ABSTRACT
The differential diagnosis of chorea encompasses a broad range of disorders. In psychiatry, tardive dyskinesia may be difficult to discern from other causes, particularly when the family history is negative. A 59-year-old man with an unclear medical history had been using risperidone for over a decade when we first saw him. He presented with severe dyskinesia in all extremities. The family history for neuropsychiatric disorders was negative. We interpreted the movement disorder as tardive dyskinesia, but later he turned out to suffer from Huntington’s disease. To improve diagnostic accuracy, we should have more frequently re-evaluated the differential diagnosis and our family history should have been more thorough. We outline the diagnostic considerations in patients presenting with chorea. Finally, we highlight the value of diagnostic re-evaluation and thorough family history taking to optimize diagnostic accuracy in neuropsychiatry.
Subject(s)
Chorea , Huntington Disease , Movement Disorders , Tardive Dyskinesia , Male , Humans , Middle Aged , Chorea/diagnosis , Chorea/genetics , Huntington Disease/diagnosis , Huntington Disease/genetics , RisperidoneABSTRACT
Mutations in WHRN lead to Usher syndrome type 2d or to non-syndromic hearing impairment. The WHRN-encoded gene product whirlin directly interacts with the intracellular regions of the other two Usher syndrome type 2-associated proteins, usherin and ADGRV1. In photoreceptor cells, this protein complex constitutes fibrous links between the periciliary membrane and the connecting cilium. However, the molecular mechanism(s) of retinal degeneration due to compromised formation and function of the USH2-associated protein complex remains elusive. To unravel this pathogenic mechanism, we isolated and characterized whirlin-associated protein complexes from zebrafish photoreceptor cells. We generated transgenic zebrafish that express Strep/FLAG-tagged Whrna, a zebrafish ortholog of human whirlin, under the control of a photoreceptor-specific promoter. Affinity purification of Strep/FLAG-tagged Whrna and associated proteins from adult transgenic zebrafish retinas followed by mass spectrometry identified 19 novel candidate associated proteins. Pull down experiments and dedicated yeast two-hybrid assays confirmed the association of Whrna with 7 of the co-purified proteins. Several of the co-purified proteins are part of the synaptic proteome, which indicates a role for whirlin in the photoreceptor synapse. Future studies will elucidate which of the newly identified protein-protein interactions contribute to the development of the retinal phenotype observed in USH2d patients. SIGNIFICANCE: Since protein-protein interactions identified using targeted in vitro studies do not always recapitulate interactions that are functionally relevant in vivo, we established a transgenic zebrafish line that stably expresses a Strep/FLAG-tagged ortholog of human whirlin (SF-Whrna) in photoreceptor cells. Affinity purification of in vivo-assembled SF-Whrna-associated protein complexes from retinal lysates followed by mass spectrometry, identified 19 novel candidate interaction partners, many of which are enriched in the synaptic proteome. Two human orthologs of the identified candidate interaction partners, FRMPD4 and Kir2.3, were validated as direct interaction partners of human whirlin using a yeast two-hybrid assay. The strong connection of whirlin with postsynaptic density proteins was not identified in previous in vitro protein-protein interaction assays, presumably due to the absence of a biologically relevant context. Isolation and identification of in vivo-assembled whirlin-associated protein complexes from the tissue of interest is therefore a powerful methodology to obtain novel insight into tissue specific protein-protein interactions and has the potential to improve significantly our understanding of the function of whirlin and the molecular pathogenesis underlying Usher syndrome type 2.
Subject(s)
Usher Syndromes , Adult , Animals , Humans , Membrane Proteins/metabolism , Proteome/metabolism , Retina/metabolism , Usher Syndromes/genetics , Usher Syndromes/metabolism , Zebrafish/metabolismABSTRACT
PURPOSE: The aim of the study was to compare clinical and radiological outcomes between primary and aseptic revision TKAs using the same posterior-stabilised (PS) prosthesis. The authors hypothesised similar outcomes between both groups for selected patients. METHODS: This retrospective, case-control study assessed 36 patients who underwent aseptic revision TKA compared to a match group of 72 primary TKA. Both groups had the same PS design implant (ANATOMIC®, Amplitude, Valence, France). The International Knee Society (IKS) score, radiological outcomes (postoperative alignment, patellar tilt and radiolucent lines), re-intervention and revision rate were compared between the two groups with a minimum follow-up of 3 years. RESULTS: The final study cohort included 29 patients and 63 patients respectively in the revision and primary group, with a mean follow-up of 49.1 months (range 36.1-69). Postoperatively, there was no significant difference in IKS scores between the two groups [169.8 for the revision group and 179.6 for the primary group (p = 0.09)]. No statistical difference was observed for post-operative satisfaction 86.2% versus 92.1% (p = 0.46). Between the two groups, there was no difference in mean radiological assessment, including radiolucent lines (p = 0.7). There was no significant difference for overall implant survivorship 96.5% versus 100% (p = 0.13) at 36 months. CONCLUSION: Similar clinical, radiological and survivorship outcomes were found between rTKA and primary TKA groups using the same PS level of constraint in patients undergoing revision surgery for aseptic indications at 3-year follow-up. Use of PS implants in rTKA for the correct indication suggests this to be a safe approach at least in the medium term. LEVEL OF EVIDENCE: IV, retrospective case-control study.
Subject(s)
Arthroplasty, Replacement, Knee , Knee Prosthesis , Arthroplasty, Replacement, Knee/adverse effects , Case-Control Studies , Follow-Up Studies , Humans , Knee Joint/surgery , Knee Prosthesis/adverse effects , Prosthesis Design , Prosthesis Failure , Reoperation , Retrospective Studies , Treatment OutcomeABSTRACT
Early onset cerebellar Ataxia (EOAc) comprises a large group of rare heterogeneous disorders. Determination of the underlying etiology can be difficult given the broad differential diagnosis and the complexity of the genotype-phenotype relationships. This may change the diagnostic work-up into a time-consuming, costly and not always rewarding task. In this overview, the Childhood Ataxia and Cerebellar Group of the European Pediatric Neurology Society (CACG-EPNS) presents a diagnostic algorithm for EOAc patients. In seven consecutive steps, the algorithm leads the clinician through the diagnostic process, including EOA identification, application of the Inventory of Non-Ataxic Signs (INAS), consideration of the family history, neuro-imaging, laboratory investigations, genetic testing by array CGH and Next Generation Sequencing (NGS). In children with EOAc, this algorithm is intended to contribute to the diagnostic process and to allow uniform data entry in EOAc databases.
Subject(s)
Algorithms , Decision Support Systems, Clinical , Spinocerebellar Degenerations/diagnosis , Adolescent , Child , Diagnosis, Differential , Female , Humans , MaleABSTRACT
This study focuses on further characterization of the audiovestibular phenotype and on genotype-phenotype correlations of DFNB77, an autosomal recessive type of hearing impairment (HI). DFNB77 is associated with disease-causing variants in LOXHD1, and is genetically and phenotypically highly heterogeneous. Heterozygous deleterious missense variants in LOXHD1 have been associated with late-onset Fuchs corneal dystrophy (FCD). However, up to now screening for FCD of heterozygous carriers in DFNB77 families has not been reported. This study describes the genotype and audiovestibular phenotype of 9 families with DFNB77. In addition, carriers within the families were screened for FCD. Fifteen pathogenic missense and truncating variants were identified, of which 12 were novel. The hearing phenotype showed high inter- and intrafamilial variation in severity and progression. There was no evidence for involvement of the vestibular system. None of the carriers showed (pre-clinical) symptoms of FCD. Our findings expand the genotypic and phenotypic spectrum of DFNB77, but a clear correlation between the type or location of the variant and the severity or progression of HI could not be established. We hypothesize that environmental factors or genetic modifiers are responsible for phenotypic differences. No association was found between heterozygous LOXHD1 variants and the occurrence of FCD in carriers.
Subject(s)
Carrier Proteins/genetics , Fuchs' Endothelial Dystrophy/genetics , Genetic Predisposition to Disease , Hearing Loss, Sensorineural/genetics , Adolescent , Adult , Audiometry , Child , Child, Preschool , Female , Fuchs' Endothelial Dystrophy/physiopathology , Genetic Association Studies , Genotype , Hearing Loss, Sensorineural/physiopathology , Heterozygote , Humans , Male , Middle Aged , Mutation, Missense , Pedigree , PhenotypeABSTRACT
OBJECTIVE: Genetic testing for hereditary hearing impairment has become more routinely available as a diagnostic tool in the outpatient clinic. However, little is known about the psychological impact of a genetic diagnosis. To evaluate this impact, an exploratory study was conducted. DESIGN: Prospectively, 48 individuals who underwent genetic testing for hereditary hearing impairment were included in this study. Study participants were asked to fill out the following questionnaires: Hospital Anxiety Depression Scale, Impact of Event Scale, Self-Efficacy 24, Illness Cognition Questionnaire and the Inventory for Social Reliance. Questionnaires were filled out on three occasions: before genetic testing, directly after counselling on either positive or negative test results, and six weeks thereafter. RESULTS: No significant differences were found between the group that received a genetic diagnosis for their hearing impairment and the group that did not. CONCLUSION: This study did not demonstrate differences between receiving a genetic diagnosis or not; however, special attention to psychological well-being should be offered to hearing-impaired patients who seek a genetic diagnosis for their hearing impairment. Additionally, the psychological impact of sensorineural hearing impairment might be greater than the impact of a genetic diagnosis itself. Based on the current exploratory study, there are no psychological reasons in favour of or against genetic testing for hereditary hearing impairment.
Subject(s)
Anxiety/psychology , Depression/psychology , Genetic Testing/ethics , Hearing Loss/diagnosis , Adult , Aged , Anxiety/epidemiology , Anxiety/etiology , Depression/epidemiology , Depression/etiology , Female , Follow-Up Studies , Hearing Loss/genetics , Hearing Loss/psychology , Humans , Incidence , Male , Middle Aged , Netherlands/epidemiology , Prospective Studies , Surveys and QuestionnairesABSTRACT
OBJECTIVE: To examine the impact of Embrace (Dutch: SamenOud), a new primary care model for community-living people aged over 75 years on perceived quality of care. DESIGN: Randomized controlled trial in 15 general practices in the East Groningen region of the Netherlands. METHOD: In the period January 2012-March 2013, 1456 general practice patients aged 75 years and older were stratified on the basis of self-reporting into 3 risk profiles: 'robust', 'frail' and 'complex care needs', and then randomized to the intervention or the control arm. Intervention consisted of care and support from an elderly-care team consisting of a specialist in Gerontology, a district nurse, and a social worker. Intensity and duration of the care and support were dependent on risk profile. The primary outcome measure was quality of care as reported by participants; the secondary outcome measure was the extent of implementation as reported by the caregivers. RESULTS: The level of perceived quality of care after 12 months was slightly higher in the intervention arm than in the control arm, but the effect size was quite small. The difference was significant in elderly people with the risk profiles 'frail' and 'complex care needs'; robust elderly people did not experience a significant difference. The caregivers reported increased implementation of integrated care (effect size 0.71, that means average). CONCLUSION: Embrace slightly improved the perceived quality of care, particularly for elderly people with complex care needs for whom case management was organised. Caregivers judged implementation of integrated care to be greatly improved, though there was still room for further improvement. Further research should be carried out into the effectiveness of integrated primary care for the elderly on health, service-use and healthcare costs.
ABSTRACT
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.
Subject(s)
Genes, Recessive , Hearing Loss, Sensorineural/genetics , Counseling , Genetic Predisposition to Disease , Hearing Loss, Sensorineural/rehabilitation , Humans , Phenotype , PrognosisSubject(s)
Myocardial Infarction/complications , Myocardial Infarction/diagnosis , Takotsubo Cardiomyopathy/diagnosis , Takotsubo Cardiomyopathy/etiology , Aged , Electrocardiography , Female , Humans , Myocardial Infarction/physiopathology , Precipitating Factors , Takotsubo Cardiomyopathy/physiopathologyABSTRACT
DFNB1 is the most prevalent type of hereditary hearing impairment known nowadays and the audiometric phenotype is very heterogeneous. There is, however, no consensus in literature on vestibular and imaging characteristics. Vestibular function and imaging results of 44 DFNB1 patients were evaluated in this retrospective study. All patients displayed a response during rotational velocity step testing. In 65% of the cases, the caloric results were within normal range bilaterally. The video head impulse test was normal in all patients. In 34.4% of the CT scans one or more temporal bone anomalies were found. The various anomalies found, were present in small numbers and none seemed convincingly linked to a specific DFNB1genotype. The group of DFNB1 patients presented here is the largest thus far evaluated for their vestibular function. From this study, it can be assumed that DFNB1 is not associated with vestibular dysfunction or specific temporal bone anomalies.
Subject(s)
Hearing Loss, Sensorineural/diagnostic imaging , Hearing Loss, Sensorineural/physiopathology , Temporal Bone/diagnostic imaging , Vestibule, Labyrinth/physiopathology , Adolescent , Adult , Child , Child, Preschool , Connexin 26 , Connexin 30 , Connexins/genetics , Electronystagmography , Eye Movements , Female , Genetic Predisposition to Disease , Head Movements , Hearing Loss, Sensorineural/genetics , Humans , Infant , Magnetic Resonance Imaging , Male , Middle Aged , Mutation , Nystagmus, Physiologic , Phenotype , Retrospective Studies , Tomography, X-Ray Computed , Young AdultSubject(s)
Heart Valve Prosthesis Implantation , Mitral Valve Insufficiency/diagnostic imaging , Mitral Valve Insufficiency/surgery , Severity of Illness Index , Aged, 80 and over , Female , Heart Valve Prosthesis Implantation/methods , Humans , Mitral Valve Insufficiency/complications , Pulmonary Edema/complications , Pulmonary Edema/diagnostic imaging , Pulmonary Edema/surgery , Treatment Outcome , UltrasonographyABSTRACT
Hearing impairment is an extremely heterogeneous disorder, with both environmental as well as genetic causes. This review describes the known genes involved in non-syndromic hearing impairment and their genotype-phenotype correlations where possible. Furthermore, some of the more frequent syndromic forms of hearing impairment are described, in particular where they overlap with the non-syndromic forms. Given the heterogeneity of the disorder, together with the indistinguishable phenotypes for many of the genes, it is suggested that testing for mutations is performed using massive parallel sequencing techniques, either by a large targeted set of genes or by an exome wide analysis.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Hearing Loss/genetics , Ion Channels/genetics , Audiometry , Genetic Association Studies , Genetic Loci , Genotype , Hearing Loss/classification , Hearing Loss/diagnosis , Hearing Loss/pathology , High-Throughput Nucleotide Sequencing , Humans , Mutation , PhenotypeABSTRACT
A total of 64 loci for autosomal dominant non-syndromic hearing impairment have been described, and the causative genes have been identified for 24 of these. The present study reports on the clinical characteristics of an autosomal dominantly inherited hearing impairment that is linked to a region within the DFNA60 locus located on chromosome 2 in q22.1-24.1. A pedigree spanning four generations was established with 13 affected individuals. Linkage analysis demonstrated that the locus extended over a 2.96 Mb region flanked by markers D2S2335 and D2S2275. The audiograms mainly showed a distinctive U-shaped configuration. Deterioration of hearing started at a wide age range, from 12 to 40 years. Cross-sectional analysis showed rapid progression of hearing impairment from mild to severe, between the ages of 40 and 60 years, a phenomenon that is also observed in DFNA9 patients. The results of the individual longitudinal analyses were generally in line with those obtained by the cross-sectional analysis. Speech recognition scores related to the level of hearing impairment (PTA1,2,4 kHz) appeared to be fairly similar to those of presbyacusis patients. It is speculated that hearing impairment starting in mid-life, as shown by DFNA60 patients, could play a role in the development of presbyacusis. Furthermore, speech recognition did not deteriorate appreciably before the sixth decade of life. We conclude that DFNA60 should be considered in hearing impaired patients who undergo a rapid progression in middle age and are negative for DFNA9. Furthermore, cochlear implantation resulted in good rehabilitation in two DFNA60 patients.
Subject(s)
Auditory Perception/genetics , Chromosomes, Human, Pair 2 , Genes, Dominant , Genetic Loci , Hearing Loss, Sensorineural/genetics , Hearing/genetics , Adolescent , Adult , Age Factors , Audiometry, Pure-Tone , Audiometry, Speech , Child , Cochlear Implantation , Disease Progression , Female , Genetic Predisposition to Disease , Hearing Loss, Sensorineural/diagnosis , Hearing Loss, Sensorineural/physiopathology , Hearing Loss, Sensorineural/psychology , Hearing Loss, Sensorineural/rehabilitation , Heredity , Humans , Male , Pedigree , Phenotype , Recognition, Psychology , Severity of Illness Index , Speech Intelligibility , Speech Perception , Young AdultABSTRACT
Since deafness is the most common sensorineural disorder in humans, better understanding of the underlying causes is necessary to improve counseling and rehabilitation. A Dutch family with autosomal dominantly inherited sensorineural hearing loss was clinically and genetically assessed. The MYO6 gene was selected to be sequenced because of similarities with other, previously described DFNA22 phenotypes and a pathogenic c.3610C > T (p.R1204W) mutation was found to co-segregate with the disease. This missense mutation results in a flat configured audiogram with a mild hearing loss, which becomes severe to profound and gently to steeply downsloping later in life. The age-related typical audiograms (ARTA) constructed for this family resemble presbyacusis. Speech audiometry and results of loudness scaling support the hypothesis that the phenotype of this specific MYO6 mutation mimics presbyacusis.
Subject(s)
Hearing Loss, Sensorineural/genetics , Hearing/genetics , Mutation, Missense , Myosin Heavy Chains/genetics , Presbycusis/genetics , Acoustic Stimulation , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Audiometry, Pure-Tone , Audiometry, Speech , Auditory Threshold , Child , DNA Mutational Analysis , Disease Progression , Female , Genetic Predisposition to Disease , Hearing Loss, Sensorineural/physiopathology , Hearing Loss, Sensorineural/psychology , Heredity , Humans , Male , Middle Aged , Pedigree , Phenotype , Presbycusis/physiopathology , Presbycusis/psychology , Speech Perception , Vestibule, Labyrinth/physiopathology , Young AdultABSTRACT
SPAST mutations are the most common cause of autosomal dominant hereditary spastic paraplegias (AD-HSPs), but many spastic paraplegia patients are found to carry no mutations in this gene. In order to assess the contribution of ATL1 and REEP1 in AD-HSP, we performed mutational analysis in 27 SPAST-negative AD-HSP families. We found three novel ATL1 mutations and one REEP1 mutation in five index-patients. In 110 patients with sporadic adult-onset upper motor neuron syndromes, a novel REEP1 mutation was identified in one patient. Apart from a significantly younger age at onset in ATL1 patients and restless legs in some, the clinical phenotype of ATL1 and REEP1 was similar to other pure AD-HSPs.
Subject(s)
GTP-Binding Proteins/genetics , Membrane Proteins/genetics , Membrane Transport Proteins/genetics , Motor Neuron Disease/diagnosis , Motor Neuron Disease/genetics , Mutation/genetics , Adolescent , Adult , Aged , Cohort Studies , Female , Humans , Male , Middle Aged , Motor Neuron Disease/epidemiology , Pedigree , Retrospective Studies , Young AdultABSTRACT
Spastic paraplegia type 7 is an autosomal recessive neurodegenerative disorder mainly characterized by progressive bilateral lower limb spasticity and referred to as a form of hereditary spastic paraplegia. Additional disease features may also be observed as part of a more complex phenotype. Many different mutations have already been identified, but no genotype-phenotype correlations have been found so far. From a total of almost 800 patients referred for testing, we identified 60 patients with mutations in the SPG7 gene. We identified 14 previously unreported mutations and detected a high recurrence rate of several earlier reported mutations. We were able to collect detailed clinical data for 49 patients, who were ranked based on a pure versus complex phenotype, ataxia versus no ataxia and missense versus null mutations. A generally complex phenotype occurred in 69% of all patients and was associated with a younger age at onset (trend with P = 0.07). Ataxia was observed in 57% of all patients. We found that null mutations were associated with the co-occurrence of cerebellar ataxia (trend with P = 0.06). The c.1409 G > A (p.Arg470Gln) mutation, which was found homozygously in two sibs, was associated with a specific complex phenotype that included predominant visual loss due to optical nerve atrophy. Neuropathology in one of these cases showed severe degeneration of the optic system, with less severe degeneration of the ascending tracts of the spinal cord and cerebellum. Other disease features encountered in this cohort included cervical dystonia, vertical gaze palsy, ptosis and severe intellectual disability. In this large Dutch cohort, we seem to have identified the first genotype-phenotype correlation in spastic paraplegia type 7 by observing an association between the cerebellar phenotype of spastic paraplegia type 7 and SPG7 null alleles. An overlapping phenotypic presentation with its biological counterpart AFG3L2, which when mutated causes spinocerebellar ataxia type 28, is apparent and possibly suggests that abnormal levels of the SPG7 protein impact the function of the mitochondrial ATPases associated with diverse cellular activities-protease complex (formed by SPG7 and AFG3L2) in the cerebellum. In addition, a missense mutation in exon 10 resulted in predominant optical nerve atrophy, which might suggest deleterious interactions of this SPG7 variant with its substrate OPA1, the mutated gene product in optic atrophy type 1. Functional studies are required to further investigate these interactions.
Subject(s)
Angiopoietins/genetics , Genetic Association Studies , Metalloendopeptidases/genetics , Mutation/genetics , Spastic Paraplegia, Hereditary/genetics , ATPases Associated with Diverse Cellular Activities , Angiopoietin-Like Protein 6 , Angiopoietin-like Proteins , Cerebellar Ataxia/genetics , Cerebellar Ataxia/physiopathology , Cohort Studies , Genotype , Humans , Netherlands , Optic Nerve Diseases/genetics , Optic Nerve Diseases/physiopathology , Phenotype , Spastic Paraplegia, Hereditary/physiopathologyABSTRACT
OBJECTIVE: Investigation of the audiometric characteristics of a large Dutch DFNX4 family with a p.Glu72X mutation in the SMPX gene. PATIENTS AND METHODS: Sixty family members participated in this study and examination consisted of medical history, otoscopy, pure tone and speech audiometry. Linkage and mutation analysis revealed a pathogenic mutation in the SMPX gene. RESULTS: All 25 mutation carriers exhibited hearing impairment, except one woman aged 25 years. The men (n = 10) showed more severe hearing impairment than the women (n = 14) and already at a younger age. The age of onset according to history was 2-10 years (mean: 3.3 years) in men and 3-48 years (mean: 26.4 years) in women. In the men, severe threshold deterioration mainly occurred during the first two decades of life, especially at the higher frequencies. The women showed milder threshold deterioration and more pronounced across-subjects and individual inter-aural variation, especially at 2-8 kHz. Longitudinal linear regression analysis demonstrated significant progression of at least two frequencies in five individuals (3 men and 2 women). The speech recognition scores of the mutation carriers with hearing impairment were decreased at relatively young ages compared to a reference group of patients with only presbycusis, especially in men. However, all these patients tended to have better speech recognition scores than the presbycusis patients at matching PTA(1,2,4 kHz) levels. CONCLUSION: This study demonstrates the phenotypic heterogeneity in this large family with an X-linked pattern of inherited sensorineural hearing impairment. The men showed more severe hearing impairment at a younger age with more pronounced progression during the first two decades of life, while women demonstrated less severe hearing impairment with more gradual progression and a wider variation in age of onset, degree of hearing impairment and inter-aural asymmetry in thresholds.
Subject(s)
Auditory Perception/genetics , Hearing Loss, Sensorineural/genetics , Muscle Proteins/genetics , Mutation , Persons With Hearing Impairments , Acoustic Stimulation , Adolescent , Adult , Age of Onset , Audiometry, Pure-Tone , Audiometry, Speech , Auditory Threshold , Child , Child, Preschool , Disease Progression , Female , Genetic Predisposition to Disease , Hearing Loss, Sensorineural/diagnosis , Hearing Loss, Sensorineural/physiopathology , Hearing Loss, Sensorineural/psychology , Heredity , Humans , Linear Models , Linkage Disequilibrium , Male , Middle Aged , Netherlands , Nonlinear Dynamics , Otoscopy , Persons With Hearing Impairments/psychology , Phenotype , Reflex, Vestibulo-Ocular/genetics , Severity of Illness Index , Sex Factors , Speech Perception/genetics , Young AdultABSTRACT
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-1ß 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.
Subject(s)
Audiometry, Pure-Tone , Audiometry, Speech , Auditory Perception/genetics , Carrier Proteins/genetics , Cryopyrin-Associated Periodic Syndromes/genetics , Hearing Loss/diagnosis , Mutation , Acoustic Stimulation , Adolescent , Adult , Auditory Threshold , Child , Child, Preschool , Cryopyrin-Associated Periodic Syndromes/complications , Cryopyrin-Associated Periodic Syndromes/drug therapy , DNA Mutational Analysis , Disease Progression , Female , Genetic Predisposition to Disease , Hearing Loss/genetics , Hearing Loss/physiopathology , Hearing Loss/psychology , Hearing Loss/therapy , Heredity , Humans , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Linear Models , Loudness Perception , Male , Middle Aged , NLR Family, Pyrin Domain-Containing 3 Protein , Netherlands , Noise/adverse effects , Otoscopy , Pedigree , Perceptual Masking , Phenotype , Predictive Value of Tests , Reflex, Acoustic/genetics , Reflex, Vestibulo-Ocular/genetics , Speech Perception/genetics , Vestibular Function Tests , Young AdultABSTRACT
Five patients with adult-onset metachromatic leukodystrophy (MLD) underwent allo-SCT. Conditioning was reduced in intensity and grafts were obtained from voluntary unrelated donors. All but one graft were depleted of T-lymphocytes. Patient age at transplantation varied from 18 to 29 (median, 27) years. Two patients rejected their graft and MLD progressed. The recipient of the unmanipulated graft converted to complete donor chimerism with normalization of arylsulphatase A (ARSA) levels. Despite ARSA normalization, he deteriorated. Another patient was a mixed chimera. Following escalated doses of donor lymphocyte infusions he converted to complete donor chimerism. His levels of ARSA correlated positively with the percentage of donor cells and MLD was not progressive. The fifth patient died after 35 days from complications associated with GVHD. We conclude that results of allo-SCT in symptomatic MLD patients are poor. However, allo-SCT may stop progression of MLD in selected patients.