Essential and dystonic head tremor: More similarities than differences.

INTRODUCTION: Head tremor is a common symptom of essential tremor (ET) and cervical dystonia (CD). In clinical practice, it is often difficult to distinguish between these two conditions, especially in cases where head tremor predominates. OBJECTIVES: To investigate which clinical and instrumental methods best differentiate ET and CD in patients with head tremor. METHODS: 65 patients were included, of which 23 were diagnosed with ET and head tremor (HT+), 21 with ET without head tremor (HT-) and 21 with CD and dystonic head tremor. 22 healthy volunteers served as controls. All patients were examined using the rating scales for ET (TETRAS), cervical dystonia (TWSTRS), and ataxia (SARA). The Somatosensory Temporal Discrimination Threshold (STDT) was defined as the shortest interval in which an individual recognizes two tactile stimuli as temporally separated. RESULTS: TETRAS and SARA scores were higher in the HT+ group compared with HT- and CD, with no significant difference between mild head tremor subscores in HT+ and CD. In most HT+ and CD patients, head tremor disappeared supine. The STDT values were significantly higher in the HT+ group compared with controls. CONCLUSION: While TWSTRS contributed to assess dystonia severity, the scales of tremor and ataxia were not helpful in differentiating head tremor syndromes. The cessation of head tremor in the supine position could be related to the overall mild head tremor scores in both groups. Increased SARA scores and STDT values in HT+ patients suggest a possible role of cerebellar involvement and altered somatosensory timing that merit further verification.

Is retina affected in Huntington's disease? Is optical coherence tomography a good biomarker?

AIM OF THE STUDY: Comparative cross-sectional study of retinal parameters in Huntington's disease and their evaluation as marker of disease progression. CLINICAL RATIONALE FOR THE STUDY: Huntington's disease (HD) is a neurodegenerative disorder with dominant motor and neuropsychiatric symptoms. Involvement of sensory functions in HD has been investigated, however studies of retinal pathology are incongruent. Effect sizes of previous findings were not published. OCT data of the subjects in previous studies have not been published. Additional examination of structural and functional parameters of retina in larger sample of patients with HD is warranted. MATERIALS AND METHODS: This is a prospective cross-sectional study that included: peripapillary retinal nerve fiber layer thickness (RNFL) and total macular volume (TMV) measured by spectral domain optical coherence tomography (OCT) of retina, Pelli-Robson Contrast Sensitivity test, Farnsworth 15 Hue Color discrimination test, ophthalmology examination and Unified Huntington's disease Rating Scale (UHDRS). Ninety-four eyes of 41 HD patients examined in total 47 visits and 82 eyes of 41 healthy controls (HC) examined in total 41 visits were included. Analyses were performed by repeated measures linear mixed effects model with age and gender as covariates. False discovery rate was corrected by Benjamini-Hochberg procedure. RESULTS: HD group included 21 males and 20 females (age 50.6±12.0 years [mean ± standard deviation], disease duration 7.1±3.6 years, CAG triplet repeats 44.1±2.4). UHDRS Total Motor Score (TMS) was 30.0±12.3 and Total Functional Capacity 8.2±3.2. Control group (HC) included 19 males and 22 females with age 48.2±10.3 years. There was no statistically significant difference between HD and HC in age. The effect of the disease was not significant in temporal segment RNFL thickness. It was significant in the mean RNFL thickness and TMV, however not passing false discovery rate adjustment and with small effect size. In the HD group, the effect of disease duration and TMS was not significant. The Contrast Sensitivity test in HD was within normal limits and the 15-hue-test in HD did not reveal any specific pathology. CONCLUSIONS: The results of our study support possible diffuse retinal changes in global RNFL layer and in macula in Huntington's disease, however, these changes are small and not suitable as a biomarker for disease progression. We found no other structural or functional changes in retina of Huntington's disease patients using RNFL layer and macular volume spectral domain OCT and Contrast Sensitivity Test and 15-hue-test. CLINICAL IMPLICATIONS: Current retinal parameters are not appropriate for monitoring HD disease progression.

Scoring Algorithm-Based Genomic Testing in Dystonia: A Prospective Validation Study.

BACKGROUND: Despite the established value of genomic testing strategies, practice guidelines for their use do not exist in many indications. OBJECTIVES: We sought to validate a recently introduced scoring algorithm for dystonia, predicting the diagnostic utility of whole-exome sequencing (WES) based on individual phenotypic aspects (age-at-onset, body distribution, presenting comorbidity). METHODS: We prospectively enrolled a set of 209 dystonia-affected families and obtained summary scores (0-5 points) according to the algorithm. Singleton (N = 146), duo (N = 11), and trio (N = 52) WES data were generated to identify genetic diagnoses. RESULTS: Diagnostic yield was highest (51%) among individuals with a summary score of 5, corresponding to a manifestation of early-onset segmental or generalized dystonia with coexisting non-movement disorder-related neurological symptoms. Sensitivity and specificity at the previously suggested threshold for implementation of WES (3 points) was 96% and 52%, with area under the curve of 0.81. CONCLUSIONS: The algorithm is a useful predictive tool and could be integrated into dystonia routine diagnostic protocols. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Clinically relevant copy-number variants in exome sequencing data of patients with dystonia.

INTRODUCTION: Next-generation sequencing is now used on a routine basis for molecular testing but studies on copy-number variant (CNV) detection from next-generation sequencing data are underrepresented. Utilizing an existing whole-exome sequencing (WES) dataset, we sought to investigate the contribution of rare CNVs to the genetic causality of dystonia. METHODS: The CNV read-depth analysis tool ExomeDepth was applied to the exome sequences of 953 unrelated patients with dystonia (600 with isolated dystonia and 353 with combined dystonia; 33% with additional neurological involvement). We prioritized rare CNVs that affected known disease genes and/or were known to be associated with defined microdeletion/microduplication syndromes. Pathogenicity assessment of CNVs was based on recently published standards of the American College of Medical Genetics and Genomics and the Clinical Genome Resource. RESULTS: We identified pathogenic or likely pathogenic CNVs in 14 of 953 patients (1.5%). Of the 14 different CNVs, 12 were deletions and 2 were duplications, ranging in predicted size from 124bp to 17 Mb. Within the deletion intervals, BRPF1, CHD8, DJ1, EFTUD2, FGF14, GCH1, PANK2, SGCE, UBE3A, VPS16, WARS2, and WDR45 were determined as the most clinically relevant genes. The duplications involved chromosomal regions 6q21-q22 and 15q11-q13. CNV analysis increased the diagnostic yield in the total cohort from 18.4% to 19.8%, as compared to the assessment of single-nucleotide variants and small insertions and deletions alone. CONCLUSIONS: WES-based CNV analysis in dystonia is feasible, increases the diagnostic yield, and should be combined with the assessment of single-nucleotide variants and small insertions and deletions.

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. FUNDING: Else Kröner-Fresenius-Stiftung, Technische Universität München, Helmholtz Zentrum München, Medizinische Universität Innsbruck, Charles University in Prague, Czech Ministry of Education, the Slovak Grant and Development Agency, the Slovak Research and Grant Agency.

Pseudodominant Nanophthalmos in a Roma Family Caused by a Novel PRSS56 Variant.

BACKGROUND: The aim of the study was to identify the molecular genetic cause of two different Mendelian traits with ocular involvement present in the members of a single consanguineous Czech Roma family. METHODS: We have performed ocular examination and review of medical records in two individuals diagnosed with nanophthalmos (proband and her father) and one individual followed for bilateral congenital cataract and microcornea (uncle of the proband). DNA of subjects with nanophthalmos was analysed by exome sequencing. Sanger sequencing was applied for targeted screening of potentially pathogenic variants and to follow segregation of identified variants within the family. RESULTS: A homozygous variant c.1509G>C; p.(Met503Ile), in PRSS56 was found in the two individuals affected with nanophthalmos. The change was absent from the gnomAD dataset, but two out of 118 control Roma individuals were also shown to be heterozygous carriers. Analysis of single nucleotide polymorphisms in linkage disequilibrium with the c.1509G>C in PRSS56 suggested a shared chromosomal segment. The nanophthalmos phenotype, characterized in detail in the younger individual, encompassed bilateral corneal steepening, retinal folds, buried optic head drusen, and restricted visual fields, but no signs of retinal dystrophy. A known pathogenic founder CTDP1 variant c.863+389C>T in a homozygous state was identified in the other family member confirming the suspected diagnosis of congenital cataracts, facial dysmorphism, and demyelinating neuropathy syndrome. CONCLUSIONS: Herein, we report the first occurrence of nanophthalmos in the Roma population. We have identified pseudodominant inheritance for this phenotype caused by a novel variant in PRSS56, representing a possible founder effect. Despite advances in genetic technologies such as exome sequencing, careful phenotype evaluation in patients from an isolated population, along with an awareness of population-specific founder effects, is necessary to ensure that accurate molecular diagnoses are made.

Characterizing vocal tremor in progressive neurological diseases via automated acoustic analyses.

OBJECTIVE: Voice tremor represents a common but frequently overlooked clinical feature of neurological disease. Therefore, we aimed to quantitatively and objectively assess the characteristics of voice tremor in a large sample of patients with various progressive neurological diseases. METHODS: Voice samples were acquired from 240 patients with neurological disease and 40 healthy controls. The robust automated method was designed, allowing precise tracking of multiple tremor frequencies and distinguish pathological from the physiological tremor. RESULTS: Abnormal tremor was revealed in Huntington's disease (65%), essential tremor (50%), multiple system atrophy (40%), cerebellar ataxia (40%), amyotrophic lateral sclerosis (40%), progressive supranuclear palsy (25%), Parkinson's disease (20%), cervical dystonia (10%), and multiple sclerosis (8%) but not in controls. Low-frequency voice tremor (<4 Hz) was common in all investigated diseases, whereas medium tremor frequencies (4-7 Hz) were specific for movement disorders of Parkinson's disease, multiple system atrophy, essential tremor, and cervical dystonia. CONCLUSIONS: Careful estimation of vocal tremor may help with accurate diagnosis and tailored treatment. SIGNIFICANCE: This study provides (i) more insights into the pathophysiology of vocal tremor in a wide range of neurological diseases and (ii) an accurate method for estimation of vocal tremor suitable for clinical practice.

Eye movement abnormalities are associated with brainstem atrophy in Wilson disease.

BACKGROUNDS: This study aims to characterize eye movement abnormalities in Wilson disease and examine their association with the degree of brainstem atrophy. METHODS: Twenty patients (10 males, mean age 46.8, SD 8.9 years) with genetically confirmed neurological WD on stable anti-copper treatment and 20 age- and sex-matched healthy subjects were examined. Eye movements, including prosaccade and antisaccade tasks, were evaluated using infrared videooculography. MRI was performed using 1.5 T system, and T2-weighted images were used for the measurement of midbrain and pontine area on mid-sagittal slices. Clinical severity was assessed using the Unified Wilson's Disease Rating Scale (UWDRS). RESULTS: Compared to healthy controls, WD patients showed prolonged latencies of horizontal prosaccades and hypometry of both horizontal (p = 0.04) and vertical (p = 0.0046) prosaccades. In the antisaccade task, WD patients showed prolonged latency of both horizontal (p = 0.04) and vertical antisaccades (p = 0.047) and increased error rate of vertical antisaccades (p = 0.04). There is a significant association between midbrain area and horizontal latencies (r = -0.53; p = 0.02) and vertical maximum speed in prosaccades (r = 0.47; p = 0.04). The pons area inversely correlated with horizontal prosaccade and antisaccade latencies (p = 0.007). CONCLUSIONS: We showed impairments of ocular saccades such as prolonged latencies, hypometry, and increased error rate in antisaccades. The strong association between prolonged latencies of prosaccades and the brainstem atrophy suggests that VOG might serve as a sensitive electrophysiological marker of brainstem dysfunction in WD.

Relations of non-motor symptoms and dopamine transporter binding in REM sleep behavior disorder.

The aim of this study was to evaluate associations of motor and non-motor symptoms with dopamine transporter binding in prodromal stage of synucleinopathies. We examined 74 patients with idiopathic REM sleep behavior disorder (RBD), which is a prodromal synucleinopathy, and 39 controls using Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Montreal Cognitive Assessment, University of Pennsylvania Smell Identification Test (UPSIT), Farnsworth-Munsell 100 hue test, orthostatic test, Scales for Outcomes in PD-Autonomic, Beck depression inventory-II, State-Trait Anxiety Inventory, and video-polysomnography. Electromyographic muscle activity during REM sleep was quantified according to Sleep Innsbruck-Barcelona criteria. In 65 patients, dopamine transporter single-photon emission computed tomography (DAT-SPECT) imaging was performed, putaminal binding ratio was calculated and scans were classified as normal, borderline, or abnormal. Compared to controls, RBD patients had significantly more severe scores in all examined tests. Patients with abnormal DAT-SPECT had higher MDS-UPDRS motor score (p = 0.006) and higher prevalence of orthostatic hypotension (p = 0.008). Putaminal binding ratio was positively associated with UPSIT score (p = 0.03) and negatively associated with tonic (p = 0.003) and phasic (p = 0.01) muscle activity during REM sleep. These associations likely reflect simultaneous advancement of underlying pathology in substantia nigra and susceptible brainstem and olfactory nuclei in prodromal synucleinopathy.

Eye movements in idiopathic rapid eye movement sleep behaviour disorder: High antisaccade error rate reflects prefrontal cortex dysfunction.

Abnormalities of eye movements have been reported in patients with Parkinson's disease (PD). However, it is unclear if they occur in the prodromal stage of synucleinopathy represented by idiopathic rapid eye movement sleep behaviour disorder (iRBD). We thus aimed to study eye movements in subjects with iRBD and in de novo PD, to assess if their abnormalities may serve as a clinical biomarker of neurodegeneration. Fifty subjects with polysomnography-confirmed iRBD (46 male, age 40-79 years), 18 newly diagnosed, untreated PD patients (13 male, age 43-75 years) and 25 healthy controls (20 male, age 42-79 years) were prospectively enrolled. Horizontal and vertical ocular prosaccades and antisaccades were investigated with video-oculography. All patients completed the MDS-UPDRS and the Montreal Cognitive Assessment. In addition, a neuropsychological battery was performed on iRBD subjects. When compared with healthy controls, both de novo PD patients and iRBD subjects showed increased error rates in the horizontal antisaccade task (p < 0.01, p < 0.05 respectively). In the iRBD group, the error rates in horizontal and vertical antisaccades correlated with performances in the Prague Stroop Test and the Grooved Pegboard Test, as well as with motor scores of the MDS-UPDRS. De novo PD patients showed a lower gain (p < 0.01) compared with controls. In conclusion, the increased error rate in the antisaccade task of iRBD and PD patients reflects a dysfunction of the dorsolateral prefrontal cortex and is related to the impairment of executive functions and attention.

Correction to: Segregation of a novel p.(Ser270Tyr) MAF mutation and p.(Tyr56*) CRYGD variant in a family with dominantly inherited congenital cataracts.

There was a spacing error in the initial online publication, and there were errors in the Acknowledgments section. The original article has been updated.

General and selective brain connectivity alterations in essential tremor: A resting state fMRI study.

Although essential tremor is the most common movement disorder, there is little knowledge about the pathophysiological mechanisms of this disease. Therefore, we explored brain connectivity based on slow spontaneous fluctuations of blood oxygenation level dependent (BOLD) signal in patients with essential tremor (ET). A cohort of 19 ET patients and 23 healthy individuals were scanned in resting condition using functional magnetic resonance imaging (fMRI). General connectivity was assessed by eigenvector centrality (EC) mapping. Selective connectivity was analyzed by correlations of the BOLD signal between the preselected seed regions and all the other brain areas. These measures were then correlated with the tremor severity evaluated by the Fahn-Tolosa-Marin Tremor Rating Scale (FTMTS). Compared to healthy subjects, ET patients were found to have lower EC in the cerebellar hemispheres and higher EC in the anterior cingulate and in the primary motor cortices bilaterally. In patients, the FTMTS score correlated positively with the EC in the putamen. In addition, the FTMTS score correlated positively with selective connectivity between the thalamus and other structures (putamen, pre-supplementary motor area (pre-SMA), parietal cortex), and between the pre-SMA and the putamen. We observed a selective coupling between a number of areas in the sensorimotor network including the basal ganglia and the ventral intermediate nucleus of thalamus, which is widely used as neurosurgical target for tremor treatment. Finally, ET was marked by suppression of general connectivity in the cerebellum, which is in agreement with the concept of ET as a disorder with cerebellar damage.

Segregation of a novel p.(Ser270Tyr) MAF mutation and p.(Tyr56∗) CRYGD variant in a family with dominantly inherited congenital cataracts.

A bilaterally blind woman, with a three generation family history of autosomal dominant congenital cataracts, variably associated with iris colobomata and microcornea, sought preconception genetic consultation. Whole-exome sequencing was performed in three affected family members, one unaffected first degree relative, and one spouse. The sequence variant c.168C>G; p.(Tyr56∗) in CRYGD, previously reported as pathogenic, and a novel mutation c.809C>A; p.(Ser270Tyr) in MAF, were identified in two affected family members; the grandmother, and half-brother of the proband. The proband inherited only the MAF mutation, whereas her clinically unaffected sister had the CRYGD change. In silico analysis supported a pathogenic role of p.(Ser270Tyr) in MAF, which was absent from publicly available whole-exome datasets, and 1161 Czech individuals. The frequency of CRYGD p.(Tyr56∗) in the ExAC dataset was higher than the estimated incidence of congenital cataract in the general population. Our study highlights that patients with genetically heterogeneous conditions may exhibit rare variants in more than one disease-associated gene, warranting caution with data interpretation, and supporting parallel screening of all genes known to harbour pathogenic mutations for a given phenotype. The pathogenicity of sequence variants previously reported as cataract-causing may require re-assessment in light of recently released datasets of human genomic variation.

Intermittent bilateral coherence in physiological and essential hand tremor.

OBJECTIVE: To investigate the prevalence and the temporal structure of bilateral coherence in physiological (PT) and essential (ET) hand tremor. METHODS: Triaxial accelerometric recordings from both hands in 30 healthy subjects and 34 ET patients were analyzed using spectral coherence and wavelet coherence methods. In 12 additional healthy subjects, the relation between the hand tremor and the chest wall acceleration was evaluated using partial coherence analysis. RESULTS: The majority of both PT and ET subjects displayed significant bilateral coherence. While in PT, bilateral coherence was most frequently found in resting hand position (97% of subjects), in ET the prevalence was comparable for resting (54%) and postural (49%-57%) positions. In both PT and ET, epochs of strong coherence lasting several to a dozen seconds were separated by intervals of insignificant coherence. In PT, bilateral coherence at the main tremor frequency (8-12Hz) was coupled with the ballistocardiac rhythm. CONCLUSION: The oscillations of the two hands are intermittently synchronized in both PT and ET. We propose that in postural PT, bilateral coherence at the main tremor frequency arises from transient simultaneous entrainment of the left and right hand oscillations to ballistocardiac forcing. SIGNIFICANCE: Bilateral coherence of hand kinematics provides a sensitive measure of synchronizing influences on the left and right tremor oscillators.

Comparison of transcranial sonography-magnetic resonance fusion imaging in Wilson's and early-onset Parkinson's diseases.

INTRODUCTION: Wilson's disease (WD) is a hereditary disorder caused by ATP7B mutations resulting in systemic copper accumulation. WD may manifest as early-adulthood parkinsonism; and atypical cases may be difficult to distinguish from early-onset Parkinson's disease (EO-PD), a neurodegenerative disorder with onset ≤40 years of age. The aim of our study was to compare transcranial sonography (TCS)-magnetic resonance fusion imaging in WD and EO-PD and examine whether TCS can provide clinically useful information. METHODS: We examined 22 WD, 16 EO-PD, and 24 healthy control subjects. We measured echogenicity and determined presence of MRI signal changes in T2-weighted images in the substantia nigra (SN) and lentiform nucleus (NL). TCS with the capability of magnetic resonance fusion and Virtual Navigator was used. The echogenicity indices of SN and NL were processed using digital image analysis to eliminate subjective evaluation errors. RESULTS: Mean SN echogenicity index in EO-PD (39.8 ± 5.9 [SD]) was higher compared to WD (28.0 ± 4.6, p < 0.0001) and control subjects (28.8 ± 4.9, p < 0.0001). Mean NL echogenicity index was higher in WD (117.5 ± 37.0) compared to EO-PD (61.6 ± 5.4, p < 0.0001) and control subjects (54.9 ± 11.2, p < 0.0001). The SN hyperechogenicity had sensitivity 93.8%, and specificity 90.9%, while the NL hyperechogenicity had sensitivity 95.5% and specificity 93.8% for differentiation of WD and EO-PD. NL hyperechogenicity was more pronounced in WD subjects with putaminal MRI T2 hyperintensity (p < 0.05) but was also present in subjects without MRI abnormality. CONCLUSIONS: There are distinct TCS findings in WD and EO-PD complementary to MRI that can be utilized as highly sensitive and specific biomarkers of these disorders.

Quantitative assessment of motor speech abnormalities in idiopathic rapid eye movement sleep behaviour disorder.

OBJECTIVE: Patients with idiopathic rapid eye movement sleep behaviour disorder (RBD) are at substantial risk for developing Parkinson's disease (PD) or related neurodegenerative disorders. Speech is an important indicator of motor function and movement coordination, and therefore may be an extremely sensitive early marker of changes due to prodromal neurodegeneration. METHODS: Speech data were acquired from 16 RBD subjects and 16 age- and sex-matched healthy control subjects. Objective acoustic assessment of 15 speech dimensions representing various phonatory, articulatory, and prosodic deviations was performed. Statistical models were applied to characterise speech disorders in RBD and to estimate sensitivity and specificity in differentiating between RBD and control subjects. RESULTS: Some form of speech impairment was revealed in 88% of RBD subjects. Articulatory deficits were the most prominent findings in RBD. In comparison to controls, the RBD group showed significant alterations in irregular alternating motion rates (p = 0.009) and articulatory decay (p = 0.01). The combination of four distinctive speech dimensions, including aperiodicity, irregular alternating motion rates, articulatory decay, and dysfluency, led to 96% sensitivity and 79% specificity in discriminating between RBD and control subjects. Speech impairment was significantly more pronounced in RBD subjects with the motor score of the Unified Parkinson's Disease Rating Scale greater than 4 points when compared to other RBD individuals. CONCLUSION: Simple quantitative speech motor measures may be suitable for the reliable detection of prodromal neurodegeneration in subjects with RBD, and therefore may provide important outcomes for future therapy trials.

Changes of retina are not involved in the genesis of visual hallucinations in Parkinson's disease.

Parkinson's disease (PD) is characterized by motor and nonmotor symptoms. Nonmotor symptoms include primarily visual hallucinations (VH). The aim of our study was to establish whether patients with PD and visual hallucinations (PDH+) have structural changes of retina detected by an optical coherence tomography (OCT) in comparison with PD patients without visual hallucinations (PDH-). We examined 52 PD patients (18 with VH, 34 without VH) and 15 age and sex matched healthy controls. Retinal nerve fiber layer (RNFL) thickness and macular thickness and volume were assessed by OCT. Functional impairment of retina was assessed using 2.5% contrast sensitivity test. For OCT outcomes we analyzed 15 PDH+ and 15 PDH- subjects matched for age, gender, and PD duration. For contrast sensitivity we analyzed 8 pairs of patients matched for age, gender, and visual acuity. There was no significant difference in RNFL thickness and macular thickness and macular volume between 15 PDH+ and 15 PDH- subjects, and also between a group of 44 PD patients (both PDH+ and PDH-) and 15 age and gender matched healthy controls. No significant difference was found for 2.5% contrast sensitivity test values between PDH+ and PDH- subjects. Therefore we conclude that functional and structural changes in retina play no role in genesis of VH in PD.

Novel OPA1 missense mutation in a family with optic atrophy and severe widespread neurological disorder.

PURPOSE: To identify the underlying molecular genetic cause in a Czech family with optic atrophy, deafness, ptosis, ophthalmoplegia, polyneuropathy and ataxia transmitted as an autosomal dominant trait. METHODS: Ophthalmological and neurological examination followed by molecular genetic analyses. RESULTS: Seven family members were clinically affected. There was a variable but progressive visual, hearing and neurological disability across the family as a whole. The majority of subjects presented with impairment of visual function and a variable degree of ptosis and/or ophthalmoplegia from the first to the third decade of life. Deafness, neuropathy and ataxia appeared later, in the third and fourth decade. Migraine, tachycardia, intention tremor, nystagmus and cervical dystonia were observed in isolated individuals. A significant overall feature was the high level of neurological disability leading to 3 of 4 members being unable to walk or stand unaided before the age of 60 years. A novel missense mutation c.1345A>C (p.Thr449Pro) in OPA1 segregating with the disease phenotype over three generations was detected. In silico analysis supported pathogenicity of the identified sequence variant. CONCLUSION: Our work expands the spectrum of mutation in OPA1, which may lead to severe multisystem neurological disorder. The molecular genetic cause of dominant optic atrophy in the Czech population is reported for the first time. We propose that regular cardiac follow-up in patients diagnosed with dominant optic atrophy and widespread neurological disease should be considered.