Reflexive and voluntary saccadic eye movements as biomarker of Huntington's Disease.

INTRODUCTION: Subtle abnormalities in the preclinical stage of Huntington's Disease (HD) can be detected using saccadic eye movement assessment reflecting disease progression. This study was aimed to evaluate abnormalities in saccade parameters in asymptomatic carriers and symptomatic HD patients at various stages of HD. MATERIAL AND METHODS: The study enrolled 104 participants, including 14 asymptomatic carriers of HTT mutations, 44 symptomatic HD patients, and 46 control subjects. HD severity was measured using the Unified Huntington's Disease Rating Scale Total Motor Score (UHDRS-TMS) and Total Functional Capacity Scale (TFC). The evaluation of rapid eye movements (reflexive saccades, anti-saccades, memory-guided saccades) was carried out using 'Saccadometer Research'. RESULTS: Measures of reflexive and volitional saccades did not differ between the asymptomatic carriers and controls. Significant latency prolongation and increased physiological variability of latency times, as well as higher error rates among HD patients, were found in all saccade tasks (p < 0.001) compared to the controls. Abnormalities in saccade parameters were more pronounced in the advanced stages of the disease. Latency of saccades and error rate of volitional saccades correlated with the UHDRS-TMS and TFC scores. CONCLUSIONS: The saccade parameters in asymptomatic HD carriers with a long time to disease development were similar to those in the control group. Saccade abnormalities appeared in symptomatic patients at the beginning of the disease, and correlated with HD severity.

Is deep brain stimulation effective in Huntington's Disease? - a systematic literature review.

INTRODUCTION: Huntington's Disease (HD) is an autosomal dominant neurodegenerative disorder. Substantial for a diagnosis of the disease are motor disorders, with chorea as a hallmark symptom. Other disease manifestations include cognitive dysfunction and psychiatric disorders. Currently, pharmacological treatment plays the most important role in the therapy of HD patients. However, deep brain stimulation (DBS) is considered a potential therapeutic option. AIM OF THE STUDY: Systematic review of current literature on DBS efficacy and safety in the management of motor, behavioural and cognitive functions in patients with HD. MATERIAL AND METHODS: A systematic review was conducted with the use of the Scopus database and the following search criteria: TITLE (huntington*) AND TITLE-ABS-KEY ('deep brain stimulation' OR 'neuromodulation'). Our search criteria included original studies with at least five patients, reporting any motor, cognitive and/or behavioural, and functional assessment data with at least a 6-month follow-up. Finally, four selected publications were analysed. RESULTS: In all analysed publications, we found a statistically significant improvement of Unified Huntington's Disease Rating Scale (UHDRS) chorea subscore by an average of 40, to over 60% after DBS implantation. Heterogeneous results were obtained for UHDRS total motor score. DBS did not improve functional capacity of HD patients in the analysed studies. We found no systematic assessment concerning the effect of DBS in HD on behaviour, cognition or speech. CONCLUSIONS: DBS implantation could be considered as a therapeutic option for patients with severe, drug-resistant chorea. However, the evidence for this is limited. To date, no high-quality data based on randomised controlled trials supports the long-term safety and efficacy of DBS in HD. This treatment option should therefore currently be considered as investigational.

Cathepsin B p.Gly284Val Variant in Parkinson's Disease Pathogenesis.

Parkinson's disease (PD) is generally considered a sporadic disorder, but a strong genetic background is often found. The aim of this study was to identify the underlying genetic cause of PD in two affected siblings and to subsequently assess the role of mutations in Cathepsin B (CTSB) in susceptibility to PD. A typical PD family was identified and whole-exome sequencing was performed in two affected siblings. Variants of interest were validated using Sanger sequencing. CTSB p.Gly284Val was genotyped in 2077 PD patients and 615 unrelated healthy controls from the Czech Republic, Ireland, Poland, Ukraine, and the USA. The gene burden analysis was conducted for the CTSB gene in an additional 769 PD probands from Mayo Clinic Florida familial PD cohort. CTSB expression and activity in patient-derived fibroblasts and controls were evaluated by qRT-PCR, western blot, immunocytochemistry, and enzymatic assay. The CTSB p.Gly284Val candidate variant was only identified in affected family members. Functional analysis of CTSB patient-derived fibroblasts under basal conditions did not reveal overt changes in endogenous expression, subcellular localization, or enzymatic activity in the heterozygous carrier of the CTSB variant. The identification of the CTSB p.Gly284Val may support the hypothesis that the CTSB locus harbors variants with differing penetrance that can determine the disease risk.

Characteristics of transitional locomotor tasks performed by patients with dementia.

Elderly individuals may be at increased risk of falls than their peers. Early identification of balance disorders and their appropriate intervention are crucial for patients with dementia. The aim of this study was to identify postural instability in patients from mild to moderate dementia while performing transitional locomotor tasks under different conditions. Fifty-four patients with dementia and 30 healthy controls voluntarily participated in the study. The transitional locomotor task was performed on two force platforms under four conditions: unimpeded transition, obstacle clearance, step-up and step-down trials. The recording of center of foot pressure displacements was divided into three distinct phases: 1st phase-quiet standing before the transitional locomotor task, 2nd phase-forward stepping, 3rd phase-quiet standing after the transitional locomotor task. Patients with dementia were characterized by a longer transitional locomotor task time than the control group under all conditions (P < 0.03). Significant differences in quiet standing before the transitional locomotor task were observed between patients with dementia and the control group, but only in unimpeded transition and obstacle clearance trials (P < 0.02). No significant differences in quiet standing after step transition were observed between patients with dementia and the control group (P > 0.05). Postural control research in patients with dementia should focus on the functional motor task rather than on a simple motor task (quiet standing). Because even patients with mild dementia have impaired dynamic balance, the assessment of transitional locomotor tasks performed by patients with dementia might provide an indicator of an early diagnosis of dementia and might lead to better individualized physiotherapy.

The Role of Single Nucleotide Polymorphisms of Monoamine Oxidase B, Dopamine D2 Receptor, and DOPA Decarboxylase Receptors Among Patients Treated for Parkinson's Disease.

This study aimed to investigate the association between selected variants of genes related to dopamine metabolism pathways and the risk of and progression of Parkinson's disease (PD). This prospective cohort study was conducted in one academic teaching hospital. The study was conducted on 126 patients diagnosed with idiopathic Parkinson's disease. Blood samples were collected to conduct a genotyping of MAOB, DRD1, DRD2, and DDC genes. Genotype and allele frequencies of MAOB (rs1799836) variants were not associated with the course of PD. Genotype and allele frequencies of DRD2 (rs2283265) variants were associated with risk of dementia (p = 0.001) and resulted in parts II and III of the UPDRS scale (p = 0.001). Genotype and allele frequencies of DRD2 (rs1076560) variants were associated with risk of dementia (p = 0.001) and resulted in parts II and III of the UPDRS scale (p = 0.001). Genotype and allele frequencies of DDC (rs921451) variants were not associated with the course of PD.

The Role of the Western Diet and Oral Microbiota in Parkinson's Disease.

The type of diet not only affects the composition of the oral microflora but is also one of the more critical factors associated with an increased risk of Parkinson's disease, PD. This study compared diet preferences and oral microbiota profiles in patients with PD vs. healthy controls. This study compared the oral microbiota composition of 59 patients with PD and 108 healthy controls (without neurodegeneration) using 16S rRNA gene amplicon sequencing. According to results, oral microbiota in patients with PD is different compared from healthy controls. In particular, decreased abundance of Proteobacteria, Pastescibacteria, and Tenercutes was observed. The oral cavity of patients with PD was characterized by the high relative abundance of bacteria from the genera Prevotella, Streptococcus, and Lactobaccillus. There were also differences in food preferences between patients with PD and healthy controls, which revealed significantly higher intake of margarine, fish, red meat, cereals products, avocado, and olives in the patients with PD relative to healthy controls. Strong positive and negative correlations between specific food products and microbial taxa were identified.

Differences in the Composition of Gut Microbiota between Patients with Parkinson's Disease and Healthy Controls: A Cohort Study.

Gut microbiome and colonic inflammation can be associated with the predisposition and progression of Parkinson's disease (PD). The presented study aimed to compare gastrointestinal microbiota composition between patients diagnosed with PD and treated only with Levodopa to healthy controls. In this prospective study, patients were recruited in 1 academic hospital from July 2019 to July 2020. The detailed demographic data and medical history were collected using a set of questionnaires. Fecal samples were obtained from all participants. Next-Generation Sequencing was used to assess the microbiota composition. The endpoint was the difference in composition of the gut microbiota. In this study, we enrolled 27 hospitalized PD patients with well-controlled symptoms. The control group included 44 healthy subjects matched for age. Among PD patients, our results presented a higher abundance of Bacteroides phylum, class Corynebacteria among phylum Actinobacteria, class Deltaproteobacteria among phylum Proteobacteria, and genera such as Butyricimonas, Robinsoniella, and Flavonifractor. The species Akkermansia muciniphila, Eubacterium biforme, and Parabacteroides merdae were identified as more common in the gut microbiota of PD patients. In conclusion, the patients diagnosed with PD have significantly different gut microbiota profiles in comparison with healthy controls.

The Utility of BDNF Detection in Assessing Severity of Huntington's Disease.

Brain-derived neurotrophic factor (BDNF) is involved in the survival and maturation of neurons, and also promotes and controls neurogenesis. Its levels are lowered in many neurodegenerative diseases, including Huntington's disease (HD). Clinical pictures of HD can be very diverse, which makes it difficult to assess its severity; however, molecular markers may be helpful. The aim of the study was to determine the relationship between HD severity and the plasma BDNF concentration in HD patients. The study recruited 42 patients with diagnosed and genetically confirmed HD and 40 healthy volunteers. BDNF levels were determined in plasma with the enzyme-linked immunosorbent assay (ELISA). Correlations between BDNF levels and clinical profiles and HD severity were also investigated. The BDNF level was significantly lower in HD patients compared to the control. There was no correlation between the BDNF level and motor symptoms and cognitive impairment. In the early disease stages, BDNF levels were associated with a better neurological examination, independence, and functional evaluation, in contrast to later HD stages, where the correlations were inverse. Multidirectional correlations between parameters of saccadic disorders and the BDNF level do not allow for drawing a conclusion, whether or not there is a relationship between the severity of saccadic disorders and the BDNF concentration.

Is TGF-ß1 a Biomarker of Huntington's Disease Progression?

Huntington's disease (HD) is an autosomal dominant genetic disease that can be divided into preclinical and symptomatic stages. Due to the diverse HD phenotype, there is an urgent need to identify markers that would independently assess its severity. The aim of this study was to evaluate the use of plasma levels of TGF-ß1 in the assessment of HD severity. One hundred HD patients and 40 healthy volunteers were included in the study. All HD patients underwent neurological and cognitive function assessment. TGF-ß1 levels were determined in the plasma of all patients. The correlations between TGF-ß1 levels and clinical profile and HD severity were also investigated. In symptomatic patients, cognitive decline was demonstrated, while in preclinical patients, no symptoms were found. Plasma levels of TGF-ß1 in HD patients did not differ significantly from the control group and did not change with the progression of the disease. In addition, TGF-ß1 levels also did not correlate with the severity of motor dysfunction. Positive correlations between plasma TGF-ß1 concentration and intensity of cognitive impairment were found, but only in the early disease stage. There was no clear benefit in assessing plasma TGF-ß1 levels in HD patients as a marker of disease severity.

Botulinum toxin type-A preparations are not the same medications - basic science (Part 1).

Botulinum neurotoxin type A (BoNT/A) formulations are widely used in clinical practice. Although they share a common mechanism of action resulting in presynaptic block in acetylocholine release, their structure and pharmacological properties demonstrate some similarities and many differences. Bioequivalence has been discussed since the onset of the clinical use of BoNT/A. In this review, we provide an update on the studies and compare the molecular structure, mechanisms of action, diffusion and spread, as well as immunogenicity and dose equivalence of onabotulinumtoxinA, abobotulinumtoxinA and incobotulinumtoxinA.

Frequency of mutations in PRKN, PINK1, and DJ1 in Patients With Early-Onset Parkinson Disease from neighboring countries in Central Europe.

INTRODUCTION: Approximately 10% of patients with Parkinson disease (PD) present with early-onset disease (EOPD), defined as diagnosis before 50 years of age. Genetic factors are known to contribute to EOPD, with most commonly observed mutations in PRKN, PINK1, and DJ1 genes. The aim of our study was to analyze the frequency of PRKN, PINK1, and DJ1 mutations in an EOPD series from 4 neighboring European countries: Czech Republic, Germany, Poland, and Ukraine. METHODS: Diagnosis of PD was made based on UK Brain Bank diagnostic criteria in departments experienced in movement disorders (1 from Czech Republic, 1 from Germany, 9 from Poland, and 3 from Ukraine). EOPD was defined as onset at or before 50 years of age. Of the 541 patients recruited to the study, 11 were Czech, 38 German, 476 Polish, and 16 Ukrainian. All cohorts were fully screened with Sanger sequencing for PRKN, PINK1, and DJ1 and multiplex ligation-dependent probe amplification for exon dosage. RESULTS: PRKN homozygous or double heterozygous mutations were identified in 17 patients: 1 Czech (9.1%), 1 German (2.6%), 14 Polish (2.9%), and 1 Ukrainian (6.3%). PINK1 homozygous mutations were only identified in 3 Polish patients (0.6%). There were no homozygous or compound heterozygous DJ1 mutations in analyzed subpopulations. One novel variant in PRKN was identified in the Ukrainian series. CONCLUSION: In the analyzed cohorts, mutations in the genes PRKN, PINK1, and DJ1 are not frequently observed.

Validation of the Polish version of the Unified Dyskinesia Rating Scale (UDysRS).

BACKGROUND: In 2008, the Movement Disorders Society published the Unified Dyskinesia Rating Scale (UDysRS). This has become the established tool for assessing the severity and disability associated with dyskinesia in patients with Parkinson's Disease (PD). We translated and validated the Polish version of the UDysRS, explored its dimensionality, and compared it to the Spanish version, which is the Reference Standard for UDysRS translations. MATERIAL AND METHODS: The UDysRS was translated into Polish by a team led by JS and GO. The back-translation, completed by colleagues fluent in both Polish and English who were not involved in the original translation, was reviewed and approved by the Executive Committee of the MDS Rating Scales Programme. Then the translated version of the UDysRS underwent cognitive pretesting, and the translation was modified based on the results. The approved version was considered to be the Official Working Document of the Polish UDysRS and was tested on 250 Polish PD patients recruited at movement disorder centres. Data was compared to the Reference Standard used for validating UDysRS translations. RESULTS: The overall factor structure of the Polish version was consistent with that of the Reference Standard version, as evidenced by the high Confirmatory Fit Index score (CFI = 0.98). The Polish UDysRS was thus confirmed to share a common factor structure with the Reference Standard. CONCLUSIONS: The Official Polish UDysRS translation is recommended for use in clinical and research settings. Worldwide use of uniform rating measures offers a common ground to study similarities and differences in disease manifestations and progression across cultures.

The Effect of Repeated abobotulinumtoxinA (Dysport®) Injections on Walking Velocity in Persons with Spastic Hemiparesis Caused by Stroke or Traumatic Brain Injury.

BACKGROUND: Botulinum toxin (BoNT) injections were shown to improve muscle tone of limbs in patients with spasticity. However, limited data are available regarding the effects of repeated BoNT injections on walking ability. OBJECTIVE: To assess changes in walking velocity (WV), step length, and cadence under different test conditions after repeated treatment with abobotulinumtoxinA (aboBoNT-A; Dysport) in spastic lower limb muscles. DESIGN: Secondary analysis of an open-label, multiple-cycle extension (National Clinical Trials number NCT01251367) to a phase III, double-blind, randomized, placebo-controlled, single-treatment cycle study, in adults with chronic hemiparesis (NCT01249404). SETTING: Fifty-two centers across Australia, Belgium, the Czech Republic, France, Hungary, Italy, Poland, Portugal, Russia, Slovakia, and the United States. PATIENTS: 352 Ambulatory adults (18-80 years) with spastic hemiparesis and gait dysfunction caused by stroke or traumatic brain injury, with a comfortable barefoot WV of 0.1 to 0.8 m/s. INTERVENTIONS: Up to four aboBoNT-A treatment cycles, administered to spastic lower limb muscles. MAIN OUTCOME MEASUREMENTS: Changes from baseline in comfortable and maximal barefoot and with shoes WV (m/s), step length (m/step), and cadence (steps/minutes). RESULTS: At Week 12 after four injections, WV improved by 0.08 to 0.10 m/s, step length by 0.03 to 0.04 m/step, and cadence by 3.9 to 6.2 steps/minutes depending on test condition (all P < .0001 to .0003 vs baseline). More patients (7% to 17%) became unlimited community ambulators (WV ≥0.8 m/s) across test conditions compared with baseline, with 39% of 151 patients classified as unlimited community ambulators in at least one test condition and 17% in all four test conditions. CONCLUSIONS: Clinically meaningful and statistically significant improvements in WV, step length, and cadence under all four test conditions were observed in patients with spastic hemiparesis after each aboBoNT-A treatment cycle.

Validation of the Polish version of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS).

BACKGROUND: In 2008, the Movement Disorders Society (MDS) published a new Unified Parkinson's Disease Rating Scale (MDS-UPDRS) as the official benchmark scale for Parkinson's Disease (PD). We have translated and validated the Polish version of the MDS-UPDRS, explored its dimensionality, and compared it to the original English one. METHODS: The MDS-UPDRS was translated into Polish by a team of Polish investigators led by JS and GO. The back-translation was completed by colleagues fluent in both languages (Polish and English) who were not involved in the original translation, and was reviewed by members of the MDS Rating Scales Programme. Then the translated version of the MDS-UPDRS underwent cognitive pretesting, and the translation was modified based on the results. The final translation was approved as the Official Working Document of the MDS-UPDRS Polish version, and was tested on 355 Polish PD patients recruited at movement disorders centres all over Poland (at Katowice, Gdansk, Lódz, Warsaw, Wroclaw, and Kraków). Confirmatory and explanatory factor analyses were applied to determine whether the factor structure of the English version could be confirmed in the Polish version. RESULTS: The Polish version of the MDS-UPDRS showed satisfactory clinimetric properties. The internal consistency of the Polish version was satisfactory. In the confirmatory factor analysis, all four parts had greater than 0.90 comparative fit index (CFI) compared to the original English MDS-UPDRS. Explanatory factor analysis suggested that the Polish version differed from the English version only within an acceptable range. CONCLUSIONS AND CLINICAL IMPLICATIONS: The Polish version of the MDS-UPDRS meets the requirements to be designated as the Official Polish Version of the MDS-UPDRS, and is available on the MDS web page. We strongly recommend using the MDS-UPDRS instead of the UPDRS for research purposes and in everyday clinical practice.

Transitional Locomotor Tasks in People With Mild to Moderate Parkinson's Disease.

Background: People with Parkinson's disease (PD) exhibit deficits in maintaining balance both during quiet standing and during walking, turning, standing up from sitting, and step initiation. Objective: The purpose of this study was to examine balance disorders during a transitional task under different conditions in participants with PD. Methods: The research was conducted on 15 PD-II (mild) and 15 PD-III (moderate) individuals (H&Y II-III stage) and 30 healthy elderly. The transitional task was measured on two force platforms (A and B). The procedure consisted of three phases: (1) quiet standing on platform A, (2) crossing to platform B, and (3) quiet standing on platform B, each until measurements were completed. There were four conditions: crossing without an obstacle, crossing with an obstacle, and walking up and down the step. Results: There were no significant differences between mild PD individuals and healthy elderly during quiet standing before the transitional task and after completing the task. The temporal aspects describing the different transitional tasks were comparable between mild PD and healthy subjects. Moderate PD participants presented a significantly higher COP velocity after the transitional task compared to the healthy older adults (p < 0.05). Additionally, the moderate PD group showed significantly higher values for transit time relative to healthy subjects during the transitional task in all conditions (p < 0.05). Conclusions: Disease severity affects the temporal aspects of different transitional tasks in people with PD. The procedure of completing a transitional task under different conditions allowed differences between moderate and mild PD stages and healthy subjects to be observed.

Clinical phenotype heterogeneity in a family with ε-sarcoglycan gene mutation.

AIM OF THE STUDY: This paper describes six cases of patients with myoclonus-dystonia syndrome who are members of a family in which an SGCE gene mutation has been confirmed. CLINICAL RATIONALE FOR THE STUDY: Myoclonus-dystonia syndrome is a very rare disease, with an incidence in Europe of about 2 in every million. Due to the fact that only a few case reports of this illness are accessible in the literature, the material we collected seems to be valuable for clinical practice. MATERIALS AND METHODS: A history was taken, and physical and genetic examinations of the patients were performed. Furthermore, the clinical examination of three patients was video-recorded. RESULTS: The clinical picture of the disease varied significantly between the described individuals, from a healthy carrier of the SGCE mutation to patients presenting mild to moderate symptoms. The differences concerned the age at onset of the disease, the initial symptoms, the intensity of involuntary movements, and the predominant symptoms. In addition to the typical movement disorders which are myoclonus and dystonia, in the described family there was also the coexistence of epilepsy, obsessive-compulsive behaviour, dyslexia, dysgraphia, non-harmonious development of cognitive processes, as well as mild phenotypic features of muscular dystrophy. The mutation (NM_001099401.2:c.806-809delACTG) found in the presented family has not been described elsewhere. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our description of six cases of patients demonstrates the heterogeneity of the natural course of the disease, even in patients with the same mutation. It seems reasonable to regularly examine relatives of patients with myoclonus-dystonia syndrome, who should be observed for involuntary movements as well as non-motor symptoms.

Posterior Subthalamic Area Deep Brain Stimulation for Treatment of Refractory Holmes Tremor.

Three right-handed patients diagnosed with Holmes tremor (HT), who suffered from pharmacotherapy-refractory tremor, were eligible for unilateral posterior subthalamic area deep brain stimulation (PSA-DBS). All patients were evaluated with the Fahn-Tolosa-Marin Tremor Rating Scale (FTMTRS) and Clinical Global Impression scale (CGI) before DBS, 6, and 12 months after the PSA-DBS as well as at the last follow-up. In all patients, we observed a significant improvement of tremor control as demonstrated by changes in the FTMTRS and the CGI scales. Mean improvement of tremor in all patients was 56% for the FTMRTS with a corresponding change in the CGI scale. Our study demonstrates that PSA-DBS is efficacious in the treatment of HT. Indeed, PSA is a promising target for DBS for intractable proximal and distal tremor, even in cases of previous, suboptimal functional neurosurgery. The beneficial effect lasts over a long-term follow-up. PSA-DBS may be considered as an alternative target of DBS in tremor treatment.

[Sleep disorders in Parkinson's disease].

Sleep disorder are common non-motor symptoms in Parkinson`s disease (PD). They can be found in different sleep stages or appear during the daytime. They correlate with faster progression of motor problems and lower quality of a patient's life. Sleep physiology, different sleep dysfunction such as: RBD-REM sleep behavior disorder, EDS - excessive daytime sleepiness, insomnia, OSAS-obstructive sleep apnea syndrome, and their clinical manifestation have been presented in this review. Diagnostic and therapy possibilities have been summarized as well. Particular attention has also been paid to the coexistence of various non-motor symptoms such as pain, depression or nocturia, and their correlations with sleeping problems.

A study in a Polish ataxia cohort indicates genetic heterogeneity and points to MTCL1 as a novel candidate gene.

Inherited ataxias are a group of highly heterogeneous, complex neurological disorders representing a significant diagnostic challenge in clinical practice. We performed a next-generation sequencing (NGS) analysis in 10 index cases with unexplained progressive cerebellar ataxia of suspected autosomal recessive inheritance. A definite molecular diagnosis was obtained in 5/10 families and included the following diseases: autosomal recessive spastic ataxia of Charlevoix-Saguenay, POLR3B-related hypomyelinating leukodystrophy, primary coenzyme Q10 deficiency type 4, Niemann-Pick disease type C1 and SYNE1-related ataxia. In addition, we found a novel homozygous MTCL1 loss of function variant p.(Lys407fs) in a 23-year-old patient with slowly progressive cerebellar ataxia, mild intellectual disability, seizures in childhood and episodic pain in the lower limbs. The identified variant is predicted to truncate the protein after first 444 of 1586 amino acids. MTCL1 encodes a microtubule-associated protein highly expressed in cerebellar Purkinje cells; its knockout in a mouse model causes ataxia. We propose MTCL1 as a candidate gene for autosomal recessive cerebellar ataxia in humans. In addition, our study confirms the high diagnostic yield of NGS in early-onset cerebellar ataxias, with at least 50% detection rate in our ataxia cohort.

Whole-exome sequencing for variant discovery in blepharospasm.

BACKGROUND: Blepharospasm (BSP) is a type of focal dystonia characterized by involuntary orbicularis oculi spasms that are usually bilateral, synchronous, and symmetrical. Despite strong evidence for genetic contributions to BSP, progress in the field has been constrained by small cohorts, incomplete penetrance, and late age of onset. Although several genetic etiologies for dystonia have been identified through whole-exome sequencing (WES), none of these are characteristically associated with BSP as a singular or predominant manifestation. METHODS: We performed WES on 31 subjects from 21 independent pedigrees with BSP. The strongest candidate sequence variants derived from in silico analyses were confirmed with bidirectional Sanger sequencing and subjected to cosegregation analysis. RESULTS: Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17, TRPV4, CAPN11, VPS13C, UNC13B, SPTBN4, MYOD1, and MRPL15 were found in two or more independent pedigrees. To our knowledge, none of these genes have previously been associated with isolated BSP, although other CACNA1A mutations have been associated with both positive and negative motor disorders including ataxia, episodic ataxia, hemiplegic migraine, and dystonia. CONCLUSIONS: Our WES datasets provide a platform for future studies of BSP genetics which will demand careful consideration of incomplete penetrance, pleiotropy, population stratification, and oligogenic inheritance patterns.