (© 2023 American Academy of Neurology.)

Background and Objective: Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is an autosomal recessive neurodegenerative disease characterized by adult-onset and slowly progressive sensory neuropathy, cerebellar dysfunction, and vestibular impairment. In most cases, the disease is caused by biallelic (AAGGG) n repeat expansions in the second intron of the replication factor complex subunit 1 ( RFC1 ). However, a small number of cases with typical CANVAS do not carry the common biallelic repeat expansion. The objective of this study was to expand the genotypic spectrum of CANVAS by identifying sequence variants in RFC1 -coding region associated with this condition., Methods: Fifteen individuals diagnosed with CANVAS and carrying only 1 heterozygous (AAGGG) n expansion in RFC1 underwent whole-genome sequencing or whole-exome sequencing to test for the presence of a second variant in RFC1 or other unrelated gene. To assess the effect of truncating variants on RFC1 expression, we tested the level of RFC1 transcript and protein on patients' derived cell lines., Results: We identified 7 patients from 5 unrelated families with clinically defined CANVAS carrying a heterozygous (AAGGG) n expansion together with a second truncating variant in trans in RFC1 , which included the following: c.1267C>T (p.Arg423Ter), c.1739_1740del (p.Lys580SerfsTer9), c.2191del (p.Gly731GlufsTer6), and c.2876del (p.Pro959GlnfsTer24). Patient fibroblasts containing the c.1267C>T (p.Arg423Ter) or c.2876del (p.Pro959GlnfsTer24) variants demonstrated nonsense-mediated mRNA decay and reduced RFC1 transcript and protein., Discussion: Our report expands the genotype spectrum of RFC1 disease. Full RFC1 sequencing is recommended in cases affected by typical CANVAS and carrying monoallelic (AAGGG) n expansions. In addition, it sheds further light on the pathogenesis of RFC1 CANVAS because it supports the existence of a loss-of-function mechanism underlying this complex neurodegenerative condition., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To determine the clinical significance of an intronic biallelic pentanucleotide repeat expansion in the gene encoding replication factor C subunit 1 ( RFC1 ) in patients with late-onset cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), in patients with other ataxias, and in healthy controls by comprehensive genetic analyses., Methods: In this case-control study, we included 457 individuals comprising 26 patients with complete or incomplete CANVAS, 70 patients with late-onset cerebellar ataxia, 208 healthy controls, and 153 individuals from 39 multigenerational families without ataxia to determine repeat stability. All 96 patients were screened for the repeat expansion by duplex PCR. To further characterize the repeat type and lengths, we used fragment length analysis, repeat-primed PCR, Sanger sequencing, and Southern blotting. Expression of RFC1 and the neighboring gene WDR19 were determined by quantitative PCR., Results: Massive biallelic pentanucleotide expansions were found in 15/17 patients with complete CANVAS (88%), in 2/9 patients with incomplete CANVAS (22%), in 4/70 patients with unspecified, late-onset cerebellar ataxia (6%), but not in controls. In patients, the expansion comprised 800-1,000 mostly AAGGG repeats. Nonmassively expanded repeat numbers were in the range of 7-137 repeats and relatively stable during transmission. Expression of RFC1 and WDR19 were unchanged and RFC1 intron retention was not found., Conclusions: A biallelic pentanucleotide repeat expansion is a frequent cause of CANVAS and found in a considerable number of patients with an incomplete clinical presentation or other forms of cerebellar ataxia. The mechanism by which the repeat expansions are causing disease remains unclear and warrants further investigations., (© 2020 American Academy of Neurology.)

Purpose: Kabuki syndrome (KS) is a rare congenital disorder characterized by multiple systemic anomalies and unique facial characteristics. Here, we present the first case, to the best of our knowledge, of bilateral congenital corneal opacities as an early-onset ocular manifestation of KS associated with a KMT2D gene mutation., Methods: The proband is a girl. At birth, bilateral corneal opacities, short fifth fingers, patent ductus arteriosus, absence of the uvula, and an ectopic kidney on the right side were noted. Ophthalmic examinations revealed vascularized, nonhomogeneous opacities in both corneas; to prevent deprivation amblyopia, bilateral corneal transplantations were performed., Results: At 1 year and 10 months of age, she was referred by a general practitioner to our pediatric endocrinologist for failure to thrive. Genetic analysis at that age revealed the presence of a KMT2D gene mutation, and the patient was diagnosed with KS., Conclusions: The clinical diagnosis of KS is challenging because the most remarkable facial features are not evident until early childhood. In this case, bilateral congenital corneal opacities were identified as an early-onset ocular manifestation of KS. KS should be considered as a differential diagnosis in patients with bilateral congenital corneal opacities.

Objective: To evaluate the progression of peripheral vestibular dysfunction in patients with an A-to-G point mutation at nucleotide pair 3243 in mitochondrial DNA (A3243G mutation)., Study Design: Retrospective patient series., Setting: Tertiary referral center., Patients: Six unrelated patients with an A3243G mutation (four mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; and two maternally inherited diabetes and deafness; five females and one male; average age 41 ± 11.3 yr old), who underwent repeated vestibular examinations, were included (average interval between the first and second examinations: 5.7 ± 2.1 yr)., Intervention: Diagnostic., Main Outcome Measure: Results of caloric testing and cervical vestibular evoked myogenic potential testing in response to air-conducted sound were analyzed., Results: All the patients except one, who was already completely deaf in both ears at the first examination, showed progression of hearing loss (average 4.0 ± 6.3 dB per year). Five of the six patients had vestibular symptoms at the first examination. The other patient developed dizziness later. Caloric responses were abnormal in four patients at the first examination and in five patients at the second examination. Cervical vestibular evoked myogenic potential responses were bilaterally absent in three patients at the first examination and in five patients at the second examination., Conclusions: The A3243G mutation causes progression of peripheral vestibular dysfunction as well as that of hearing loss.

Kabuki syndrome is a rare genetic disorder characterized by congenital anomalies and developmental delay. It is often associated with impaired immune response and autoimmune abnormalities. We report the clinical case of a girl with Kabuki syndrome who developed autoimmune neutropenia, not previously reported, followed by hemolytic anemia and autoimmune thrombocytopenia.

Purpose of Review: The primary purpose of this review is to summarize current literature in the field of vestibular regeneration with a focus on recent developments in molecular and gene therapies., Recent Findings: Since the discovery of limited vestibular hair cell regeneration in mammals in the 1990s, many elegant studies have improved our knowledge of mechanisms of development and regeneration of the vestibular system. A better understanding of the developmental pathways of the vestibular organs has fueled various biological strategies to enhance regeneration, including novel techniques in deriving vestibular hair cells from embryonic and induced pluripotent stem cells. In addition, the identification of specific genetic mutations responsible for vestibular disorders has opened various opportunities for gene replacement therapy., Summary: Vestibular dysfunction is a significant clinical problem with limited therapeutic options, warranting research on biological strategies to repair/regenerate the vestibular organs to restore function. The use of gene therapy appears promising in animal models of vestibular dysfunction.

A 3-year-old Japanese girl treated for hypoplastic left heart syndrome and Dandy-Walker syndrome was diagnosed with Kabuki syndrome (KS) with a mutation of KMT2D; c.13285C>T:p.Q4429*. Concurrently, macrohematuria portended the diagnosis of Wilms tumor. Postoperative chemotherapy has achieved complete remission despite a prolonged and reduced regimen due to liver dysfunction and convulsions. Cancer predisposition has been suggested for KS due to oncogenic mutations in KMT2D or KDM6A. The first case of nephroblastoma exemplified the treatability of malignancies in KS patients, as shown in the 9 cases reviewed. Active screening and intervention are recommended for the cure of malignancy in KS children.

Purpose of Review: The increased availability of next generation sequencing has enabled a rapid progress in the discovery of genetic variants associated with vestibular disorders. We have summarized molecular genetics finding in vestibular syndromes during the last 18 months., Recent Findings: Genetic studies continue to shed light on the genetic background of vestibular disorders. Novel genes affecting brain development and otolith biogenesis have been associated with motion sickness. Exome sequencing has made possible to identify three rare single nucleotide variants in PRKCB, DPT and SEMA3D linked with familial Meniere disease. Moreover, superior canal dehiscence syndrome might be related with variants in CDH3 gene, by increasing risk of its development. On the other hand, the association between vestibular schwannoma and enlarged vestibular aqueduct with variants in NF2 and SLC26A4, respectively, seems increasingly clear. Finally, the use of mouse models is allowing further progress in the development gene therapy for hearing and vestibular monogenic disorders., Summary: Most of episodic or progressive syndromes show familial clustering. A detailed phenotyping with a complete familial history of vestibular symptoms is required to conduct a genetic study. Progress in these studies will allow us to understand diseases mechanisms and improve their current medical treatments.

Kabuki syndrome is a rare genetic malformation syndrome that is characterized by distinct facies, structural defects and intellectual disability. Kabuki syndrome may be caused by mutations in one of two histone methyltransferase genes: KMT2D and KDM6A. We describe a male child of nonconsanguineous Irish parents presenting with multiple malformations, including bilateral extreme microphthalmia; cleft palate; congenital diaphragmatic hernia; duplex kidney; as well as facial features of Kabuki syndrome, including interrupted eyebrows and lower lid ectropion. A de-novo germline mutation in KMT2D was identified. Whole-exome sequencing failed to reveal mutations in any of the known microphthalmia/anopthalmia genes. We also identified four other patients with Kabuki syndrome and microphthalmia. We postulate that Kabuki syndrome may produce this type of ocular phenotype as a result of extensive interaction between KMT2D, WAR complex proteins and PAXIP1. Children presenting with microphthalmia/anophthalmia should be examined closely for other signs of Kabuki syndrome, especially at an age where the facial gestalt might be less readily appreciable.

Purpose of Review: Recent advances in next generation sequencing techniques (NGS) are increasing the number of novel genes associated with cerebellar and vestibular disorders. We have summarized clinical and molecular genetics findings in neuro-otolology during the last 2 years., Recent Findings: Whole-exome and targeted sequencing have defined the genetic basis of dizziness including new genes causing ataxia: GBA2, TGM6, ANO10 and SYT14. Novel mutations in KCNA1 and CACNA1A genes are associated with episodic ataxia type 1 and type 2, respectively. Moreover, new variants in genes such as COCH, MYO7A and POU4F3 are associated with nonsyndromic deafness and vestibular dysfunction. Several susceptibility loci have been linked to familial vestibular migraine, suggesting genetic heterogeneity, but no specific gene has been identified. Finally, loci for complex and heterogeneous diseases such as bilateral vestibular hypofunction or familial Ménière disease have not been identified yet, despite their strong familial aggregation., Summary: Cerebellar and vestibular disorders leading to dizziness or episodic vertigo may show overlapping clinical features. A deep phenotyping including a complete familial history is a key step in performing a reliable molecular genetic diagnosis using NGS. Personalized molecular medicine will be essential to understand disease mechanisms as well as to improve their diagnosis and treatment.

Background: Kabuki syndrome is a rare condition characterized by distinct dysmorphic features and a broad spectrum of organ anomalies. Differentiating it from other syndromes can be difficult, particularly in patients with incomplete phenotypic manifestation. Recently, MLL2 gene mutations were identified as the underlying genetic cause of Kabuki syndrome in the majority of cases., Observations: We report the case of an adolescent with an uncommon combination of manifestations, including hypogammaglobulinemia and severe chronic thrombopenia associated with a novel MLL2 mutation., Conclusions: This report adds to the growing knowledge on the mutational and phenotypic spectrum of Kabuki syndrome.

Purpose of Review: To focus on recent advances in the genetics of recurrent vertigo, with an overview on episodic ataxia, benign recurrent vertigo (mainly migraine-associated vertigo), bilateral vestibulopathy, and Ménière's disease., Recent Findings: Since the identification more than a decade ago of the genetic causes of episodic ataxia type 1 with myokymia caused by KCNA1 mutations and episodic ataxia type 2 with nystagmus caused by CACNA1A mutations, the list of episodic ataxia syndromes with distinct clinical features and genetic loci is slowly expanding, now up to episodic ataxia type 7. There is growing recognition for a correlation between benign recurrent vertigo and migraine, and acceptance for vertigo as a manifestation of migraine; efforts to identify susceptibility loci for migraine and migraine-associated vertigo are underway. A handful of families with vestibulopathy spanning several generations have been identified. Although no gene has yet been found, vestibulopathy with normal hearing variably associated with migraine is likely monogenic and heterogeneous, similar to nonsydromic deafness. There is also continuing effort to identify genetic causes of familial Ménière's disease., Summary: Overlapping clinical features among different familial syndromes of recurrent vertigo and strong association with migraine suggest shared mechanisms. Collaborative efforts in patient identification and recruitment will facilitate progress in understanding disease mechanisms to improve diagnosis and treatment of recurrent vertigo.

Hypothesis: Hypoxia-inducible factor (HIF)-1alpha, erythropoietin (Epo), Epo receptor (EpoR), and bcl-2 are expressed in both sporadic unilateral vestibular schwannomas (VSs) and those associated with neurofibromatosis Type 2, and the expression data correlate with clinicopathological tumor features including microvessel density and Ki-67-labeling index., Background: Erythropoietin expression is regulated by the transcription factor, HIF-1alpha. Erythropoietin signaling via EpoR results in stimulation of cell proliferation and elevated expression of the antiapoptotic protein, bcl-2, and then inhibition of apoptosis. Erythropoietin has been shown to be associated with Schwann cell proliferation, and a recent report suggested a role in VS growth., Methods: Immunohistochemical analysis of HIF-1alpha, Epo, EpoR, and bcl-2 was performed on formalin-fixed paraffin-embedded archival surgical specimens. Microvessel density and Ki-67-labeling index of VS were analyzed and correlated with the immunoreactivity pattern of the examined factors., Results: Immunoreactivity data demonstrate robust protein expression for HIF-1alpha, Epo, EpoR, and bcl-2 in VS. Sixty-six percent of the cases showed Epo expression, and EpoR was found in 85% of tumor samples. A significantly positive correlation of the immunoreactivity scores of Epo/EpoR and bcl-2 expression could be noted. In case of tumor specimens with high levels of HIF-1alpha expression, a significantly higher Ki-67-labeling index was observed. There was no correlation between the expression of HIF-1alpha, Epo, EpoR, and bcl-2 and microvessel density, tumor size, sex, and age., Conclusion: Expression of Epo and EpoR might suggest a functional role in VS biology. The observed correlation of Epo/EpoR and bcl-2 expression levels may suggest a proliferative and antiapoptotic role of the Epo/EpoR system in VS.

Objective: To evaluate the hypothesis that there are differences in the morphology of the lateral semicircular canal (LSCC) between patients with large vestibular aqueduct syndrome (LVAS) and control subjects and to investigate the clinical implications of these differences., Study Design: Retrospective case review., Setting: Tertiary referral center., Patients: Nine patients (two male patients and seven female patients; age range, 8-54 yr) with LVAS (one patient had unilateral LVAS, and eight patients had bilateral LVAS). Five patients had vertigo, and four patients, including the one with unilateral LVAS, did not have vertigo., Main Outcome Measures: The area of the LSCC was traced on the magnetic resonance imaging console and compared between LVAS patients and 12 control subjects who did not have sensorineural hearing loss. The LSCC fluid-containing area was divided by the sum of the LSCC inner area and the LSCC fluid-containing area for evaluation of the degree of the LSCC dysplasia., Results: The LSCC fluid-containing ratio was significantly larger in LVAS patients than in control subjects. Moreover, the LSCC fluid-containing ratio was significantly larger in the eight ears with vertigo than in the nine ears without vertigo. There was no relationship between hearing level and the LSCC fluid-containing ratio., Conclusion: Patients with LVAS may have disturbed morphogenesis of both membranous and bony labyrinths. Our results reveal that the morphology of semicircular canals is clinically associated with vertigo.

Objective: To compare audiometric and quality-of-life results in DFNA 9 patients who received a cochlear implant with cochlear implant patients with adult-onset progressive sensorineural hearing loss., Study Design: Prospective comparative design; results were collected cross-sectionally., Setting: Tertiary referral center., Patients: Eleven DFNA 9 patients were included in the study as well as a comparative group of 39 post-lingually deafened cochlear implant subjects with adult-onset progressive sensorineural hearing loss., Interventions: All patients received a cochlear implant. Subjects were implanted with either the Nucleus 24 M/RCS or Med-el Combi 40+ cochlear implant systems implementing the SPEAK, ACE, or CIS+ coding strategies., Mean Outcome Measures: Speech recognition was determined by means of phonetically balanced monosyllabic word lists. The Hearing Handicap Inventory for Adults, the Glasgow Benefit Inventory, and the Scale for the Prediction of Hearing Disability in Sensorineural Hearing Loss were used to quantify the quality of life., Results: The results show that the speech perception and the quality of life of the DFNA 9 patients do not differ significantly from the control group (p=0.179; p=0.56)., Conclusion: In spite of the fact that DFNA 9 is a disease that is known to involve cochlear dendrites, cochlear implantation is a good option for treatment of deafness in DFNA 9.

The gap junctional network of the inner ear plays an important role in cochlear ionic homoeostasis. Mutations of connexin 26 can induce different types of hearing loss and even deafness. Therefore, it is hypothesized that gap junctions of the human vestibular organ are functionally impaired by mutations of connexin 26. In a prospective, nonrandomized study, the functional status of the semicircular canals and the otolith organs was assessed in one homozygous and six heterozygous carriers of connexin 26 mutations. Five out of seven patients (71.4%) had pathological vestibular evoked myogenic potentials, indicating a loss of saccular function. The utricular function (as tested by subjective haptic vertical) and the function of the semicircular canals (as tested by recording the vestibuloocular reflex) were largely normal. Thus, connexin 26 mutations can be associated with saccular defects of the vestibular receptors.

Background: Of the more than 40 genetically defined dominantly inherited hearing loss syndromes, only a few are associated with bilateral vestibulopathy. No genetic mutations have been identified in families with bilateral vestibulopathy and normal hearing., Objective: To perform a genome-wide scan for linkage in four families with dominantly inherited bilateral vestibulopathy., Methods: Patients in four families reported brief episodes of vertigo followed by imbalance and oscillopsia. Bilateral vestibulopathy was documented with quantitative rotational testing. Most patients with bilateral vestibulopathy also had migraine. A 10 cM genome-wide screen was conducted using 423 microsatellite markers to identify linkage with vestibulopathy., Results: The authors identified a 24 cM region on chromosome 6q suggestive of linkage to vestibulopathy in these four families (maximum lod score of 2.9 at marker D6S1556). A small fifth family with a different phenotype was not linked to this region on chromosome 6q., Conclusions: This is the first report of linkage in families with dominantly inherited vestibulopathy and normal hearing. Genetic heterogeneity is likely with inherited vestibulopathy.

Hypothesis: Balance anomalies are often associated with abnormalities of the vestibular part of the inner ear. We studied a newly generated mouse mutant with balance defects and asked whether its behavioral anomalies were associated with inner ear defects. Furthermore, we asked whether the mutation responsible for the defects was located in the same region of mouse chromosome 4 as several other mouse mutations that we have previously described., Background: Phenotypic and genotypic analysis of mouse mutants with hearing or balance problems has helped greatly with the identification of the genes involved in deafness and has contributed to the understanding of mechanisms of normal hearing and balance. This article describes a new mouse mutant, flouncer, that shows a balance defect. The flouncer mutation shows semidominant inheritance, and was generated by mutagenesis using N- ethyl-N- nitrosourea., Methods: Hearing was assessed by the Preyer reflex (ear-flick) test. Behavioral tests including open field and swimming tests were performed. The morphology of the middle and inner ears was investigated by microdissection, clearing using glycerol, paint-filling of the labyrinth, and scanning electron microscopy., Results: Flouncer mutants showed vestibular dysfunction but do respond to sounds. Phenotypically, mutants had various degrees of truncation of the lateral semicircular canals, small or obliterated round window of the cochlea, and mild morphologic anomalies of the stapes. Flouncer mutants showed circling behavior and hyperactivity. Linkage mapping using a backcross has indicated that the mutation lies in proximal chromosome 4 proximal to D4Mit171., Conclusion: The lateral semicircular canal has been described to be the most commonly affected part of the inner ear in humans, and flouncer provides a mouse model for genetic and developmental analysis of such defects.

Objective: To describe the findings of audiovestibular and ophthalmologic examinations in four families with mutations in the CDH23 gene., Study Design: Family study., Setting: Tertiary referral center., Patients: Four DFNB12 patients from a large consanguineous Dutch family and six patients from three different Usher syndrome Type ID families were examined. All were identified by at least one pathogenic mutation in the CDH23 gene., Methods: Audiovestibular examinations consisted of standard pure-tone audiometry, vestibulo-ocular reflex, optokinetic nystagmus, and in some cases the cervico-ocular reflex. Linear regression analysis was used to evaluate progression of hearing impairment, and the degree of hearing impairment of DFNB12 was compared with that found for USH1D. Ophthalmologic examinations consisted of best-corrected visual acuity, Goldmann perimetry, slit-lamp examinations, color vision testing, dark adaptation, electroretinography, electro-oculography, funduscopy and photography of the retina, and sometimes fluorescein angiography., Results: The USH1D patients had significantly worse hearing impairment than the DFNB12 patients. The DFNB12 patients, identified by missense mutations in CDH23, had normal retinal and vestibular function. All USH1D patients had splice-site mutations in CDH23 and a typical Usher syndrome Type I phenotype. One DFNB12 patient had slightly abnormal yellowish flecks in the posterior poles of both eyes., Conclusion: Recessive missense mutations in CDH23 lead to a milder phenotype (DFNB12) than splice-site mutations (USH1D); however, abnormal bilateral flecks, suggestive for lipofuscin accumulation, can be observed in DFNB12 patients.

Objective: To evaluate audiometric and vestibular signs and symptoms in a new DFNA9 family., Setting: Tertiary referral centers., Methods: A multigeneration Belgian family with late-onset progressive sensorineural hearing loss and concomitant ves-tibular impairment with an autosomal dominant pattern of inheritance underwent clinical and genetic evaluation. Medical history was recorded. Blood samples were taken for genetic linkage and mutation analyses. Pure-tone audiometry, speech audiometry and vestibular examinations were performed. Onset and progression in hearing impairment were evaluated with linear regression analysis of longitudinal threshold-on-age data., Results: Linkage to DFNA9 was confirmed and mutation analysis revealed a P51S mutation in the COCH gene. Several patients had a Ménière's-like presentation. All patients developed late-onset progressive sensorineural hearing loss eventually leading to severe deafness and vestibular failure.

Background: Four sets of clinical diagnostic criteria for neurofibromatosis 2 (NF2) have been developed by groups of expert clinicians, but sensitivity has never been formally assessed. The sets of criteria differ for people without bilateral vestibular schwannomas, which are pathognomonic for NF2., Objective: To empirically evaluate the four existing sets of clinical diagnostic criteria for NF2., Methods: The study was based on 163 of 403 people in the United Kingdom NF2 registry (41%) who presented without bilateral vestibular schwannomas. The authors applied the sets of criteria to each person at initial assessment and at the most recent clinical evaluation (mean +/- SE length of follow-up, 13 +/- 1 years)., Results: In people with "definite NF2" and a negative family history of NF2, the 1987 US NIH and 1991 NIH criteria each identify 78% of people at the most recent clinical evaluation but 0% at initial assessment. The National Neurofibromatosis Foundation (NNFF) criteria and the Manchester criteria each identify higher proportions at both time points (NNFF criteria, 91% and 10%; Manchester criteria, 93% and 14%), but the proportions at initial assessment are still low., Conclusions: None of the existing sets of criteria are adequate at initial assessment for diagnosing people who present without bilateral vestibular schwannomas as having NF2, particularly people with a negative family history of NF2. The authors recommend that a single, revised set of diagnostic criteria be devised to replace all of the existing sets of criteria.

Objective: To report the clinical, auditory, and vestibular characteristics of a nonsyndromic otovestibular dysfunction in a large Belgian family caused by a missense mutation of the DFNA9 gene: COCH., Study Design: Retrospective study of the clinical, audiologic, and vestibular data of 60 genetically affected cases., Setting: Tertiary referral center., Patients: All members of a Belgian kindred who carry the genetic (P51S) defect linked to the inherited hearing and vestibular impairment., Interventions: Diagnostic otologic, audiometric, and vestibular analysis and imaging., Main Outcome Measures: Pure tone audiometry, supraliminary audiometry. and vestibular investigation., Results: The autosomal dominant inherited impairment was characterized by peripheral degeneration of the inner ear, leading to total deafness and bilateral vestibular areflexia., Conclusions: The genetically affected persons of a Belgian family shared a progressive sensorineural hearing loss starting between the third and sixth decade. Vestibular symptoms started at about the same age as the hearing loss. The vestibular symptoms consisted of instability in darkness, a tendency to fall sideways, light-headiness, a drunken feeling, and attacks of vertigo. Most of the patients reported tinnitus, and half of them reported pressure in the ears. Clinically, 9 of the 60 patients met the criteria for definite Ménière's disease, and another 13 and 17 patients met the criteria for probable or possible Ménière's disease, respectively. All 9 were older than the age of 35, but only 1 was older than 55 years, so more than 30% of the patients were between 35 and 55 years old. A specific pattern could be recognized in the evolution of the otovestibular impairment. Under the age of 35 years, almost all the affected family members had normal hearing, whereas above the age of 55 years, the hearing loss was at least moderate, and vestibular hypofunction occurred. In between, there was a transition period of two to three decades, when deterioration of the cochleovestibular function occurred, with a temporary audiometric and vestibular asymmetry.

Three patients who presented with episodic vertigo followed by gait imbalance and oscillopsia had profound bilateral vestibular loss despite normal hearing. All had a parent with similar findings. The patients, their affected parent, and multiple other family members had a history of migraine headaches, although several of the latter had normal vestibular function. Acetazolamide stopped or markedly decreased the frequency of vertigo attacks in the three patients treated but had little effect on the chronic vestibular loss. This is the first report of a dominantly inherited bilateral vestibulopathy associated with normal hearing.

Five patients who presented with long-standing episodic vertigo had ocular motor signs localizing to the vestibulocerebellum. In each patient, the episodic vertigo was either abolished or markedly decreased in frequency and severity with acetazolamide therapy. In 4, other family members had identical symptoms and signs. This syndrome is 1 of the few treatable causes of chronic episodic vertigo.