Monogenic variants in dystonia: an exome-wide sequencing study

Background Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia. Methods For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow. Findings We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222;excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism. Interpretation In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations

L'APPARATO UDITIVO:FISIOLOGIA E PATOLOGIA

Objective: The purpose of this study was to determine the effectiveness of a new physical maneuver in the treatment of the apogeotropic variant of horizontal canal benign paroxysmal positional vertigo. Study Design: Case review. Setting: Outpatient clinic. Patients: The diagnosis of apogeotropic horizontal canal benign paroxysmal positional vertigo was based on the history of recurrent sudden crisis of vertigo associated with bursts of horizontal apogeotropic paroxysmal nystagmus provoked by turning the head from the supine to either lateral position. The patients were three men and five women ranging in age from 31 to 73 years (average, 49.2 yr). Interventions: All patients were treated with a repositioning maneuver based on the hypothesis that the syndrome is caused by the presence of free-floating dense particles inside the endolymph of the anterior arm of the horizontal canal. The maneuver favors their shifting into the posterior arm of the canal. Patients were reexamined immediately after the treatment and underwent Gufoni's liberatory maneuver for the geotropic variant of horizontal canal benign paroxysmal positional vertigo. Main Outcome Measure: The treatment outcome was considered as responsive when, after one repositioning maneuver, nystagmus shifted from apogeotropic to geotropic. Results: The repositioning maneuver resulted in a transformation from the apogeotropic variant into a geotropic variant of horizontal canal benign paroxysmal positional vertigo in all patients. Conclusion: This maneuver represents a simple and effective approach to the treatment of the apogeotropic variant of horizontal canal benign paroxysmal positional vertigo. It favors the shifting of the canaliths from the anterior into the posterior arm of the horizontal canal from where they can migrate into the utricle with Gufoni's maneuver

ACUFENI

per acufene si intende una sensazione sonora percepita dal paziente,non sostenuta da sorgenti esterne, causata da attività proprie dell'apparato acustico o da alterazioni dei meccanismi di elaborazione sensoriale

SOME EFFECTS OF TONAL FATIGUING ON SPONTANEOUS AND DISTORTION-PRODUCT OTOACOUSTIC EMISSIONS

Auditory fatiguing can be considered a suitable test to assess some cochlear mechanisms and diseases otherwise not easily detectable. Since spontaneous otoacoustic emissions (SOAEs) originate from active sources within the cochlea they show sensitive and early vulnerability to noise, displaying informative time-courses after overstimulation in the short (0-6 s) and in the long term (1-10 min) depending on the frequency of the fatiguing stimulus. Distortion product otoacoustic emissions too, in subjects with SOAEs, show interesting modifications after pure-tone exposure, detectable either on distortion product audiograms or in the growth functions. The modifications take place within a period of 5-7 minutes and strongly depend on the frequency of the fatiguing stimulus and on the closeness between SOAE and distortion product place. The data suggest that not only the interaction place between f1 and f2 has to be considered from a biomechanical and clinical point of view, but also the specific distortion product place on the cochlear partition