Auditory-perceptual voice and speech evaluation in ATP1A3 positive patients.

INTRODUCTION: Bulbar symptoms are frequent in patients with rapid-onset dystonia-parkinsonism (RDP). RDP is caused by ATP1A3 mutations, with onset typically within 30 days of stressor exposure. Most patients have impairments in speech (dysarthria) and voice (dysphonia). These have not been quantified. We aimed to formally characterize these in RDP subjects as compared to mutation negative family controls. METHODS: We analyzed recordings in 32 RDP subjects (male = 21, female = 11) and 29 mutation negative controls (male = 15, female = 14). Three raters, blinded to mutation status, rated speech and vocal quality. Dysarthria was classified by subtype. Dysphonia was rated via the GRBAS (Grade, Roughness, Breathiness, Asthenia, Strain) scale. We used general neurological exams and the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) to assess dysarthria, dystonia, and speech/swallowing dysfunction. RESULTS: The presence of dysarthria was more frequent in RDP subjects compared to controls (72% vs. 17%, p < 0.0001). GRBAS voice ratings were worse in the RDP cohort across nearly all categories. Dysarthria in RDP was associated with concordant cranial nerve 9-11 dysfunction (54%, p = 0.048), speech/swallowing dysfunction (96%, p = 0.0003); and oral dystonia (88%, p = 0.001). CONCLUSIONS: Quantitative voice and speech analyses are important in assessing RDP. Subjects frequently experience dysarthria and dysphonia. Dystonia is not the exclusive voice abnormality present in this population. In our analysis, RDP subjects more frequently experienced bulbar symptoms than controls. GRBAS scores are useful in quantifying voice impairment, potentially allowing for better assessments of progression or treatment effects. Future directions include using task-specific diagnostic and perceptual voice evaluation tools to further assess laryngeal dystonia.

FARS2 Causing Complex Hereditary Spastic Paraplegia With Dysphonia: Expanding the Disease Spectrum.

Herein we present two siblings with hereditary spastic paraplegia caused by novel compound heterozygous variant and deletion in FARS2 and expansion of the disease spectrum to include dysphonia.

Polygenic Risk of Spasmodic Dysphonia is Associated With Vulnerable Sensorimotor Connectivity.

Spasmodic dysphonia (SD), or laryngeal dystonia, is an isolated task-specific dystonia of unknown causes and pathophysiology that selectively affects speech production. Using next-generation whole-exome sequencing in SD patients, we computed polygenic risk score from 1804 genetic markers based on a genome-wide association study in another form of similar task-specific focal dystonia, musician's dystonia. We further examined the associations between the polygenic risk score, resting-state functional connectivity abnormalities within the sensorimotor network, and SD clinical characteristics. We found that the polygenic risk of dystonia was significantly associated with decreased functional connectivity in the left premotor/primary sensorimotor and inferior parietal cortices in SD patients. Reduced connectivity of the inferior parietal cortex was correlated with the age of SD onset. The polygenic risk score contained a significant number of genetic variants lying near genes related to synaptic transmission and neural development. Our study identified a polygenic contribution to the overall genetic risk of dystonia in the cohort of SD patients. Associations between the polygenic risk and reduced functional connectivity of the sensorimotor and inferior parietal cortices likely represent an endophenotypic imaging marker of SD, while genes involved in synaptic transmission and neuron development may be linked to the molecular pathophysiology of this disorder.

Phenotype- and genotype-specific structural alterations in spasmodic dysphonia.

BACKGROUND: Spasmodic dysphonia is a focal dystonia characterized by involuntary spasms in the laryngeal muscles that occur selectively during speaking. Although hereditary trends have been reported in up to 16% of patients, the causative etiology of spasmodic dysphonia is unclear, and the influences of various phenotypes and genotypes on disorder pathophysiology are poorly understood. In this study, we examined structural alterations in cortical gray matter and white matter integrity in relationship to different phenotypes and putative genotypes of spasmodic dysphonia to elucidate the structural component of its complex pathophysiology. METHODS: Eighty-nine patients with spasmodic dysphonia underwent high-resolution magnetic resonance imaging and diffusion-weighted imaging to examine cortical thickness and white matter fractional anisotropy in adductor versus abductor forms (distinct phenotypes) and in sporadic versus familial cases (distinct genotypes). RESULTS: Phenotype-specific abnormalities were localized in the left sensorimotor cortex and angular gyrus and the white matter bundle of the right superior corona radiata. Genotype-specific alterations were found in the left superior temporal gyrus, supplementary motor area, and the arcuate portion of the left superior longitudinal fasciculus. CONCLUSIONS: Our findings suggest that phenotypic differences in spasmodic dysphonia arise at the level of the primary and associative areas of motor control, whereas genotype-related pathophysiological mechanisms may be associated with dysfunction of regions regulating phonological and sensory processing. Identification of structural alterations specific to disorder phenotype and putative genotype provides an important step toward future delineation of imaging markers and potential targets for novel therapeutic interventions for spasmodic dysphonia. © 2017 International Parkinson and Movement Disorder Society.

Dystonia-Causing Mutations as a Contribution to the Etiology of Spasmodic Dysphonia.

OBJECTIVE: Spasmodic dysphonia is a focal dystonia of the larynx with heterogeneous manifestations and association with familial risk factors. There are scarce data to allow precise understanding of etiology and pathophysiology. Screening for dystonia-causing genetic mutations has the potential to allow accurate diagnosis, inform about genotype-phenotype correlations, and allow a better understanding of mechanisms of disease. STUDY DESIGN: Cross-sectional study. SETTING: Tertiary academic medical center. SUBJECTS AND METHODS: We enrolled patients presenting with spasmodic dysphonia to the voice clinic of our academic medical center. Data included demographics, clinical features, family history, and treatments administered. The following genes with disease-causing mutations previously associated with spasmodic dysphonia were screened: TOR1A (DYT1), TUBB4 (DYT4), and THAP1 (DYT6). RESULTS: Eighty-six patients were recruited, comprising 77% females and 23% males. A definite family history of neurologic disorder was present in 15% (13 of 86). Average age (± standard deviation) of symptom onset was 42.1 ± 15.7 years. Most (99%; 85 of 86) were treated with botulinum toxin, and 12% (11 of 86) received oral medications. Genetic screening was negative in all patients for the GAG deletion in TOR1A (DYT1) and in the 5 exons currently associated with disease-causing mutations in TUBB4 (DYT4). Two patients tested positive for novel/rare variants in THAP1 (DYT6). CONCLUSION: Genetic screening targeted at currently known disease-causing mutations in TOR1A, THAP1, and TUBB4 appears to have low diagnostic yield in sporadic spasmodic dysphonia. In our cohort, only 2 patients tested positive for novel/rare variants in THAP1. Clinicians should make use of genetic testing judiciously and in cost-effective ways.

GNAL mutation in isolated laryngeal dystonia.

BACKGROUND: Up to 12% of patients with laryngeal dystonia report a familial history of dystonia, pointing to involvement of genetic factors. However, its genetic causes remain unknown. METHOD: Using Sanger sequencing, we screened 57 patients with isolated laryngeal dystonia for mutations in known dystonia genes TOR1A (DYT1), THAP1 (DYT6), TUBB4A (DYT4), and GNAL (DYT25). Using functional MRI, we explored the influence of the identified mutation on brain activation during symptomatic task production. RESULTS: We identified 1 patient with laryngeal dystonia who was a GNAL mutation carrier. When compared with 26 patients without known mutations, the GNAL carrier had increased activity in the fronto-parietal cortex and decreased activity in the cerebellum. CONCLUSIONS: Our data show that GNAL mutation may represent one of the rare causative genetic factors of isolated laryngeal dystonia. Exploratory evidence of distinct neural abnormalities in the GNAL carrier may suggest the presence of divergent pathophysiological cascades underlying this disorder. © 2016 International Parkinson and Movement Disorder Society.

Trastorno específico del lenguaje: subtipos de una patología compleja / Specific language impairment: subtypes of a complex disorder

Existen distintas propuestas sobre marcadores psicolingüísticos y sobre taxonomías del trastorno específico del lenguaje (TEL). Este trabajo presenta los resultados obtenidos en 8 tareas psicolingüísticas por 2 grupos de niños: 31 niños con TEL (GTEL) y 31 niños igualados en edad cronológica (GC). Las tareas han sido elaboradas ad hoc para valorar los marcadores psicolingüísticos en las 4 áreas clásicas: fonología, morfosintaxis, semántica y pragmática. En primer lugar, se comprueba que los niños del GTEL rinden significativamente peor que los niños del GC en las 8 tareas. En segundo lugar, un análisis de conglomerados K-medias clasifica a los 31 sujetos del grupo TEL en 4 conglomerados. En tercer lugar, un análisis discriminante comprueba si la clasificación clínica hecha a priori se mantiene tras los resultados del estudio. Se presenta el perfil de los conglomerados y se discuten sus características respecto a los subtipos de la taxonomía clínica de Rapin y Allen. Finalmente, se analizan las similitudes y diferencias entre ambas tipologías. Los resultados obtenidos ayudan a esclarecer los marcadores psicolingüísticos del TEL en niños de habla española y refuerzan la utilidad clínica de su clasificación en subtipos y la vigencia de la taxonomía de Rapin y Allen (AU)

There are various proposals for psycholinguistic markers and for taxonomies of specific language impairment (SLI). This study presents the results obtained in eight psycholinguistic tasks by two groups of Spanish-speaking children: 31 children with SLI (SLI) and 31 children matched for chronological age (CA). The tasks were developed ad hoc to assess psycholinguistic markers in the four traditional areas: phonology, morphosyntax, semantics and pragmatics. Firstly, we found that SLI group scored significantly worse than CA group in the eight tasks. Secondly, a K-Means cluster analysis distinguished five clusters within the 31 subject of SLI group. Thirdly, a discriminant analysis checks whether an a priori clinical classification is maintained after the study results. We present the profile of these clusters and discuss their features regarding Rapin & Allen taxonomy clinical subtypes. Finally, the similarities and differences between the two classifications are analyzed. The results obtained in this work help shed light on the psycholinguistic markers of the Spanish-SLI and reinforce the clinical utility of its classification into subtypes and the validity of the Rapin & Allen taxonomy (AU)

Mutation in TWINKLE in a Large Iranian Family with Progressive External Ophthalmoplegia, Myopathy, Dysphagia and Dysphonia, and Behavior Change.

BACKGROUND: TWINKLE (c10orf2) gene is responsible for autosomal dominant progressive external ophthalmoplegia (PEO). In rare cases, additional features such as muscle weakness, peripheral neuropathy, ataxia, cardiomyopathy, dysphagia, dysphonia, cataracts, depression, dementia, parkinsonism, and hearing loss have been reported in association with heterozygous mutations of the TWINKLE gene. METHODS: We have studied a large Iranian family with myopathy, dysphonia, dysphagia, and behavior change in addition to PEO in affected members. RESULTS: We identified a missense mutation c.1121G > A in the c10orf2 gene in all affected members. Early death is a novel feature seen in affected members of this family that has not been reported to date. CONCLUSION: The association of PEO, myopathy, dysphonia, dysphagia, behavior change and early death has not been previously reported in the literature or other patients with this mutation.

Obstacles to communication in children with cri du chat syndrome.

BACKGROUND: Cri du chat syndrome (CCS) is a genetic disorder resulting from the deletion of the short arm of chromosome 5. Perhaps the most distinctive characteristic of this syndrome is the congenital high-pitched cry, which frequently brings these patients to the attention of an otolaryngologist. Speech and language development in children with CCS is notable for a reduced receptive vocabulary and a profound deficit in expressive language. Currently, no clear guidelines have been established for the treatment of the speech and language difficulties exhibited by these patients. In this article, we present a case report and discuss the current literature regarding the challenges to effective communication in CCS. METHODS: Case report. CASE: We present a 7-year-old girl with CCS who sought help to improve her ability to communicate. The patient presented with a persistent high-pitched voice unchanged since birth and a breathy dysphonia. Findings on examination were significant for an abnormally oriented larynx with atrophic vocal folds. She continues to undertake intensive speech therapy to assist in her language development. CONCLUSION: CCS is a genetic disorder that universally results in profound deficits in expressive speech. Although patients with CCS commonly present with a high-pitched voice and marked laryngeal abnormalities, they are unlikely to benefit from surgical intervention. Speech and language therapy, including augmentative communication devices, may enhance effective communication and improve the quality of life of these patients.

Genetic and environmental effects on vocal symptoms and their intercorrelations.

PURPOSE: Recently, Simberg et al. (2009) found genetic effects on a composite variable consisting of 6 vocal symptom items measuring dysphonia. The purpose of the present study was to determine genetic and environmental effects on the individual vocal symptoms in a population-based sample of Finnish twins. METHOD: The sample comprised 1,728 twins (125 monozygotic and 108 dizygotic twin pairs) born between 1961 and 1989, who completed a questionnaire concerning 6 vocal symptoms. Values for additive genetic, dominant genetic, shared environmental, and nonshared environmental components were computed separately for all symptoms. Multivariate analyses to determine genetic and environmental associations between the vocal symptoms were also performed. RESULTS: Variance was explained by significant additive genetic effects (27%) in only one of the vocal symptoms, namely, voice gets low or hoarse, whereas the variance of one of the vocal symptoms, voice gets strained or tires, could be explained by nonshared environmental influence alone. Multivariate analyses showed that the correlations for most of the symptom combinations were significant. CONCLUSIONS: Both genetic and environmental components influence vocal symptoms. Genetic and environmental influences seem to be differently balanced in different vocal symptoms. Genetic effects are moderate, whereas environmental effects seem to be the most important factor contributing to the presence of vocal symptoms.

Consideration of genetic contributions to the risk for spasmodic dysphonia.

Spasmodic dysphonia, a form of the neurologic condition known as dystonia, results from involuntary spasms of the larynx, producing interruptions of speech and changes in voice quality. The pathogenesis of spasmodic dysphonia is not well understood. However, several genetic mutations have been identified that cause different forms of dystonia. In some individuals, these genetic mutations result in spasmodic dysphonia, either with no other signs of dystonia or as part of a broader dystonia phenotype. Thus, research in the growing field of dystonia genetics may help to inform our understanding of the pathogenesis of spasmodic dysphonia.

Reconsidering the role of psychosocial factors in functional dysphonia.

PURPOSE OF REVIEW: Functional dysphonia, defined as alteration or loss of voice in the absence of physical pathology, is known to be associated with a variety of psychosocial factors including anxiety, depression and reduced quality of life. Models of functional dysphonia have tended to conceptualize the voice disorder as being the result of a failure to acknowledge and/or express this associated distress. The current literature was reviewed to identify psychosocial factors that predispose to, precipitate and perpetuate functional dysphonia and to assess the evidence for these models. RECENT FINDINGS: Recent studies have identified evidence of genetic susceptibility, occupational susceptibility, a history of sexual and/or physical abuse and perfectionism as being predisposing factors. Precipitants include life events, frequency of vocal use and infections. General fatigue is identified as being a potential perpetuating factor. A recent novel theoretical model of functional dysphonia is reported, which proposes deficits in emotional processing as the core process in voice loss. SUMMARY: Current research confirms that functional dysphonia is associated with multiple psychosocial factors. However, these findings are shown to be true of other medically unexplained symptoms in which vocal problems are absent. It is argued that, whilst intuitively appealing, there is insufficient evidence to support the popular notion that the loss of voice is the consequence of unexpressed emotion.

Vocal fold bowing in elderly male monozygotic twins: a case study.

This case study examined case histories, diagnostic features, and treatment response in two 79-year-old male monozygotic (identical) twins with vocal fold bowing, exploring both genetic and environmental factors. DNA concordance was examined via cheek swab. Case histories, videostroboscopy, auditory- and visual-perceptual assessment, electromyography, acoustic measures, and Voice Handicap ratings were undertaken. Both twins underwent surgical intervention and subsequent voice therapy. Monozygosity was confirmed for DNA polymorphisms, with 10 of 10 concordance for STR DNA markers. For both twins, auditory- and visual-perceptual assessments indicated severe bowing, hoarseness, and breathiness, although Twin 1 was judged to be extremely severe. Differences in reference to root-mean-square amplitudes were observed for thyroarytenoid and lateral cricoarytenoid muscles, with smaller relative amplitudes observed for the Twin 1 versus Twin 2. No consistent voice improvement was observed after surgical intervention(s), despite improved mid-membranous vocal fold closure. Marked reductions in Voice Handicap Index total scores were observed after behavioral voice therapy, coinciding with increased mid-membranous and posterior laryngeal (interarytenoid) glottal closure. No substantive differences in acoustic measures were observed. Vocal fold bowing was more severe for Twin 1 versus Twin 2 despite identical heritability factors. Overall voice improvement with treatment was greater for Twin 2 than Twin 1. Environmental factors might partially account for the differences observed between the twins, including variability in their responsiveness to behavioral voice therapy. Voice therapy was useful in improving mid-membranous and posterior laryngeal closure, although dysphonia remained severe in both cases.

Sulcus vocalis in monozygotic twins.

Sulcus vocalis is the presence of a groove extending along the vibratory surface of a vocal fold and may result in dysphonia. Depending on the level of severity, this condition may require treatment involving complicated surgical techniques. Cases of sulcus vocalis are classified as physiological, vergeture, or pouch type. A clear explanation of the etiology has not been established, and the currently proposed congenital origin, as described in the literature, remains controversial. This paper presents findings from monozygotic twin sisters with bilateral sulcus vocalis; these patients had similar morphologies, vibratory characteristics, and vocal quality measurements, which support the theory of a congenital etiology.

Autosomal-dominant distal myopathy associated with a recurrent missense mutation in the gene encoding the nuclear matrix protein, matrin 3.

Distal myopathies represent a heterogeneous group of inherited skeletal muscle disorders. One type of adult-onset, progressive autosomal-dominant distal myopathy, frequently associated with dysphagia and dysphonia (vocal cord and pharyngeal weakness with distal myopathy [VCPDM]), has been mapped to chromosome 5q31 in a North American pedigree. Here, we report the identification of a second large VCPDM family of Bulgarian descent and fine mapping of the critical interval. Sequencing of positional candidate genes revealed precisely the same nonconservative S85C missense mutation affecting an interspecies conserved residue in the MATR3 gene in both families. MATR3 is expressed in skeletal muscle and encodes matrin 3, a component of the nuclear matrix, which is a proteinaceous network that extends throughout the nucleus. Different disease related haplotype signatures in the two families provided evidence that two independent mutational events at the same position in MATR3 cause VCPDM. Our data establish proof of principle that the nuclear matrix is crucial for normal skeletal muscle structure and function and put VCPDM on the growing list of monogenic disorders associated with the nuclear proteome.

Exploring genetic and environmental effects in dysphonia: a twin study.

PURPOSE: To explore the existence of genetic effects as well as the interaction between potential genetic effects and a voice-demanding occupation on dysphonia. METHOD: One thousand seven hundred and twenty-eight Finnish twins (555 male; 1,173 female) born between 1961 and 1989 completed a questionnaire concerning vocal symptoms and occupation. The zygosity determination resulted in 125 monozygotic and 108 dizygotic full twin pairs. A composite variable called dysphonia was formed by summing 6 vocal symptoms based on the results of a factor analysis. Twin model fitting was used to explore the contribution of genetic and environmental effects on the dysphonia variable. RESULTS: Individual differences in dysphonia were explained by genetic effects (35%) and nonshared environmental effects (65%). Shared environmental effects were estimated at 0%. Also, the authors found that for the participants who worked in voice-demanding occupations, the causes of dysphonia were more environmental, whereas the etiology of the symptoms was more strongly affected by genes in the participants with less voice-demanding occupations. However, this gene-environment interaction was not statistically significant. CONCLUSION: Both genetic and environmental factors have an impact on the etiology of voice problems. Environmental factors, either independently or interacting with genetic factors, seem to play the key role, especially if the person has a voice-demanding occupation.