Whole exome sequencing in Serbian patients with hereditary spastic paraplegia.

Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases with a high genetic and clinical heterogeneity. Numerous HSP patients remain genetically undiagnosed despite screening for known genetic causes of HSP. Therefore, identification of novel variants and genes is needed. Our previous study analyzed 74 adult Serbian HSP patients from 65 families using panel of the 13 most common HSP genes in combination with a copy number variation analysis. Conclusive genetic findings were established in 23 patients from 19 families (29%). In the present study, nine patients from nine families previously negative on the HSP gene panel were selected for the whole exome sequencing (WES). Further, 44 newly diagnosed adult HSP patients from 44 families were sent to WES directly, since many studies showed WES may be used as the first step in HSP diagnosis. WES analysis of cohort 1 revealed a likely genetic cause in five (56%) of nine HSP families, including variants in the ETHE1, ZFYVE26, RNF170, CAPN1, and WASHC5 genes. In cohort 2, possible causative variants were found in seven (16%) of 44 patients (later updated to 27% when other diagnosis were excluded), comprising six different genes: SPAST, SPG11, WASCH5, KIF1A, KIF5A, and ABCD1. These results expand the genetic spectrum of HSP patients in Serbia and the region with implications for molecular genetic diagnosis and future causative therapies. Wide HSP panel can be the first step in diagnosis, alongside with the copy number variation (CNV) analysis, while WES should be performed after.

ANO10-Related Spinocerebellar Ataxia: MDSGene Systematic Literature Review and a Romani Case Series.

BACKGROUND: Biallelic pathogenic variants in the ANO10 gene cause autosomal recessive progressive ataxia (ATX-ANO10). METHODS: Following the MDSGene protocol, we systematically investigated genotype-phenotype relationships in ATX-ANO10 based on the clinical and genetic data from 82 published and 12 newly identified patients. RESULTS: Most patients (>80%) had loss-of-function (LOF) variants. The most common variant was c.1150_1151del, found in all 29 patients of Romani ancestry, who had a 14-year earlier mean age at onset than patients homozygous for other LOF variants. We identified previously undescribed clinical features of ATX-ANO10 (e.g., facial muscle involvement and strabismus) suggesting the involvement of brainstem pathology, and we propose a diagnostic algorithm that may aid clinical ATX-ANO10 diagnosis. CONCLUSIONS: The early disease onset in patients with c.1150_1151del may indicate the existence of genetic/environmental disease-modifying factors in the Romani population. Our findings will inform patient counseling and may improve our understanding of the disease mechanism. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Adherence to Medication among Parkinson's Disease Patients Using the Adherence to Refills and Medications Scale.

Objectives: Adherence to medication is an important factor that can influence Parkinson's disease (PD) control. We aimed to explore patients' adherence to antiparkinsonian medication and determine factors that might affect adherence to medications among PD patients. Methods: A cross-sectional, exploratory survey of PD patients treated with at least one antiparkinsonian drug and with a total score of MoCA (Montreal Cognitive Assessment) ≥26 was conducted. The final sample included 112 PD patients. A patient's adherence was assessed through ARMS (Adherence to Refills and Medications Scale). ARMS scores higher than 12 were assumed lower adherence. In addition, each patient underwent neurological examination, assessment of depression, anxiety, and evaluation of the presence of PD nonmotor symptoms. Results: The mean ARDS value in our cohort was 14.9 ± 2.5. Most PD patients (74.1%) reported lower adherence to their medication. Participants in the lower adherence group were younger at PD onset, had significantly higher UPDRS (Unified PD Rating Scale) scores, as well as UPDRS III and UPDRS IV subscores, HARS (Hamilton Anxiety Rating Scale), and NMSQuest (Non-Motor Symptoms Questionnaire for PD) scores compared to the fully adherent group (p=0.013, p=0.017, p=0.041, p=0.043, and p=0.023, respectively). Among nonmotor PD symptoms, the presence of cardiovascular, apathy/attention-deficit/memory disorders, hallucinations/delusions, and problems regarding changes in weight, diplopia, or sweating were associated with lower adherence. Multivariate regression analysis revealed depression as the strongest independent predictor of lower adherence. Conclusion: Depressed PD patients compared to PD patients without clinical depression had a three times higher risk for lower adherence to pharmacotherapy. Recognition and adequate treatment of depression might result in improved adherence.

Brain Structural Changes in Focal Dystonia-What About Task Specificity? A Multimodal MRI Study.

BACKGROUND: The neural basis of task specificity in dystonia is still poorly understood. This study investigated gray and white matter (WM) brain alterations in patients with task-specific dystonia (TSD) and non-task-specific dystonia (NTSD). METHODS: Thirty-six patients with TSD (spasmodic dysphonia, writer's cramp), 61 patients with NTSD (blepharospasm, cervical dystonia), and 83 healthy controls underwent 3D T1-weighted and diffusion tensor magnetic resonance imaging (MRI). Whole brain cortical thickness and voxel-based morphometry; volumes of basal ganglia, thalamus, nucleus accumbens, amygdala, and hippocampus; and WM damage were assessed. Analysis of variance models were used to compare MRI measures between groups, adjusting for age and botulinum toxin (BoNT) treatment. RESULTS: The comparison between focal dystonia patients showed cortical thickness and gray matter (GM) volume differences (ie, decreased in NTSD, increased in TSD) in frontal, parietal, temporal, and occipital cortical regions; basal ganglia; thalamus; hippocampus; and amygdala. Cerebellar atrophy was found in NTSD patients relative to controls. WM damage was more severe and widespread in task-specific relative to NTSD patients. TSD patients receiving BoNT, relative to nontreated patients, had cortical thickening and increased GM volume in frontoparietal, temporal, and occipital regions. NTSD patients experiencing pain showed cortical thickening of areas involved in pain-inhibitory mechanisms. CONCLUSIONS: TSD and NTSD are characterized by opposite alterations of the main cortical and subcortical sensorimotor and cognitive-controlling brain structures, suggesting the possible presence of different pathophysiological and/or compensatory mechanisms underlying the complexity of the two clinical phenotypes of focal dystonia. © 2020 International Parkinson and Movement Disorder Society.

The Profile and Evolution of Neuropsychiatric Symptoms in Multiple System Atrophy: Self- and Caregiver Report.

OBJECTIVE: Recent research shows that patients with multiple system atrophy (MSA) have significant cognitive and neuropsychiatric comorbidities that can color the clinical presentation of the disease and affect their quality of life. The aims of this study were to determine the neuropsychiatric profile in a cohort of patients with the parkinsonian type of MSA (MSA-P) and their dynamic changes over a 1-year follow-up period and to compare rates of neuropsychiatric symptoms (NPSs) reported by caregivers and the patients themselves. METHODS: Forty-seven patients were assessed at baseline; of these, 25 were assessed again after 1 year. NPS assessment tools included the Neuropsychiatric Inventory (NPI), the Beck Depression Inventory, the Hamilton Depression Rating Scale, the Hamilton Anxiety Rating Scale, and the Apathy Evaluation Scale. RESULTS: The prevalence of NPSs in patients with MSA-P was very high, with depression, sleep disturbances, apathy, and anxiety being the most frequently occurring features. The evolution of NPSs was found to be independent of motor, autonomic, and cognitive symptoms. None of the scales measuring NPSs, including the NPI, were capable of detecting changes over the 1-year follow-up period. Although the overall prevalence of depression, apathy, and anxiety obtained from caregivers and the patients themselves was similar, reports from these two sources cannot be considered interchangeable. CONCLUSIONS: The progression of neuropsychiatric symptoms was not a subject of rapid change in MSA-P, in contrast to the observed motor, autonomic, and cognitive deterioration. These findings suggest the need to investigate the utility of available instruments in capturing the evolution of NPSs in MSA over time.

Optical coherence tomography in patients with Wilson's disease.

OBJECTIVES: Wilson disease (WD) is an autosomal recessive disorder that leads to copper accumulation and deposition in different organs, frequently affecting visual pathways. Recent studies have detected morphological changes of the retina in patients with WD using optical coherence tomography (OCT). Measuring the thickness of the retinal nerve fibre layer (RNFL) with OCT provides an objective assessment of integrity and morphological abnormalities of the retina. The aim of this study was to evaluate the relationship between OCT parameters and form of the disease, therapy and symptoms duration, as well as severity of neurological impairment. METHODS: The study comprised of 52 patients with WD and 52 healthy controls (HC). All the patients were on a regular and stable chelation therapy and/or zinc salts. Patients were divided into two groups, with neurological (NWD) or hepatic form of the disease (HWD). OCT was performed to assess the RNFL thickness. RESULTS: The WD patients had significantly lower intraocular pressure in both eyes and lower RNFL thickness than the HC. There were no differences between NWD and HWD in any of the ophthalmologically tested parameters. No significant correlations were found between clinical features and retinal thickness parameters. Stratification of the cohort according to the disease duration showed that disease duration did not influence the RNFL thickness. CONCLUSION: We found that involvement of the retina represented a subclinical finding in neurologically intact patients in the HWD group. Nevertheless, the value of OCT as a biomarker for the assessment of the clinical course and progression of WD still remains uncertain.

Breakdown of the affective-cognitive network in functional dystonia.

Previous studies suggested that brain regions subtending affective-cognitive processes can be implicated in the pathophysiology of functional dystonia (FD). In this study, the role of the affective-cognitive network was explored in two phenotypes of FD: fixed (FixFD) and mobile dystonia (MobFD). We hypothesized that each of these phenotypes would show peculiar functional connectivity (FC) alterations in line with their divergent disease clinical expressions. Resting state fMRI (RS-fMRI) was obtained in 40 FD patients (12 FixFD; 28 MobFD) and 43 controls (14 young FixFD-age-matched [yHC]; 29 old MobFD-age-matched [oHC]). FC of brain regions of interest, known to be involved in affective-cognitive processes, and independent component analysis of RS-fMRI data to explore brain networks were employed. Compared to HC, all FD patients showed reduced FC between the majority of affective-cognitive seeds of interest and the fronto-subcortical and limbic circuits; enhanced FC between the right affective-cognitive part of the cerebellum and the bilateral associative parietal cortex; enhanced FC of the bilateral amygdala with the subcortical and posterior cortical brain regions; and altered FC between the left medial dorsal nucleus and the sensorimotor and associative brain regions (enhanced in MobFD and reduced in FixFD). Compared with yHC and MobFD patients, FixFD patients had an extensive pattern of reduced FC within the cerebellar network, and between the majority of affective-cognitive seeds of interest and the sensorimotor and high-order function ("cognitive") areas with a unique involvement of dorsal anterior cingulate cortex connectivity. Brain FC within the affective-cognitive network is altered in FD and presented specific features associated with each FD phenotype, suggesting an interaction between brain connectivity and clinical expression of the disease.

Change in fear of falling in Parkinson's disease: a two-year prospective cohort study.

ABSTRACTBackground:Fear of falling in Parkinson's disease (PD) has been suggested as predictor of future falling. The purpose of this study was to compare fear of falling score after two years of follow-up with those observed at baseline and to assess factors associated with change in fear of falling over time. METHODS: A total of 120 consecutive persons with PD were recruited and followed for two years. Fear of falling was assessed by using the 10-item Falls Efficacy Scale (FES). Occurrence of falling was registered during the first year of follow-up. RESULTS: After two years, the average FES score statistically significantly changed (p = 0.003) from 30.5 to 37.5 out of 100 (increase of 22.9%). We observed that median scores of all FES items, except for "Preparing a meal, not requiring carrying of heavy or hot objects" and "Personal grooming," significantly increased after two-year follow-up. After accounting for age, gender, PD duration, levodopa dosage, Hoehn and Yayhr stage, Unified Parkinson's Disease Rating Scale score three, depression, anxiety, and falling, we observed that sustaining greater number of falls in the first year of follow-up was associated with higher increase in FES score after two years (odds ratio 3.08, 95% confidence interval 1.30-4.87). CONCLUSION: After two years of follow-up, we observed a decrease in confidence at performing nearly all basic daily activities. Fall prevention programs should be prioritized in management of PD.

Quantitative Assessment of Head Tremor in Patients with Essential Tremor and Cervical Dystonia by Using Inertial Sensors.

Tremor is most common among the movement disabilities that affect older people, having a prevalence rate of 4.6% in the population older than 65 years. Despite this, distinguishing different types of tremors is clinically challenging, often leading to misdiagnosis. However, due to advances in microelectronics and wireless communication, it is now possible to easily monitor tremor in hospitals and even in home environments. In this paper, we propose an architecture of a system for remote health-care and one possible implementation of such system focused on head tremor monitoring. In particular, the aim of the study presented here was to test new tools for differentiating essential tremor from dystonic tremor. To that aim, we propose a number of temporal and spectral features that are calculated from measured gyroscope signals, and identify those that provide optimal differentiation between two groups. The mean signal amplitude feature results in sensitivity = 0.8537 and specificity = 0.8039 in distinguishing patients having cervical dystonia with or without tremor. In addition, mean signal amplitude was shown to be significantly higher in patients with essential tremor than in patients with cervical dystonia, whereas the mean peak frequency is not different between two groups.

Use of the Neuropsychiatric Inventory to Characterize the Course of Neuropsychiatric Symptoms in Progressive Supranuclear Palsy.

The aim of this study was to determine the neuropsychiatric profile in a cohort of progressive supranucelar palsy (PSP) patients and their dynamic changes over a follow-up period of 1 year. A total of 59 patients were assessed at baseline, while 25 of them were accessible after 1 year of the follow-up. The most common symptoms were apathy and depression, which were also found to be, among other variables, the independent determinants of increased Neuropsychiatric Inventory (NPI) total score. Moreover, apathy deteriorated most profoundly over the follow-up period. The NPI seemed to be a sensitive measure of behavioral changes in PSP.

Dynamics of change in self-reported disability among persons with Parkinson's disease after 2 years of follow-up.

Symptoms of Parkinson's disease (PD) progress over time causing significant disability. Yet, change in disability over shorter time periods has not been entirely understood. The purpose of this study was to assess the Self-Assessment Disability Scale (SADS) in persons with Parkinson's disease (PD) after 2 years of follow-up and compare it with the score observed at baseline. Additionally, we aimed at evaluating association of motor and non-motor PD features at baseline with a higher disability after 2 years of follow-up. A total of 120 consecutive persons with PD, who denied falling in the past 6 months, were initially recruited. After 2 years of follow-up, 88 (73.3%) persons with PD were evaluated for SADS. The total disability (SADS) score did not change after follow-up (p = 0.529). We observed increase in difficulty at "Getting out of bed" (p = 0.006), "Getting up out of armchair" (p = 0.013), "Walking about house/flat" (p = 0.003), "Walking outside" (p = 0.010), and "Traveling by public transport" (p = 0.014). After adjusting for several potential confounding factors, falls in the past year (ß = 8.32, 95% confidence interval (CI) 1.04-15.59) and higher Unified Parkinson's Disease Rating Scale part 3 at baseline (ß = 0.26, 95%CI 0.01-0.51) remained associated with higher PD-related disability. This finding suggests that accumulation of overall PD-related disability tends to occur over a longer time span. Further studies are needed to gradually assess long-term evolution of disability in PD.

Psychiatric Symptoms in the Initial Motor Stage of Parkinson's Disease.

Neuropsychiatric symptoms (NPS) are common in Parkinson's disease (PD). The aim of this study was to estimate the correlates of NPS in patients with PD in the initial motor stage of the disease (hemiparkinsonism). A total of 111 patients with PD and 105 healthy control participants were assessed. Patients with PD experienced apathy, depression, and anxiety more frequently compared with healthy controls. Sleep disturbances occurred commonly in early PD patients. Patients with PD and mild cognitive impairment (MCI) had depression and anxiety more frequently, but not apathy, compared with patients with PD without MCI. The results of this study confirm a high burden of NPS even in the earliest motor stage of PD.

Indoor and outdoor falls in persons with Parkinson's disease after 1 year follow-up study: differences and consequences.

Falls among persons with Parkinson's disease (PD) often result in activity limitations, participation restrictions, social isolation or premature mortality. The purpose of this 1-year follow-up study was to compare potential differences in features of PD attributing to falls in relation to fall location (outdoor vs. indoor). We recruited 120 consecutive persons with PD who denied having fallen in the past 6 months. Disease stage and severity was assessed using the Hoehn and Yahr scale and the newer version of the Unified Parkinson's Disease Rating Scale. Occurrence of falling and characteristics of falls was followed for 1 year. Results were assessed statistically. Outdoor falls were more commonly preceded by the extrinsic factors (tripping and slipping). Slipping was more common outdoors (p = 0.001). Indoor falls were mostly preceded by the intrinsic factors (postural instability, lower extremity weakness, vertigo). Vertigo was more common indoors (p = 0.006). Occurrence of injuries was more common after outdoor falls (p = 0.001). Indoor falls resulted in contusions only, while outdoor falls resulted in lacerations and fractures as well. In the regression model adjusted for age, disease duration, on/off phase during fall, Hoehn and Yahr stage of disease and levodopa dosage, slipping was associated with outdoor falling (odds ratio = 17.25, 95 % confidence interval 3.33-89.20, p = 0.001). These findings could be used to tailor fall prevention program with emphasis on balance recovery and negotiation of objects in environment.

Health-related quality of life as a predictor of recurrent falling in Parkinson's disease: 1-year follow-up study.

OBJECTIVE: The aim of this study was to assess whether various domains related to health-related quality of life could be predictive of recurrent falls among persons with Parkinson's disease (PD) during a 1-year follow-up study. METHODS: A total of 120 consecutive persons with PD who had denied falling in past 6 months were recruited at regular check-ups at the Department of Movement Disorders, Neurology Clinic, Clinical Center of Serbia in Belgrade, from 15 August 2011 to 15 December 2012. At baseline, study participants were clinically assessed. Health-related quality of life was evaluated with the generic 36-item Short Form Health Survey. Participants were prospectively followed for 1 year, and occurrence of falls was registered. RESULTS: The median age of subjects was 60.0 years, with a median disease duration of 4.0 years. Of 120 persons with PD, 42 (35%) experienced falls during the 12-month study period, including 23 (19.2%) who fell repeatedly. After adjustment for gender, age, PD duration, levodopa dosage, Hoehn and Yahr stage, Unified Parkinson's Disease Rating Scale I-IV, Hamilton Depression Rating Scale, and Hamilton Anxiety Rating Scales, we identified the 36-item Short Form Health Survey domains of role physical (P = 0.033) and vitality (P = 0.019) as being associated with recurrent falls of persons with PD within the 1-year follow-up period. CONCLUSION: Baseline 36-item Short Form Health Survey scores regarding both the physical and mental components of overall health may be related to recurrent falling among persons with PD. These HRQoL domains could be considered as potential markers for persons with PD who are prone to recurrent falls.

Quality of life in patients with primary restless leg syndrome: community-based study.

Restless leg syndrome (RLS) is frequently associated with poor mental health and impaired quality of life (QoL), due to discomfort, pain, fatigue, inability to rest, sleep disturbances, and consequently, anxiety and depression. The aim of this study is to address this issue in a community-based cohort of patients with RLS. The present study is a sub-analysis of the community-based prevalence study. In this door-to-door survey, we identified according to four essential IRLSSG diagnostic criteria 107 people with RLS. Clinical characteristics of RLS, including QoL, were obtained from 94 subjects (88 %), who completed the Serbian translation of SF-36. The main finding of our study was that the severity of RLS, in particular frequency of symptoms, negatively influenced majority of the SF-36 domains. The severity of depressive and anxiety symptoms was negatively associated with all domains of SF-36. Age of participants significantly correlated with both physical and mental composite scores. In multivariate linear regression model, higher scores of Hamilton depression (p = 0.001) and anxiety (p = 0.003) Rating scales were the most significant negative contributors of the total SF-36 score in persons with RLS. Suggesting particular role of comorbid depression and anxiety, our results may have a practical implication in terms of different psychosocial treatment and support in addition to the regular therapeutic protocols in RLS patients.

De novo mutation in the GNAL gene causing seemingly sporadic dystonia in a Serbian patient.

BACKGROUND: Mutations in GNAL (DYT25) have recently been established as the first confirmed cause of focal or segmental adult-onset dystonia. Mutation carriers show craniocervical involvement; however, the GNAL mutational and phenotypic spectrum remain to be further characterized, and guidelines for diagnostic testing need to be established. METHODS: The authors used Sanger sequencing to test for changes in the GNAL coding or splice-site regions in 236 Serbian patients suffering from isolated dystonia with craniocervical involvement. RESULTS: One novel likely pathogenic substitution (c.1061T>C; p.Val354Ala) in GNAL was detected in a sporadic cervical dystonia patient (mutation frequency: 0.4%). This mutation was not present in the DNA of either parent, despite confirmed parentage. CONCLUSIONS: This is the first report of a de novo GNAL mutation causing genetically proven, seemingly sporadic DYT25 dystonia. Our finding highlights the importance of genetic testing for GNAL mutations in establishing the molecular diagnosis even for patients with a negative family history.

Genome-wide association study in musician's dystonia: a risk variant at the arylsulfatase G locus?

Musician's dystonia (MD) affects 1% to 2% of professional musicians and frequently terminates performance careers. It is characterized by loss of voluntary motor control when playing the instrument. Little is known about genetic risk factors, although MD or writer's dystonia (WD) occurs in relatives of 20% of MD patients. We conducted a 2-stage genome-wide association study in whites. Genotypes at 557,620 single-nucleotide polymorphisms (SNPs) passed stringent quality control for 127 patients and 984 controls. Ten SNPs revealed P < 10(-5) and entered the replication phase including 116 MD patients and 125 healthy musicians. A genome-wide significant SNP (P < 5 × 10(-8) ) was also genotyped in 208 German or Dutch WD patients, 1,969 Caucasian, Spanish, and Japanese patients with other forms of focal or segmental dystonia as well as in 2,233 ethnically matched controls. Genome-wide significance with MD was observed for an intronic variant in the arylsulfatase G (ARSG) gene (rs11655081; P = 3.95 × 10(-9) ; odds ratio [OR], 4.33; 95% confidence interval [CI], 2.66-7.05). rs11655081 was also associated with WD (P = 2.78 × 10(-2) ) but not with any other focal or segmental dystonia. The allele frequency of rs11655081 varies substantially between different populations. The population stratification in our sample was modest (λ = 1.07), but the effect size may be overestimated. Using a small but homogenous patient sample, we provide data for a possible association of ARSG with MD. The variant may also contribute to the risk of WD, a form of dystonia that is often found in relatives of MD patients.

Circumstances of falls and fall-related injuries among patients with Parkinson's disease in an outpatient setting.

Falls represent continuing, disabling and costly problem in Parkinson's disease (PD). The study was carried out at the Neurology Clinic in Belgrade from August 2011 to December 2012. As many as 180 community dwelling persons with PD aged 22-83 years who sustained a fall in past 6 months were included. Characteristics of the most recent fall were obtained through detailed interviews. Inclusion criteria were: Mini Mental State Examination (MMSE)≥24, ability to walk independently for at least 10 m and ability to statically stand for at least 90 s. Exclusion criteria were: presence of other neurologic as well as psychiatric, visual, audio-vestibular and orthopedic impairments. Falls more frequently took place outside (57.2%) and in the morning (53.9%). As much as 38.9% of persons with PD sustained an injury. Soft-tissue contusion was the most common injury (71.8%) both after indoor and outdoor falls. Fractures accounted for 5% of all fall-related injuries. All the fractures were either arm, clavicle or rib fractures. Tripping was identified as risk factor for outdoor falls (OR=7.90; 95% confidence interval [95% CI] 3.21-19.39; p=0.001). In contrast, lower extremity weakness (OR=0.20; 95% CI 0.05-0.72; p=0.015) and internal sense of sudden loss of balance (OR=0.19; 95% CI 0.05-0.73; p=0.015) were risk factors for indoor falls. To accomplish long-term results, development of particular prevention programs for persons with PD who fall at home vs. outdoors is recommended.