Features of autosomal recessive non-syndromic hearing impairment: a review to serve as a reference.

OBJECTIVE: Non-syndromic sensorineural hearing impairment is inherited in an autosomal recessive fashion in 75-85% of cases. To date, 61 genes with this type of inheritance have been identified as related to hearing impairment, and the genetic heterogeneity is accompanied by a large variety of clinical characteristics. Adequate counselling on a patient's hearing prognosis and rehabilitation is part of the diagnosis on the genetic cause of hearing impairment and, in addition, is important for the psychological well-being of the patient. TYPE OF REVIEW: Traditional literature review. DATA SOURCE: All articles describing clinical characteristics of the audiovestibular phenotypes of identified genes and related loci have been reviewed. CONCLUSION: This review aims to serve as a summary and a reference for counselling purposes when a causative gene has been identified in a patient with a non-syndromic autosomal recessively inherited sensorineural hearing impairment.

Audiometric characteristics of a dutch family with a new mutation in GATA3 causing HDR syndrome.

We present the case of a Dutch family with a new mutation (c523_528dup) in GATA3 causing HDR syndrome. HDR syndrome is characterised by hypoparathyroidism, deafness and renal defects. In this study, we describe the audiometric characteristics of 5 patients from this family. Their hearing impairment was congenital, bilateral and symmetric. Audiograms showed mild-to-moderate hearing impairment with a flat audiogram configuration. Higher frequencies tended to be affected more strongly. Cross-sectional analyses showed no progression, and a mean audiogram was established. Psychophysical measurements in 3 HDR patients - including speech reception in noise, loudness scaling, gap detection and difference limen for frequency - were obtained to assess hearing function in greater detail. Overall, the results of the psychophysical measurements indicated characteristics of outer hair cell loss. CT scanning showed no anomalies in 3 of the HDR patients. Although 2 patients displayed vestibular symptoms, no anomalies in the vestibular system were found by vestibulo-ocular examination. Our results are in agreement with the theory that outer hair cell malfunctioning can play a major role in HDR syndrome.

Usefulness of additional measurements of the median nerve with ultrasonography.

High resolution sonography is a relatively new diagnostic technique in diagnosing carpal tunnel syndrome (CTS). Normal values in different studies, however, vary and this makes their practical use difficult. The aim of this study was to establish normal values for the median nerve cross-sectional area (CSA) and to investigate the value of measuring additional parameters. Ninety-eight wrists of 29 women and 25 men without signs or symptoms of CTS were included. Width and circumference of the wrist were measured. The CSA of the median nerve at the level of the pisiform bone was measured using ultrasonography. We found a significant correlation between the CSA of the median nerve at the wrist and wrist circumference. Measuring wrist circumference will establish the upper level of normal more accurately compared to predictions solely based upon gender. This has important implications in diagnosing CTS with ultrasonography.

Flat threshold and mid-frequency hearing impairment in a Dutch DFNA8/12 family with a novel mutation in TECTA. Some evidence for protection of the inner ear.

A novel TECTA mutation (c.5331G>A) was identified affecting alpha-tectorin just N-terminally of the zona pellucida domain in a Dutch family with nonsyndromic autosomal dominant sensorineural hearing impairment. The present mutation is clearly associated with a flat-threshold type of hearing impairment. Intriguingly, our results demonstrated that the present TECTA mutation had a significant protective effect against presbyacusis. Substantial protection against presbyacusis is a novel finding in a family with autosomal dominant hearing impairment.

Familial aggregation of tinnitus: a European multicentre study.

INTRODUCTION AND AIM: Tinnitus is a common condition affecting approximately 20% of the older population. There is increasing evidence that changes in the central auditory system following cochlear malfunctioning are responsible for tinnitus. To date, few investigators have studied the influence of genetic factors on tinnitus. The present report investigates the presence of a familial effect in tinnitus subjects. METHODS: In a European multicentre study, 198 families were recruited in seven European countries. Each family had at least 3 siblings. Subjects were screened for causes of hearing loss other than presbyacusis by clinical examination and a questionnaire. The presence of tinnitus was evaluated with the question "Nowadays, do you ever get noises in your head or ear (tinnitus) which usually last longer than five minutes". Familial aggregation was tested using three methods: a mixed model approach, calculating familial correlations, and estimating the risk of a subject having tinnitus if the disorder is present in another family member. RESULTS: All methods demonstrated a significant familial effect for tinnitus. The effect persisted after correction for the effect of other risk factors such as hearing loss, gender and age. The size of the familial effect is smaller than that for age-related hearing impairment, with a familial correlation of 0.15. CONCLUSION: The presence of a familial effect for tinnitus opens the door to specific studies that can determine whether this effect is due to a shared familial environment or the involvement of genetic factors. Subsequent association studies may result in the identification of the factors responsible. In addition, more emphasis should be placed on the effect of role models in the treatment of tinnitus.

A mutation in the gamma actin 1 (ACTG1) gene causes autosomal dominant hearing loss (DFNA20/26).

Linkage analysis in a multigenerational family with autosomal dominant hearing loss yielded a chromosomal localisation of the underlying genetic defect in the DFNA20/26 locus at 17q25-qter. The 6-cM critical region harboured the gamma-1-actin (ACTG1) gene, which was considered an attractive candidate gene because actins are important structural elements of the inner ear hair cells. In this study, a Thr278Ile mutation was identified in helix 9 of the modelled protein structure. The alteration of residue Thr278 is predicted to have a small but significant effect on the gamma 1 actin structure owing to its close proximity to a methionine residue at position 313 in helix 11. Met313 has no space in the structure to move away. Moreover, the Thr278 residue is highly conserved throughout eukaryotic evolution. Using a known actin structure the mutation could be predicted to impair actin polymerisation. These findings strongly suggest that the Thr278Ile mutation in ACTG1 represents the first disease causing germline mutation in a cytoplasmic actin isoform.

A genotype-phenotype correlation for GJB2 (connexin 26) deafness.

INTRODUCTION: Mutations in GJB2 are the most common cause of non-syndromic autosomal recessive hearing impairment, ranging from mild to profound. Mutation analysis of this gene is widely available as a genetic diagnostic test. OBJECTIVE: To assess a possible genotype-phenotype correlation for GJB2. DESIGN: Retrospective analysis of audiometric data from people with hearing impairment, segregating two GJB2 mutations. SUBJECTS: Two hundred and seventy seven unrelated patients with hearing impairment who were seen at the ENT departments of local and university hospitals from Italy, Belgium, Spain, and the United States, and who harboured bi-allelic GJB2 mutations. RESULTS: We found that 35delG homozygotes have significantly more hearing impairment, compared with 35delG/non-35delG compound heterozygotes. People with two non-35delG mutations have even less hearing impairment. We observed a similar gradient of hearing impairment when we categorised mutations as inactivating (that is, stop mutations or frame shifts) or non-inactivating (that is, missense mutations). We demonstrated that certain mutation combinations (including the combination of 35delG with the missense mutations L90P, V37I, or the splice-site mutation IVS1+1G>A, and the V37I/V37I genotype) are associated with significantly less hearing impairment compared with 35delG homozygous genotypes. CONCLUSIONS: This study is the first large systematic analysis indicating that the GJB2 genotype has a major impact on the degree of hearing impairment, and identifying mild genotypes. Furthermore, this study shows that it will be possible to refine this correlation and extend it to additional genotypes. These data will be useful in evaluating habilitation options for people with GJB2 related deafness.

Sensorineural hearing impairment in patients with Pmp22 duplication, deletion, and frameshift mutations.

OBJECTIVE: To characterize and distinguish the types of sensorineural hearing impairment (SNHI) that occur in hereditary motor and sensory neuropathy Type 1a (HMSN-1a) and hereditary neuropathy with liability to pressure palsies (HNPP), which are caused by deletion or frameshift mutation. STUDY DESIGN: Prospective study. SETTING: Ambulatory patients in a university hospital. PATIENTS: Twelve patients with HMSN-1a due to a duplication of the PMP22 gene on chromosome 17p11.2, 16 patients with HNPP due to the common PMP22 deletion (HNPP del), and 11 HNPP patients with a frame shift mutation (heterozygous PMP22 G-insertion) (HNPP mut), all confirmed by molecular genetic analysis. INTERVENTIONS: Pure-tone audiograms and speech audiograms were obtained. MAIN OUTCOME MEASURES: Results of cross-sectional analysis comprising linear regression of hearing threshold on age. RESULTS: Pure-tone audiograms showed mild to moderate SNHI, predominant at the low and the high frequencies. SNHI showed significant progression by approximately 0.4 dB per year at 0.25 to 4 kHz and up to 1 to 2 dB per year at 4 to 8 kHz. Patients with HMSN-1a had substantial, presumably congenital, SNHI but did not show significant progression beyond presbyacusis. Patients with HNPP showed postnatal onset at age 11 years with progression of SNHI in excess of presbyacusis by 0.4 dB per year. All three types of neuropathy showed normal speech recognition. CONCLUSIONS: All three types of neuropathy showed SNHI with normal speech recognition. HMSN-1a showed stable SNHI without progression beyond presbyacusis. HNPP showed progression beyond presbyacusis with postnatal onset. The differences in SNHI may be explained by the differences in PMP22 expression. The progressive SNHI in HNPP might be explained by the liability for exogenous factors associated with this disorder.

[From gene to disease; a progressive cochlear-vestibular dysfunction with onset in middle-age (DFNA9)]. / Van gen naar ziekte; een op middelbare leeftijd optredende progressieve cochleavestibulaire disfunctie (DFNA9).

DFNA9 is an autosomal dominant genetic inner-ear hearing impairment that starts to show itself in the 3rd and 4th decades of life. This hearing impairment may be of a different degree of severity in each ear. Progression of hearing loss is about 3 dB/year. In about one in three patients severe vestibular symptoms similar to those in Ménière's disease are present as a result of a progressive impairment of the vestibular system. Several mutations were found in the COCH-gene on chromosome 14. There are indications that some of the mutations disrupt the folding of the cochlin protein, an important component of the extracellular matrix in the inner ear. DNA-diagnostics confirming the diagnosis ofDFNA9 are possible.

Hearing impairment and neurological dysfunction associated with a mutation in the mitochondrial tRNASer(UCN) gene.

We studied a large Dutch family with maternally inherited, progressive, sensorineural hearing loss in 27 patients. Only in a single family member was the hearing loss accompanied by neurological symptoms including ataxia and dysarthria. DNA analysis of the mitochondrial genome revealed the insertion of a C at nucleotide position 7472 in the tRNASer(UCN) gene (7472insC mutation). We determined the percentage of mutant DNA (heteroplasmy) in blood from all family members, and found no correlation between hearing loss and leucocyte heteroplasmy. The 7472insC mutation was previously identified in a smaller family from Sicily with sensorineural hearing loss in 9 family members, six of them also presenting neurologically with ataxia and myoclonus. The presence of the 7472insC mutation in two different pedigrees strongly supports its pathogenicity. However, the interfamilial difference in penetrance of the neurologic abnormalities is most likely to be strongly influenced by secondary factors different from the 7472insC mutation, as heteroplasmy or age of the patients were similar in both families. This mutation should therefore be analysed in families with maternally inherited hearing loss, irrespective of whether the hearing loss is non-syndromic or accompanied by neurologic abnormalities.

Familial progressive vestibulocochlear dysfunction.

A kindred is presented in which several members had complaints of head movement-dependent oscillopsia due to acquired vestibular areflexia in combination with progressive hearing loss. History was noncontributory for other neurologic or otologic diseases (including infectious diseases) or use of neuro-ototoxic drugs. The pedigree suggests autosomal dominant inheritance.

Oculomotor, auditory, and vestibular responses in myotonic dystrophy.

In 13 patients with myotonic dystrophy, oculomotor, auditory, and vestibular tests were performed. All 13 patients showed one or more abnormalities. There was a significant increase in the penetrance of the separate abnormalities with age. Saccadic slowing was found in 10 patients, in a severe form in three. Seven patients had a sensorineural high-tone hearing loss (30 to 85 dB at 8 kHz), which was in excess of that expected for their age, that could be attributed to myotonic dystrophy. Brain-stem auditory evoked potentials showed a significant interwave delay of the I-V interval (0.35 to 0.7 milliseconds). An abnormal vestibulo-ocular reflex was found in six patients; three had vestibular hyperreflexia with increased gain, and three had hyporeflexia with short time constants. This study confirms that in myotonic dystrophy, sensory system involvement can be found on both a peripheral and a central level.

Familial progressive vestibulocochlear dysfunction caused by a COCH mutation (DFNA9).

OBJECTIVE: To describe the decline of vestibulocochlear function in a man with vestibulocochlear dysfunction caused by a Pro51Ser mutation within the COCH gene on chromosome 14q12-13 (DFNA9). METHODS: A follow-up of more than 15 years was performed in a single case. Clinical investigations were supplemented by oculomotor, vestibular, and auditory tests. RESULTS: A 50-year-old man had had progressive sensorineural hearing loss and dysequilibrium for 15 years; he had been asymptomatic at the age of 35 years. He suffered from instability in the dark, head movement-dependent oscillopsia, paroxysmal positional vertigo, and vertigo with and without nausea. Hearing impairment started unilaterally, predominantly in the high frequencies. He also reported tinnitus. Disease progressed to severe bilateral high-frequency hearing impairment and vestibular areflexia. Fluctuation of vestibulocochlear function was documented and mentioned by the patient. CONCLUSIONS: Our patient proved to suffer from an autosomal dominant vestibulocochlear disorder caused by a COCH gene mutation. The remarkable medical history has some features in common with Meniere disease; however, there are also different clinical and neurophysiological features. In the family, phenotypic variability is present.

Planned preoperative radiation therapy for advanced laryngeal carcinoma.

One hundred ten patients with predominantly advanced laryngeal carcinoma were treated in the period 1969-1978 with planned preoperative radiation therapy followed by surgery. Site distribution was: 63 supraglottic, 26 glottic, 15 transglottic and 6 subglottic. There were 4 Stage II patients, 66 Stage III and 40 Stage IV. Preoperative radiation therapy consisted of Telecobalt irradiation to a total dose of 25 Gy given to a target volume encompassing the larynx and regional neck nodes, given in 5 equal daily fractions of 5 Gy in 5 consecutive days. Surgery was performed 2 days later. Total laryngectomy was performed on 48 patients, total laryngectomy with neck dissection on 55 patients, supraglottic laryngectomy on 5 and supraglottic laryngectomy with neck dissection on 2 patients. Crude actuarial 5 and 10 year survival probability for the whole group is 71 and 61%, respectively. The corrected 5 and 10 year survival is 75%. For patients with T3-T4-N0 tumors 5 and 10 year survival probability is: crude 65 and 58%, and corrected 70% respectively. For T3-T4-N+ crude: 75 and 60% and corrected: 78%. Of 110 patients, one died postoperative, three died of intercurrent disease, five died as a result of second malignancy, and 23 died of their larynx carcinoma: 12/23 because of locoregional failure, and 11/23 because of distant metastasis. We concluded that short intensive preoperative radiation therapy and surgery offer a high cure rate in the treatment of advanced resectable laryngeal carcinoma. The merits of this technique are outlined in the text.

Evaluation of short-course preoperative irradiation in the treatment of resectable bronchus carcinoma: long-term analysis of a randomized pilot-study.

A randomized pilot-study on patients with resectable non small-cell lung carcinoma was conducted from December 1971 to May 1976 inclusive. Patients were randomly assigned to receive preoperative irradiation to the mediastinum followed by surgery (RT + S), or to be treated by surgery only (SO). A total of 33 patients clinically staged as T1-2, N0, M0 histologically confirmed bronchus carcinoma were entered onto the study. Sixteen patients were assigned to RT + S and 17 patients received SO. There were 3 operative mortalities, all of them in the SO group. A total of 28 patients, 14 in each group are evaluable, with a minimum period of observation of 7 years. Preoperative irradiation consisted of a Telecobalt photon-beam applied to the mediastinum as anterior and posterior portals. The thoracic spine was protected on the posterior portal by a narrow lead block. A total dose of 20 Gy calculated in the mid plane was given in 5 equal fractions each of 4 Gy administered on 5 consecutive days: Monday through Friday; patients were operated on the following Monday after the week-end. Surgical treatment was similar for both groups and consisted of lobectomy or pneumonectomy, depending on the size and site of the primary tumor. Analysis of the survival data showed an absolute crude 5 years survival rate of 58% for patients who received RT + S versus 43% for SO. The corrected actuarial 5 and 10 years survival rates are 78 and 69% for the group that received RT + S, and 67 and 55% for the group treated by SO, respectively. Nineteen patients were treated more than 10 years ago. Four of 8 (50%) treated by RT + S are alive with no evidence of disease (NED), and 3/11 (28%) treated by SO are alive with NED. The median survival period for the group that received RT + S is 72 months versus 30 months for the group treated by SO. Analysis of the adequacy of surgical resection based on histological examination of the operative specimen showed higher incidence of radical resection in the group that received RT + S (57 versus 28.5%). It is concluded that the treatment protocol of preoperative radiation therapy as outlined is well tolerated and the results are encouraging.

Oculomotor and vestibular anomalies in Pelizaeus-Merzbacher disease: a study on a kindred with 2 affected and 3 normal males, 3 obligate and 8 possible carriers.

Two males suffering from Pelizaeus-Merzbacher disease were examined, one at the age of 1 year 4 months and at the age of 7 years, and the other at the age of 7 years 8 months. The former had spontaneous vertical pendular nystagmus. He also showed horizontal "micronystagmus", present only at the age of 1 year, which might be similar to "voluntary nystagmus". Both males had jerky bilateral gaze-evoked nystagmus, defective smooth pursuit and optokinetic responses and a hyporeactive vestibulo-ocular reflex (VOR). All three obligate carriers exhibited typical VOR disinhibition in the two horizontal nystagmus directions, which may be a distinctive feature. This feature was also found in one of the 7 possible carriers examined and was not observed in the 3 non-affected males, who had normal oculomotor responses.

Familial vestibulocerebellar dysfunction: a new syndrome?

Three members of a single family with the symptom of "motion sickness" showed rebound nystagmus, saccadic pursuit eye movements, defective optokinetic slow phase velocity and lack of fixation suppression of vestibularly induced nystagmus. One of them showed vestibular hyperreactivity and a gradual build-up of the optokinetic response. In absence of other abnormalities, these findings can be localized to the vestibulocerebellum (flocculo-nodular lobe).

Multi-system signs and symptoms in X-linked ataxia carriers.

Neurological, auditory, vestibular and ocular motor examinations were performed on 3 definite and 3 possible heterozygous carriers of a previously described X-linked multi-system disorder with early childhood onset, rapid progression and a fatal outcome (Arts et al., 1993). The symptoms, i.e., delayed motor development, ataxia, hearing loss and subnormal intelligence, were so evident in 2 of the possible carriers that they could be redesignated as probable carriers. Other symptoms in the definite and probable carriers were clubfeet, dysarthria, intention tremor and abnormal gait, while their signs included dysdiadochokinesia, ataxic paraplegia, abnormal muscle tendon reflexes and extensor plantar responses. All the symptomatic carriers developed moderate-to-severe sensorineural hearing loss with normal stapedial reflexes and brain stem auditory evoked potentials (BAEPs) in those in whom this could be evaluated. Speech discrimination was disproportionally poor unilaterally in one case from whom no BAEPs could be obtained because of her degree of hearing loss. Various combinations were found of high gain of the vestibulo-ocular reflex, spontaneous nystagmus and directional preponderance of vestibularly evoked nystagmus, slowing, hypometria or multi-stepping of saccades, saccadic intrusions of eye movements (macro square wave jerks, double saccadic pulses), impairment of smooth pursuit eye movements and optokinetic nystagmus, and failure of visual fixation suppression of vestibularly evoked nystagmus. Such findings indicate major involvement of the (vestibulo)cerebellum and the vermis. MRI in one carrier showed mild cerebellar atrophy.

Hereditary vestibulo-cochlear dysfunction and vascular disorders.

A family is described with a progressive autosomal dominant vestibulocochlear dysfunction resulting in a Dandy syndrome, head movement dependent oscillopsia and hearing loss. The history was negative for other neurological or otological diseases (including infectious diseases) or use of neuro-ototoxic drugs, except for a high incidence of vascular disorders (hypertension, stroke, and heart infarction).