Long term disease burden post-transplantation: three decades of observations in 25 Hurler patients successfully treated with hematopoietic stem cell transplantation (HSCT).

BACKGROUND: Mucopolysaccharidosis type I-Hurler syndrome (MPSI-H) is a lysosomal storage disease characterized by severe physical symptoms and cognitive decline. Early treatment with hematopoietic cell transplant (HSCT) is critical to the survival of these patients. While survival rates and short-term outcomes are known to be improved by HSCT, the long-term cognitive, adaptive and psychosocial functional outcomes of children with (MPSI-H) post-HSCT are not well documented. This manuscript focuses on retrospective long-term follow-up (7-33 years) of 25 MPSI-H patients, transplanted between 1986 and 2011. RESULTS: The median age at transplantation was 21 months (range 12-57 months). Except for one death, all successfully transplanted MPSI-H patients surviving at least 1 year after HSCT are alive to-date, with a median age of 21 years (range 8-36 years) at the last follow-up evaluation. A majority of HSCT grafts were bone marrow transplants (BMT), resulting in durable full chimerism in 18 (72%). Pre-HSCT, the onset of first symptoms occurred very early, at a median age of 3 months (range birth-16 months). The most prevalent symptoms before MPSI-H diagnosis involved progressive dysostosis multiplex; almost all patients suffered from hip dysplasia and thoracolumbar spine Kyphosis. Despite HSCT, considerable residual disease burden and ensuing corrective surgical interventions were observed in all, and at every decade of follow-up post HSCT. Late-onset psychiatric manifestations were significant (n = 17 patients; 68%), including depression in 13 patients at a median onset age of 18 years (range 13-31 years), hyperactivity and attention deficit disorder (n = 4), and multiple acute psychotic episodes (APE), independent of depression observed (n = 3) at a median onset age of 18 years (range 17-31 years). The adult Welscher Intelligence Scale results (n = 16) were heterogenous across the four scale dimensions; overall lower scores were observed on both working memory index (median WMI = 69.5) and processing speed index (median PSI = 65), whereas verbal comprehension index (median VCI = 79) and perceptual reasoning index (median PRI = 74) were higher. CONCLUSION: With advanced treatment options, MPSI-H are living into 3rd and 4th decades of life, however not disease free and with poor adaptation. Residual disease (loss of mobility, limited gross and fine motor skills; low cognitive ability; suboptimal cardiopulmonary function, vision and hearing) negatively impacts the quality of life and psychosocial functioning of affected individuals.

Effect of age at cochlear implantation and at exposure to Cued Speech on literacy skills in deaf children.

The aim of this study was to investigate how age at cochlear implantation (CI) and age at exposure to Cued Speech (CS, Manual system that resolves the ambiguity inherent lipreading) could impact literacy skills in deaf children. Ninety deaf children fitted with CI (early vs late) and exposed to CS (early vs late) from primary schools (from Grade 2 to Grade 5) took part in this study. Five literacy skills were assessed: phonological skills through phoneme deletion, reading (decoding and sentence comprehension), word spelling and vocabulary. The results showed that both age at CI and age at first exposure to CS had some influence on literacy skills but there was no interaction between these factors. This implies that the positive effects of age at CI, especially on all literacy skills in the younger children, were not strengthened by age at exposure to CS.

[Tinnitus and temporomandibular joint: State of the art]. / Acouphènes et articulation temporo-mandibulaire : état des connaissances.

Tinnitus has been described in temporomandibular joint dysfunction for a long time. Yet, other disorders, such as hearing loss, stress, anxiety and depression, play a major role in the pathophysiology of tinnitus. Temporomandibular joint dysfunctions seem to increase the risk of tinnitus in patients with other predisposing factors. Especially somatosensory tinnitus, which is characterized by sound modulations with neck or mandible movements, is frequently associated with temporomandibular joint dysfunction, but it is not pathognomonic of such a disorder. In such cases, functional therapy of the temporomandibular joint should be part of the multidisciplinary rehabilitation of patients with tinnitus.

Cochlear implantation in 3 adults with auditory neuropathy/auditory dys-synchrony.

We describe 3 adult patients with auditory neuropathy/auditory dys-synchrony (AN/AD) who underwent cochlear implantation. All patients had absent or poorly formed auditory brainstem responses (ABRs) in combination with preserved otoacoustic emissions (OAEs). They exhibited various aetiologies and a large variation in clinical features known to be consistent with AN/AD. Cochlear implantation was successful in 2 out of 3 cases. We conclude that AN/AD implantee candidates should be counselled with care.

[Auditory neuropathy: clinical presentation of seven cases and review of the literature]. / Neuropathie auditive: clinique et revue de la littérature. A propos de 7 observations.

INTRODUCTION: Auditory Neuropathy (AN) is defined as a sensorineural hearing loss characterized by normal cochlear haircell function (assessed by recordable Otoacoustic Emissions) and absent or abnormal auditory brainstem evoked potentials (ABR) corroborated with absence of middle ear reflexes. PATIENTS AND METHODS: We report five cases with AN. We also report two others cases in which the presentation was different but suggestive of AN. For the majority of patients, the hearing loss had been detected during childhood. Hearing assessment of these patients included appropriate behavioral audiometric techniques (Pure Tone Audiometry - PTA, and speech audiometry), objective measures of middle ear function, acoustic reflex studies, Otoacoustic Emissions (OAE) and Auditory Brainstem Responses (ABR). RESULTS: Pure tone audiometry revealed mild-to-profound hearing loss. In patients with recordable PTA thresholds were less degraded than speech intelligibility. In all patients, tympanogram and OtoAcoustic Emissions were normal. The stapedius reflex and Auditory Brainstem Responses were absent or very degraded. CONCLUSIONS: AN can be diagnosed by the combined use of pure tone audiometry, speech audiometry, and objectives measures with the recording of OAE and ABR responses. Neonatal hearing loss OAE screening can miss babies with AN. The sooner the diagnosis is established the more successful the treatment, new opportunities being afforded by cochlear implantation.

[Genetic deafness:the primary cause of sensorineural hearing loss in children]. / Les surdités génétiques: première cause de surdité de perception de l'enfant.

Genetically-transferred hearing impairments account for more than 50% of cases of pediatric sensorineural hearing defects. Multiple clinical aspects are involved in genetic hearing impairment, including the involvement of other organs, genetic inheritance, and the degree and age at onset of hearing loss. Diagnosis relies on family history, on the systematic investigation of the symptomatology including an associated syndrome, and audiometry testing in parents and siblings. Analysis of the connexin 26 gene is also indicated, as it is frequently involved in this disorder. Further genetic analysis in affected families will aid in detecting other as yet unidentified genes responsible for hearing impairment.

[Hearing impairment in children: early diagnosis is essential]. / Surdités de l'enfant: un diagnostic précoce est impératif.

Diagnosis of hearing impairment is possible during the first days of life. Hearing tests are noninvasive and should not be delayed when hearing loss is suspected. Among children's hearing impairments, conductive hearing loss is the most frequent; it is generally acquired and reversible. At the opposite pole, sensorineural hearing loss has more severe consequences because it is irreversible and often present from birth. Early diagnosis and treatment are necessary in all cases to prevent speech delay. In cases with sensorineural hearing impairment, hearing aid fitting, or even cochlear implantation, and intensive speech therapy will help deaf children learn speech, with the view of optimal social and professional integration.

A novel C202F mutation in the connexin26 gene (GJB2) associated with autosomal dominant isolated hearing loss.

Mutations in the GJB2 gene encoding connexin26 (CX26) account for up to 50% of cases of autosomal recessive hearing loss. In contrast, only one GJB2 mutation has been reported to date in an autosomal dominant form of isolated prelingual hearing loss. We report here a novel heterozygous 605G-->T mutation in GJB2 in all affected members of a large family with late childhood onset of autosomal dominant isolated hearing loss. The resulting C202F substitution, which lies in the fourth (M4) transmembrane domain of CX26, may impair connexin oligomerisation. Finally, our study suggests that GJB2 should be screened for heterozygous mutations in patients with autosomal dominant isolated hearing impairment, whatever the severity of the disease.

Mutation in the zonadhesin-like domain of alpha-tectorin associated with autosomal dominant non-syndromic hearing loss.

A gene responsible for autosomal dominant non-syndromic hearing impairment in two families (DFNA8 and DFNA12) has recently been identified as TECTA encoding alpha-tectorin, a major component of the tectorial membrane. In these families, missense mutations within the zona pellucida domain of alpha-tectorin were associated with stable severe mid-frequency hearing loss. The present study reports linkage to DFNA12 in a new family with autosomal dominant high frequency hearing loss progressing from mild to moderate severity. The candidate region refined to 3.8 cM still contained the TECTA gene. A missense mutation (C1619S) was identified in the zonadhesin-like domain. This mutation abolishes the first of the vicinal cysteines (1619Cys-Gly-Leu- 1622Cys) present in the D4 von Willebrand factor (vWf) type D repeat. These results further support the involvement of TECTA mutations in autosomal dominant hearing impairment, and suggest that vicinal cysteines are involved in tectorial membrane matrix assembly.

[Language comprehension by children with profound congenital deafness after cochlear implant]. / Compréhension du langage par les enfants sourds profonds congénitaux au moyen de l'implant cochléaire.

The consequences of profound deafness on oral language development in children are drastic and well-known. Modern multichannel cochlear implant (CI) has been proven to enhance speech production skills in prelingually deaf children. Speech production skills, however, are known not to be a reliable reflection of oral language competence as a whole. Language is an acquired common code in a specific group, enabling exchange of ideas, feelings and knowledge. In humans, speech is one of the channels conveying language. Assessing language development in CI children is more difficult than simply assessing speech production skills. Many factors may contribute to a poor or an excellent outcome, making it difficult to compare groups of children wearing or not wearing CI. The present study compared receptive language levels in paired matched children from CI and non-CI groups. The main conclusion of this study is that language comprehension scores grow significantly higher over time post-surgery in CI than in paired-matched non-CI children, despite better initial pure tone audiometric thresholds of the latter.

Comprehension of language in congenitally deaf children with and without cochlear implants.

The consequences of profound early deafness on oral language in children are drastic. The modern cochlear implant (CI) has been shown to enhance speech production skills in prelingually deaf children. Many factors may contribute to a poor or an excellent outcome, making it difficult to compare groups of children wearing or not wearing cochlear implants. The present study compared receptive language levels in matched pairs of children from CI group and non-CI groups. The pre-op receptive language development curve suggest a possible growth over time with the maturation and the speech therapy. Comparison showed that the slope for post-op CI children to be greater than for non-CI children, and that this difference is statistically significant, and that the slope for CI children to be greater post- than pre-operatively. The main conclusion is that receptive language scores grow significantly higher over time after surgery in CI than in pair-matched non-CI children, despite better initial pure tone audiometric thresholds of the latter.

Prelingual deafness: high prevalence of a 30delG mutation in the connexin 26 gene.

Prelingual non-syndromic (isolated) deafness is the most frequent hereditary sensory defect. In >80% of the cases, the mode of transmission is autosomal recessive. To date, 14 loci have been identified for the recessive forms (DFNB loci). For two of them, DFNB1 and DFNB2, the genes responsible have been characterized; they encode connexin 26 and myosin VIIA, respectively. In order to evaluate the extent to which the connexin 26 gene (Cx26) contributes to prelingual deafness, we searched for mutations in this gene in 65 affected Caucasian families originating from various countries, mainly tunisia, France, New Zealand and the UK. Six of these families are consanguineous, and deafness was shown to be linked to the DFNB1 locus, 10 are small non consanguineous families in which the segregation of the trait has been found to be compatible with the involvement of DFNB1, and in the remaining 49 families no linkage analysis has been performed. A total of 62 mutant alleles in 39 families were identified. Therefore, mutations in Cx26 represent a major cause of recessively inherited prelingual deafness since according to the present results they would underlie approximately half of the cases. In addition, one specific mutation, 30delG, accounts for the majority (approximately 70%) of the Cx26 mutant alleles. It is therefore one of the most frequent disease mutations so far identified. Several lines of evidence indicate that the high prevalence of the 30delG mutation arises from a mutation hot spot rather than from a founder effect. Genetic counseling for prelingual deafness has been so far considerably impaired by the difficulty in distinguishing genetic and non genetic deafness in families presenting with a single deaf child. Based on the results presented here, the development of a simple molecular test could be designed which should be of considerable help.

Contralateral suppression and stimulus rate effects on evoked otoacoustic emissions.

Transiently evoked otoacoustic emissions (EOAE) were recorded in normal-hearing humans using pseudorandom pulse trains. This allowed the effect of increasing stimulus rate to be studied on EOAE amplitudes, input-output (I/O) functions and suppression by contralateral stimulation. EOAEs are very probably due to micromechanical properties of cochlear outer hair cells, and contralateral suppression is considered to result from olivo-cochlear efferent activation. EOAEs at various stimulus rates showed excellent reproducibility. Total EOAE amplitude diminished as interstimulus interval (ISI) decreased from 20 to 3 ms, but not for ISIs under 3 ms. The amplitude reduction was significant only on EOAE spectrum bands below 3.4 kHz. I/O functions, which kept a linear pattern, were steeper, and contralateral suppression was lower, with the highest stimulus rate (1111 c/s) relative to other rates. The EOAE decline with increasing stimulus rate might be due to incomplete recovery after adaptation of outer hair cells. The lower contralateral suppression at high stimulus rates suggests that crossed olivo-cochlear bundle action is lessened when outer hair cells are responding to a high-rate stimulus. An explanation may be that contralateral stimulation and a high-rate ipsilateral stimulus act via the same mechanisms, i.e., that high-rate stimulation activates an ipsilateral efferent loop.

Effect of interstimulus interval on evoked otoacoustic emissions.

In order to explore extensively the effect of interstimulus interval, including very short interstimulus intervals, on evoked otoacoustic emissions (EOAEs), several EOAE recordings were carried out using pairs of clicks: a suppressor click preceded the stimulus click generating an EOAE, with various intervals between the two clicks. EOAEs elicited by two clicks separated by intervals under 8-9 ms had significantly smaller amplitudes than EOAEs evoked by the stimulus alone. The amplitude decay correlated with the interclick interval, and was about 40% when the interclick interval decreased from 12 to 1 ms. This phenomenon has been noted before but not precisely quantified. It might reflect an adaptive mechanism within the outer hair cells, which has been previously described, or else mechanical interactions on the basilar membrane. The delay in EOAE decrease is of the same order as the first phase of neural adaptation, known as 'rapid adaptation', and these thus may prove to be correlated.

Physiopathological investigations in a family with a history of unilateral hereditary deafness.

We examined several members of the same family with unilateral sensorineural hearing loss. The defect showed dominant inheritance. Clinical examination and auditory tests, including high-definition audiogram and otoacoustic emission recording, were done to characterize the physiopathological process of hearing loss, and to investigate possible asymptomatic auditory features in the normal ear of affected subjects and nonaffected siblings. Hypotheses as to the underlying mechanisms are discussed, eg, variable expression of bilateral isolated hereditary deafness, incomplete Klein-Waardenburg syndrome with stria vascularis anomalies and highly variable gene expression, or unilateral cochlear aplasia. The phenomenon may also be related to the delayed progressive unilateral loss in patients with bilateral hereditary deafness, involving perhaps unilateral vascular disorders or a genetically induced degeneration of cochlear cells or auditory neurons.

A gene responsible for a dominant form of neurosensory non-syndromic deafness maps to the NSRD1 recessive deafness gene interval.

The first localization of a gene responsible for autosomal, neurosensory, recessive deafness recently assigned NSRD1 to the centromeric region of human chromosome 13. We now report on a dominant form of neurosensory deafness found in a family of French origin. The deafness is moderate to severe, has a prelingual onset and affects predominantly the high frequencies. The gene responsible for this form of deafness was found by linkage analysis to map to the same region of chromosome 13 as NSRD1. A multipoint analysis gave a maximum lod score of 4.66 with a most likely location close to locus D13S175. This suggests that different mutations in NSRD1 may cause both dominant and recessive neurosensory deafness.

Auditory-evoked brainstem responses elicited by maximum-length sequences in normal and sensorineural ears.

Auditory brainstem responses (ABRs) were recorded using pseudo-random pulse trains called maximum-length sequences (MLSs), which allow high stimulus rates and simultaneous recording from both ears, and were compared to ABRs obtained by conventional averaging. In normally hearing subjects, ABRs by MLSs produced the same waves as conventional ABRs, although wave latencies increased and amplitudes decreased. In normal as in sensorineural ears, MLS-ABR thresholds were similar to conventional ABR thresholds (except when binaural recordings were made) and were correlated with high-frequency audiometric thresholds. Binaural MLS-ABR recordings represent the individual response of each ear, as shown by recordings of monaurally deaf subjects.

Maturation and effect of stimulus rate on brainstem auditory evoked potentials.

Brainstem auditory evoked potentials (BAEPs) at three stimulus rates (20, 41.3 and 61.3 c/s) were recorded in 104 normal preterm infants, distributed in four age groups between 32 and 39 weeks (conceptional age), and in 20 normal adults. The latency shifts between 61.3 c/s and 20 c/s, and between 41.3 c/s and 20 c/s, were calculated for each wave, and studied as a function of age. A significant effect of conceptional age was shown on the '61.3-20 c/s' and the '41.3-20 c/s' wave V latency shifts, and a significant difference between adults and newborns was noted for the wave V and wave III latency shifts. No significant difference was obtained for the wave I latency shifts. This suggests that the changes of auditory adaptation with maturation may be predominantly at a central level, i.e. on central synapses.