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ADHD, schizophrenia and bipolar disorder are psychiatric diseases with a strong genetic component which share dopaminergic alterations. Dopamine transporter (DAT) genetics might be potentially implicated in all these disorders. However, in contrast to DAT absence, the effects of DAT hypofunction especially in developmental trajectories have been scarcely addressed. Thus, we comprehensively studied DAT hypofunctional mice (DAT+/-) from adolescence to adulthood to disentangle DAT-dependent alterations in the development of psychiatric-relevant phenotypes. From pre-adolescence onward, DAT+/- displayed a hyperactive phenotype, while responses to external stimuli and sensorimotor gating abilities were unaltered. General cognitive impairments in adolescent DAT+/- were partially ameliorated during adulthood in males but not in females. Despite this, attentional and impulsivity deficits were evident in DAT+/- adult males. At the molecular level, DAT+/- mice showed a reduced expression of Homer1a in the prefrontal cortex, while other brain regions as well as Arc and Homer1b expression were mostly unaffected. Amphetamine treatments reverted DAT+/- hyperactivity and rescued cognitive deficits. Moreover, amphetamine shifted DAT-dependent Homer1a altered expression from prefrontal cortex to striatal regions. These behavioral and molecular phenotypes indicate that a genetic-driven DAT hypofunction alters neurodevelopmental trajectories consistent with ADHD, but not with schizophrenia and bipolar disorders., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Corticotropin-releasing hormone receptor 1 (CRH-R1) in the amygdala and the stria terminalis plays an important role in the activation of central stress circuits. Genetic factors may contribute to the hyperresponsiveness of these circuits in irritable bowel syndrome (IBS)., Aims: To determine if CRH-R1 SNPs are associated with: (1) a diagnosis of IBS, (2) gastrointestinal (GI) symptoms, and (3) acoustic startle response (ASR) to threat, which is mediated by the amygdala via CRH., Methods: Three CRH-R1 SNPS (rs110402, rs242924, and rs7209436) were genotyped using salivary DNA from IBS and healthy control subjects (HCs). Eye blink ASR was obtained during safe (no shock), anticipation (abdominal shock may soon occur) and threat (abdominal shock likely) conditions in a subset of subjects. Associations between each SNP with IBS status, clinical traits and ASR were measured., Results: 235 IBS patients (mean age 37.5 yrs, 74% F) and 264 HCs (mean age 32.1 yrs, 70% F) were studied. Of these, 57 IBS and 41 HCs underwent the ASR protocol. The presence of IBS was associated with the major allele for all three CRH-R1 SNPs (p=0.009-0.025). Within IBS, the major allele for all three SNPs (p=0.017-0.065) was associated with GI symptom anxiety scores. Within subjects with at least one copy of the major allele for the CRH-R1 SNPs, IBS had significantly lower ASR compared to HCs during threat conditions (p=0.001-0.002). Within IBS, CRH-R1 SNPs were associated with a graded increase in ASR to threat (p=0.007-0.008)., Conclusion: These findings support that CRH-R1 contributes to the dysregulated stress responsiveness in IBS., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objectives: Recently, OTOG and OTOGL were identified as human deafness genes. Currently, only four families are known to have autosomal recessive hearing loss based on mutations in these genes. Because the two genes code for proteins (otogelin and otogelin-like) that are strikingly similar in structure and localization in the inner ear, this study is focused on characterizing and comparing the hearing loss caused by mutations in these genes., Design: To evaluate this type of hearing, an extensive set of audiometric and vestibular examinations was performed in the 13 patients from four families., Results: All families show a flat to downsloping configuration of the audiogram with mild to moderate sensorineural hearing loss. Speech recognition scores remain good (>90%). Hearing loss is not significantly different in the four families and the psychophysical test results also do not differ among the families. Vestibular examinations show evidence for vestibular hyporeflexia., Conclusion: Because otogelin and otogelin-like are localized in the tectorial membrane, one could expect a cochlear conductive hearing loss, as was previously shown in DFNA13 (COL11A2) and DFNA8/12 (TECTA) patients. Results of psychophysical examinations, however, do not support this. Furthermore, the authors conclude that there are no phenotypic differences between hearing loss based on mutations in OTOG or OTOGL. This phenotype description will facilitate counseling of hearing loss caused by defects in either of these two genes.

Following early clinical leads, the adenosine A(2A)R receptor (A(2A)R) has continued to attract attention as a potential novel target for treating schizophrenia, especially against the negative and cognitive symptoms of the disease because of A(2A)R's unique modulatory action over glutamatergic in addition to dopaminergic signaling. Through (i) the antagonistic interaction with the dopamine D(2) receptor, and (ii) the regulation of glutamate release and N-methyl-d-aspartate receptor function, striatal A(2A)R is ideally positioned to fine-tune the dopamine-glutamate balance, the disturbance of which is implicated in the pathophysiology of schizophrenia. However, the precise function of striatal A(2A)Rs in the regulation of schizophrenia-relevant behavior is poorly understood. Here, we tested the impact of conditional striatum-specific A(2A)R knockout (st-A(2A)R-KO) on latent inhibition (LI) and prepulse inhibition (PPI) - behavior that is tightly regulated by striatal dopamine and glutamate. These are two common cross-species translational tests for the assessment of selective attention and sensorimotor gating deficits reported in schizophrenia patients; and enhanced performance in these tests is associated with antipsychotic drug action. We found that neither LI nor PPI was significantly affected in st-A(2A)R-KO mice, although a deficit in active avoidance learning was identified in these animals. The latter phenotype, however, was not replicated in another form of aversive conditioning - namely, conditioned taste aversion. Hence, the present study shows that neither learned inattention (as measured by LI) nor sensory gating (as indexed by PPI) requires the integrity of striatal A(2A)Rs - a finding that may undermine the hypothesized importance of A(2A)R in the genesis and/or treatment of schizophrenia., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Description of the audiometric and vestibular characteristics of a Dutch family with Muckle-Wells syndrome (MWS). Examination of all family members consisted of pure tone audiometry, otoscopy and genetic analysis. In addition, a selected group underwent speech audiometry, vestibulo-ocular examination, acoustic reflex testing and tests assessing loudness scaling, gap detection, difference limen for frequency and speech perception in noise. Linear regression analyses were performed on the audiometric data. Six clinically affected family members participated in this study and all were carriers of a p.Tyr859His mutation in the NLPR3 gene. Most affected family members reported bilateral, slowly progressive hearing impairment since childhood. Hearing impairment started at the high frequencies and the low- and mid-frequency threshold values deteriorated with advancing age. Annual threshold deterioration (ATD) ranged from 1.3 to 1.9 dB/year with the highest values at the lower frequencies. Longitudinal linear regression analysis demonstrated significant progression for a number of frequencies in five individuals. Speech recognition scores were clearly affected. However, these individuals tended to have higher speech recognition scores than presbyacusis patients at similar PTA(1,2,4 kHz) levels. The loudness growth curves were steeper than those found in individuals with normal hearing, except for one family member (individual IV:6). Suprathreshold measurements, such as difference limen for frequency (DL(f)), gap detection and particularly speech perception in noise were within the normal range or at least close to data obtained in two groups of patients with a so-called conductive type of hearing loss, situated in the cochlea. Hearing impairment in MWS is variable and shows resemblance to previously described intra-cochlear conductive hearing impairment. This could be helpful in elucidating the pathogenesis of hearing impairment in MWS. Other associated symptoms of MWS were mild and nonspecific in the present family. Therefore, even without any obvious syndromic features, MWS can be the cause of sensorineural hearing impairment, especially when combined with (mild) skin rash and musculoskeletal symptoms. An early diagnosis of MWS is essential to prevent irreversible damage from amyloidosis. The effect of IL-1β inhibitors on hearing impairment is more controversial, but an early start of treatment seems to be essential. Therefore, our results are of importance in patient care and counselling., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The reticulon-4 receptor, encoded by RTN4R, limits axonal sprouting and neural plasticity by inhibiting the outgrowth of neurites. Human association studies have implicated mutations in RTN4R in the development of schizophrenia, including the identification of several rare nonconservative missense mutations of RTN4R in schizophrenia patients. To investigate the effects of missense mutation of the reticulon-4 receptor on phenotypes relevant to schizophrenia, we behaviourally characterized a novel Rtn4r mutant mouse line with an amino acid substitution (R189H) in the Nogo-66 binding site. Behavioural assays included prepulse inhibition of acoustic startle, locomotor activity, social interaction and spatial cognition. When compared with wildtype littermates, Rtn4r mutant mice exhibited greater social preference, which may reflect a social-anxyolitic effect, and a mild impairment in spatial cognition. Given the mild effect of the R189H mutation of Rtn4r on behavioural phenotypes relevant to schizophrenia, our results do not support missense mutation of RTN4R as a strong risk factor in the pathogenesis of schizophrenia., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objectives: To report on the audiometric findings in the first otosclerosis family linked to OTSC10., Study Design: Retrospective cohort study., Methods: A family study in a large otosclerosis family was performed, and a pedigree was constructed. Examination of all family members consisted of medical history guided by a questionnaire, pure-tone audiometry, otoscopy, and collection of blood samples for genetic linkage analysis. In addition, a selected group underwent stapedial reflex measurements and tympanometry. Cross-sectional as well as longitudinal analyses of audiometric data were performed., Results: Eleven family members were identified as clinically affected and were all carriers of the disease haplotype. Twelve clinically unaffected family members carried the disease haplotype as well. Cross-sectional analyses of clinically affected family members showed no significant progression of air conduction (AC) thresholds, bone conduction (BC) thresholds, and air-bone gap (ABG) levels with increasing age. Longitudinal regression analyses in one family member revealed significant deterioration of AC thresholds at all frequencies. The BC thresholds showed a significant increase with advancing age at 0.5 kHz, 2 kHz, and 4 kHz. A significant progression of ABG was seen at 8 kHz., Conclusions: The intersubject variation, in terms of age of onset, level of progression, and audiogram configuration, was remarkable, probably due to reduced penetrance and variable expression of the disease. Long-term audiometric data in one patient, however, were useful to demonstrate progression of hearing impairment., (Copyright © 2011 The American Laryngological, Rhinological, and Otological Society, Inc.)

Apolipoprotein E (apoE) is involved in the risk to develop sporadic Alzheimer's disease (AD). Since impaired central acetylcholine (ACh) function is a hallmark of AD, apoE may influence ACh function by modulating muscarinic ACh receptors (mAChRs). To test this hypothesis, mAChR binding was measured in mice lacking apoE and wild type C57BL/6J mice. Mice were also tested on the pre-pulse inhibition, delay eyeblink classical conditioning, and 5-choice serial reaction time tasks (5-SRTT), which are all modulated by ACh transmission. Mice were also given scopolamine to challenge central mAChR function. Compared to wild type mice, mice lacking apoE had reduced number of cortical and hippocampal mAChRs. Scopolamine had a small effect on delay eyeblink classical conditioning in wild type mice but a large effect in mice lacking apoE. Mice lacking apoE were also unable to acquire performance on the 5-SRTT. These results support a role for apoE in ACh function and suggest that modulation of cortical and hippocampal mAChRs might contribute to genotype differences in scopolamine sensitivity and task acquisition. Impaired apoE functioning may result in cholinergic deficits that contribute to the cognitive impairments seen in AD., (Copyright © 2008 Elsevier Inc. All rights reserved.)

In the present study, reciprocal embryo transfers were conducted to examine genetic and maternal effects on the baseline and fear-sensitized acoustic startle response (ASR) in the two inbred strains C3H/HeN and DBA/2JHd and the outbred strain NMRI. The largest differences in the ASR were found in untreated strains (effect size 0.6). The transfer procedure per se had a significant effect on the behavior of NMRI mice resulting in a reduction in the baseline, and an increase in the fear-sensitized ASR. In contrast, there were no significant effects of the transfer procedure in the two inbred strains. Autosomal genetic effects had a stronger impact on the amplitude of the ASR (effect sizes 0.5) than sex (effect sizes 0.06) as revealed by reciprocal embryo transfer. Nevertheless, the genetic effects on the fear-sensitized ASR were somewhat more variable and strain-dependent (effect sizes 0.1-0.2). Global maternal effects were detected after embryo transfer into NMRI mothers resulting in a larger reduction of the ASR in the offspring of DBA and NMRI donors than C3H donors (effect sizes 0.1-0.2). An additional fostering procedure was introduced to dissect uterine and postnatal maternal effects in NMRI offspring. Uterine factors changed the baseline ASR of the offspring in direction of the recipient mother strain. Surprisingly, postnatal maternal effects on the ASR were contrary to the behavior of the rearing mother. In conclusion, both genetic and prenatal/postnatal maternal factors persistently influenced the ASR of the offspring, whereas the fear-sensitized ASR was mainly influenced by genetic factors. Our study shows that uterine and postnatal maternal influences deserve more attention when determining the phenotype of genetically engineered mice at least in the first generation following embryo transfer.

Background: The dopamine D(3) receptor (DRD(3)) is suspected to modulate prepulse inhibition (PPI) in animals and humans, but definite conclusions cannot be drawn due to lack of selective DRD(3) ligands. The Ser9Gly polymorphism is a common variant of the DRD(3) gene and determines the gain of function of the D(3) receptor. This is the first study to examine the influence of the DRD(3) Ser9Gly polymorphism on human PPI., Methods: Prepulse inhibition was measured in 101 healthy male subjects presented with 75-dB and 85-dB prepulses at 30-, 60-, and 120-msec prepulse-pulse intervals. Subjects were grouped according to their DRD(3) status into a Gly/Gly, a Ser/Gly, and a Ser/Ser group., Results: Analyses of variance showed that at all prepulse and interval conditions, Gly/Gly individuals had the lowest PPI and the greatest onset latency facilitation and Ser/Ser individuals had the highest PPI and the lowest onset latency facilitation, while Ser/Gly individuals were intermediate., Conclusions: These results suggest that PPI is modulated by the D(3) receptor and its levels depend on the Ser9Gly polymorphism.

Clinical studies of twin pairs and families of post-traumatic stress disorder (PTSD) patients raise questions as to possible genetic predisposition to PTSD. Studies using isogenic animal populations exposed to a stress paradigm could elucidate the relative contributions of genotype and environment to endophenotypic expression. The prevalence of individuals displaying severely compromised behavioural responses to predator scent stress (PSS) was assessed in six inbred strains of mice in an animal model of PTSD that classifies individuals into groups according to the degree of their behavioural response. The choice of strains was based on the frequent use of these mice in transgenic research. The prevalence of extreme behavioural response in the elevated plus maze and the acoustic startle response paradigms, performed in sequence, was assessed at baseline and 7 d after PSS exposure between and within strains, and compared to differences in circulating corticosterone levels. Narrow-sense trait heritability was determined by comparing the between-strain variance to the total variance. Although strain-specific differences in anxiety-like behaviours were demonstrated, the results revealed a significant degree of individual variability in response patterns within each of the inbred strains, yielding a baseline heritability factor for anxiety-like behaviours of 30%, but only 10% for response to stress exposure. Baseline anxiety-like behaviours were found not to be predictive of post-exposure behavioural responses. The response of the individual to stress is multifactorial and environmental factors play a predominant role in characterizing the individual response to stress exposure, although there are significant genetic underpinnings.

Background: Previous data in both rat and mouse genetic models suggest that there is a genetic relationship between acute alcohol withdrawal responses and innate alcohol drinking behavior. The purpose of the present study was to examine whether acute alcohol withdrawal responses, as measured by acoustic startle and prepulse inhibition (PPI) of acoustic startle, may be genetically related to innate differences in alcohol preference in 2 mouse lines selectively bred for high (HAP1 and HAP2) or low (LAP1 and LAP2) alcohol preference. Line differences in startle responses at baseline, prior to alcohol or saline treatment, were also measured., Methods: Alcohol-naive, male and female HAP1 (n = 35) and LAP1 (n = 32) and HAP2 (n = 43) and LAP2 (n = 40) mice were tested under baseline conditions and during withdrawal from a single injection of 4.0 g/kg alcohol or equal volume of saline at 4, 8, and 12 hours post-injection., Results: On most trial types, baseline startle responses and PPI were greater in both HAP lines than in both LAP lines, and startle responses were greater in males than in females. During acute alcohol withdrawal, both male LAP lines, and LAP1 females, showed reduced startle responses at the 4-hour time point during acute alcohol withdrawal. In contrast, both HAP1 males and females showed a trend toward enhanced startle at 4 hours in withdrawal. No clear differences in PPI during withdrawal were evident., Conclusions: These findings indicate good evidence for a genetic relationship between greater baseline acoustic startle responses and PPI and high alcohol preference. Modest support for a genetic correlation between low alcohol preference and reduced startle responses at 4 hours in withdrawal was found in male mice. The suppression in acoustic startle during acute alcohol withdrawal in male LAP lines but not in male HAP lines suggests that a genetic propensity toward low alcohol preference may be related to greater sensitivity to alcohol as measured by acoustic startle responses during acute alcohol withdrawal.

To support the role of DISC1 in human psychiatric disorders, we identified and analyzed two independently derived ENU-induced mutations in Exon 2 of mouse Disc1. Mice with mutation Q31L showed depressive-like behavior with deficits in the forced swim test and other measures that were reversed by the antidepressant bupropion, but not by rolipram, a phosphodiesterase-4 (PDE4) inhibitor. In contrast, L100P mutant mice exhibited schizophrenic-like behavior, with profound deficits in prepulse inhibition and latent inhibition that were reversed by antipsychotic treatment. Both mutant DISC1 proteins exhibited reduced binding to the known DISC1 binding partner PDE4B. Q31L mutants had lower PDE4B activity, consistent with their resistance to rolipram, suggesting decreased PDE4 activity as a contributory factor in depression. This study demonstrates that Disc1 missense mutations in mice give rise to phenotypes related to depression and schizophrenia, thus supporting the role of DISC1 in major mental illness.

Schizophrenia is a chronic and debilitating disease which is thought to arise from a neuro-developmental disorder. Both the stable tubule-only polypeptide (STOP) protein and the N-methyl-D-aspartate (NMDA) NR1 subunit are involved in neuronal development and physiology. It has therefore been postulated that transgenic mice lacking either the STOP or the NMDAR1 gene would show a 'schizophrenic-like' phenotype. Here, STOP knockout and NMDA NR1 hypomorphic mice were assessed in a behavioural measure that can be used to detect schizophrenic-like phenotypes: a change in sensorimotor gating, measured through prepulse inhibition (PPI). STOP knockout mice were further assessed in another measure of 'schizophrenic-like behaviour': hyperlocomotion. The PPI deficit exhibited by both the STOP knockout and NMDA knockdown mice could not be reversed by acute treatment with the atyptical antipsychotic, clozapine (1 mg/kg, i.p.) but the hyperlocomotion shown by the STOP knockout mice was reversed with the same acute dose of clozapine.

Increased anxiety may occur in up to 70% of AD patients during the course of their illness. Here we show that human apoE isoforms, which differ in AD risk, have differential effects on measures of anxiety in adult Apoe-/- male mice expressing human apoE3 or apoE4 in their brains and male probable AD (PRAD) patients. Compared with wild-type mice, Apoe-/- mice without human apoE or with apoE4, but not apoE3, showed increased measures of anxiety. These behavioral alterations were associated with reduced microtubule-associated protein 2-positive neuronal dendrites in the central nucleus of the amygdala. Consistent with the mouse data, male and female PRAD patients with epsilon4/epsilon4 showed higher anxiety scores than those with epsilon3/epsilon3. We conclude that human apoE isoforms have differential effects on measures of anxiety.

GABA transporter subtype 1 (GAT1) knock-out (KO) mice display normal reproduction and life span but have reduced body weight (female, -10%; male, -20%) and higher body temperature fluctuations in the 0.2-1.5/h frequency range. Mouse GAT1 (mGAT1) KO mice exhibit motor disorders, including gait abnormality, constant 25-32 Hz tremor, which is aggravated by flunitrazepam, reduced rotarod performance, and reduced locomotor activity in the home cage. Open-field tests show delayed exploratory activity, reduced rearing, and reduced visits to the central area, with no change in the total distance traveled. The mGAT1 KO mice display no difference in acoustic startle response but exhibit a deficiency in prepulse inhibition. These open-field and prepulse inhibition results suggest that the mGAT1 KO mice display mild anxiety or nervousness. The compromised GABA uptake in mGAT1 KO mice results in an increased GABA(A) receptor-mediated tonic conductance in both cerebellar granule and Purkinje cells. The reduced rate of GABA clearance from the synaptic cleft is probably responsible for the slower decay of spontaneous IPSCs in cerebellar granule cells. There is little or no compensatory change in other proteins or structures related to GABA transmission in the mGAT1 KO mice, including GAT1-independent GABA uptake, number of GABAergic interneurons, and GABA(A)-, vesicular GABA transporter-, GAD65-, and GAT3-immunoreactive structures in cerebellum or hippocampus. Therefore, the excessive extracellular GABA present in mGAT1 KO mice results in behaviors that partially phenocopy the clinical side effects of tiagabine, suggesting that these side effects are inherent to a therapeutic strategy that targets the widely expressed GAT1 transporter system.

Objective: To describe clinical and radiologic features, results of ear surgery, and genetic analysis in three families with Teunissen-Cremers syndrome., Design: Case series., Setting: Tertiary referral center., Background: The NOG gene encodes the protein noggin, which has antagonist action in osteogenesis. Malformation of bones and joints may result from defects in noggin. Teunissen-Cremers syndrome is caused by mutations in the NOG gene. Two mutations in this gene were reported previously. The proximal symphalangism-hearing impairment syndrome, also caused by mutations in the NOG gene, is characterized by proximal symphalangism, conductive hearing loss, and occasionally synostoses., Methods: We examined nine affected members of three Dutch families. Reconstructive middle ear surgery was performed in five patients (nine ears), and we sequenced the NOG gene in these families., Results: Affected members had conductive hearing impairment, hyperopia, and broad thumbs and first toes with brachytelephalangia. Surgery manifested stapes ankylosis with additional incudal fixation frequently in the fossa incudis. Air-bone gaps decreased to less than 10 dB in six ears. Genetic analysis revealed three new mutations in the NOG gene., Conclusion: The Teunissen-Cremers syndrome is an entity in its clinical presentation, distinct from other syndromes with proximal symphalangism and hearing impairment. So far, in five families with Teunissen-Cremers syndrome, four truncating mutations and one amino acid substitution were found in the NOG gene. The majority of other mutations found in this gene are missense mutations, which might result in some residual protein activity. Reconstructive middle ear surgery is an option for treatment.

Objectives/hypothesis: Auditory neuropathy is a sensorineural hearing disorder characterized by absent or abnormal auditory brainstem responses and normal cochlear outer hair cell function as measured by otoacoustic emission recordings. Many risk factors are thought to be involved in its etiology and pathophysiology. Four Chinese pedigrees with familial auditory neuropathy were presented to demonstrate involvement of genetic factors in the etiology of auditory neuropathy., Study Design: Probands of the above-mentioned pedigrees, who had been diagnosed with auditory neuropathy, were evaluated and followed in the Department of Otolaryngology-Head and Neck Surgery, China People Liberation Army General Hospital (Beijing, China). Their family members were studied, and the pedigree maps established., Methods: History of illness, physical examination, pure-tone audiometry, acoustic reflex, auditory brainstem responses, and transient evoked and distortion-product otoacoustic emissions were obtained from members of these families. Some subjects received vestibular caloric testing, computed tomography scan of the temporal bone, and electrocardiography to exclude other possible neuropathic disorders., Results: In most affected patients, hearing loss of various degrees and speech discrimination difficulties started at 10 to 16 years of age. Their audiological evaluation showed absence of acoustic reflex and auditory brainstem responses. As expected in auditory neuropathy, these patients exhibited near-normal cochlear outer hair cell function as shown in distortion product otoacoustic emission recordings. Pure-tone audiometry revealed hearing loss ranging from mild to profound in these patients. Different inheritance patterns were observed in the four families. In Pedigree I, 7 male patients were identified among 43 family members, exhibiting an X-linked recessive pattern. Affected brothers were found in Pedigrees II and III, whereas in pedigree IV, two sisters were affected. All the patients were otherwise normal without evidence of peripheral neuropathy at the time of writing., Conclusion: Patients with characteristics of nonsyndromic hereditary auditory neuropathy were identified in one large and three smaller Chinese families. Pedigree analysis suggested an X-linked, recessive hereditary pattern in one pedigree and autosomal recessive inheritances in the other three pedigrees. The phenotypes in the study were typical of auditory neuropathy; they were transmitted in different inheritance patterns, indicating clinical and genetic heterogeneity of this disorder. The observed inheritance and clinical audiological findings are different from those previously described for nonsyndromic low-frequency sensorineural hearing loss. This information should facilitate future molecular linkage analyses and positional cloning for the relative genes contributing to auditory neuropathy.

Exogenous enzyme replacement therapy achieves satisfactory biomedical correction in Gaucher type 1 disease and may halt or reverse neurological progression in type 3, while it does not appear to influence the outcome in type 2. In view of the therapeutic possibilities, early detection and monitoring of type 3 Gaucher disease, as well as evaluation of the effectiveness of enzyme therapy on neuronopathic involvement is necessary. The objective of this study was to evaluate the extent of brainstem disease in children with proven Gaucher type 3, by means of an audiological test battery. We studied 9 patients with Gaucher type 3 disease. The tests included baseline audiometric tests, as well as auditory brainstem evoked responses (ABR), acoustic reflexes and medial olivo-cochlear suppression by contralateral noise tests, that involve overlapping but not identical efferent and afferent pathways and brainstem structures. We found a constellation of abnormalities including bilaterally raised acoustic reflexes, poor medial olivo-cochlear suppression, and very poor brainstem evoked potentials. These abnormalities could be due to a single lesion in the dorsomedial brainstem, or to multiple lesions, and further study is needed to clarify this issue. Combined audiological tests may provide information on the severity of the neurological involvement and should therefore be part of a standard assessment for the diagnosis as well as for long term neurological monitoring of Gaucher type 3 patients.

Ten obligate carriers of Usher syndrome type 2A from 5 different families with 2 affected persons all underwent audiologic, vestibular and ophthalmologic examinations. They had a sensorineural hearing loss which was in excess of that expected for their age at all of the frequencies (0.25-8 kHz) tested, however, only a 10 dB (average) excess in hearing loss at 0.25-0.5 kHz proved to be significant. The speech discrimination scores obtained conformed with the hearing thresholds. Tympanometry, acoustic reflex and brain stem auditory-evoked potential findings were generally normal. Some vestibular abnormalities were found in a minority of the carrier sample, but not beyond the level of false positivity. Ophthalmologic findings were essentially normal, although in 5 carriers there was a subnormal electrooculography (EOG). These findings are not sufficient specific for carrier detection.

Auditory function tests were performed on 13 patients with myotonic dystrophy (MD). Seven patients had a sensorineural high-frequency hearing loss (HFL) of 30-85 dB at 8 kHz in their pure-tone audiogram, which was in excess of that expected for their age and could be attributed to MD. Their hearing loss resembled 'precocious presbyacusis', i.e. if the patients had been considerably older (or 'functionally' older) than they really were, their HFL could (to some extent) have been attributed to presbyacusis alone. The HFL showed the phenomenon of (genetic) anticipation. Tympanograms and acoustic reflexes were normal. Brainstem auditory evoked potentials (BAEPs) showed a significant increase in the I-V interpeak interval (by 0.35-0.7 ms) and in the III-V interpeak interval (by 0.21-0.67 ms). There was no correlation between the BAEP and the audiometric findings. It should be noted that precocious presbyacusis may be linked to specific gene defects.