Care of Late-Stage Parkinsonism: Resource Utilization of the Disease in Five European Countries.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease that leads to progressive disability. Cost studies have mainly explored the early stages of the disease, whereas late-stage patients are underrepresented. OBJECTIVE: The aim is to evaluate the resource utilization and costs of PD management in people with late-stage disease. METHODS: The Care of Late-Stage Parkinsonism (CLaSP) study collected economic data from patients with late-stage PD and their caregivers in five European countries (France, Germany, the Netherlands, UK, Sweden) in a range of different settings. Patients were eligible to be included if they were in Hoehn and Yahr stage >3 in the on state or Schwab and England stage at 50% or less. In total, 592 patients met the inclusion criteria and provided information on their resource utilization. Costs were calculated from a societal perspective for a 3-month period. A least absolute shrinkage and selection operator approach was utilized to identify the most influential independent variables for explaining and predicting costs. RESULTS: During the 3-month period, the costs were €20,573 (France), €19,959 (Germany), €18,319 (the Netherlands), €25,649 (Sweden), and €12,156 (UK). The main contributors across sites were formal care, hospitalization, and informal care. Gender, age, duration of the disease, Unified Parkinson's Disease Rating Scale 2, the EQ-5D-3L, and the Schwab and England Scale were identified as predictors of costs. CONCLUSION: Costs in this cohort of individuals with late-stage PD were substantially higher compared to previously published data on individuals living in earlier stages of the disease. Resource utilization in the individual sites differed in part considerably among these three parameters mentioned. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Clinically approved immunomodulators ameliorate behavioral changes in a mouse model of hereditary spastic paraplegia type 11.

We have previously demonstrated that neuroinflammation by the adaptive immune system acts as a robust and targetable disease amplifier in a mouse model of Spastic Paraplegia, type 11 (SPG11), a complicated form of Hereditary Spastic Paraplegia (HSP). While we identified an impact of neuroinflammation on distinct neuropathological changes and gait performance, neuropsychological features, typical and clinically highly relevant symptoms of complicated HSPs, were not addressed. Here we show that the corresponding SPG11 mouse model shows distinct behavioral abnormalities, particularly related to social behavior thus partially reflecting the neuropsychological changes in patients. We provide evidence that some behavioral abnormalities can be mitigated by genetic inactivation of the adaptive immune system. Translating this into a clinically applicable approach, we show that treatment with the established immunomodulators fingolimod or teriflunomide significantly attenuates distinct behavioral abnormalities, with the most striking effect on social behavior. This study links neuroinflammation to behavioral abnormalities in a mouse model of SPG11 and may thus pave the way for using immunomodulators as a treatment approach for SPG11 and possibly other complicated forms of HSP with neuropsychological involvement.

Development and validation of TreatHSP-QoL: a patient-reported outcome measure for health-related quality of life in hereditary spastic paraplegia.

BACKGROUND: Hereditary spastic paraplegia (HSP) is a rare neurodegenerative disease that lacks specific and validated patient-centered outcome measures (PCOMs). We aimed to develop and validate a health-related quality of life (HRQoL) questionnaire specific to HSP ("TreatHSP-QoL") that could be used as a PCOM. RESULTS: The pilot-items of the TreatHSP-QoL (45 five-level Likert scale items, with values per item between 0 and 4) were developed based on a qualitative data analysis of 54 semi-structured interviews, conducted in person with 36 HSP patients and 18 caregivers. It was then reduced and modified through the validation process to 25 items. The main validation was performed using the online questionnaire in 242 HSP patients and 56 caregivers. The exploratory factor analysis defined five subdomains. Cronbach's alpha ranged from 0.57 to 0.85 for the subdomains and reached 0.85 for the total score. The test-retest Pearson correlation reached 0.86 (95% Confidence Interval (CI) [0.79, 0.91]). Pearson correlations with the EuroQol-5 Dimension (5 levels) (EQ-5D-5L) and Friedreich Ataxia Rating Scale-Activities of Daily Living (FARS-ADL) questionnaires varied strongly among the subdomains, with the total scores reaching 0.53 (95% CI [0.42, 0.61]) and -0.45 (95% CI [- 0.55, - 0.35]), respectively. The caregiver-patient response Pearson correlation ranged between 0.64 and 0.82 for subdomains and reached 0.65 (95% CI [0.38, 0.81]) for the total score. CONCLUSIONS: TreatHSP-QoL can be used in high-quality clinical trials and clinical practice as a disease-specific PCOM (i.e., HRQoL measure) and is also applicable as a proxy questionnaire. Score values between 0 and 100 can be reached, where higher value represents better HRQoL. The Pearson correlations to the EQ-5D-5L and FARS-ADL support the additional value and need of HSP-specific PCOM, while non-specific QoL-assessment and specific clinical self-assessment tools already exist. All in all, the results demonstrate good validity and reliability for this new patient-centered questionnaire for HSP.

Expanding the phenotypic spectrum of CLCN2-related leucoencephalopathy and ataxia.

Mutations in CLCN2 are a rare cause of autosomal recessive leucoencephalopathy with ataxia and specific imaging abnormalities. Very few cases have been reported to date. Here, we describe the clinical and imaging phenotype of 12 additional CLCN2 patients and expand the known phenotypic spectrum of this disorder. Informed consent was obtained for all patients. Patients underwent either whole-exome sequencing or focused/panel-based sequencing to identify variants. Twelve patients with biallelic CLCN2 variants are described. This includes three novel likely pathogenic missense variants. All patients demonstrated typical MRI changes, including hyperintensity on T2-weighted images in the posterior limbs of the internal capsules, midbrain cerebral peduncles, middle cerebellar peduncles and cerebral white matter. Clinical features included a variable combination of ataxia, headache, spasticity, seizures and other symptoms with a broad range of age of onset. This report is now the largest case series of patients with CLCN2-related leucoencephalopathy and reinforces the finding that, although the imaging appearance is uniform, the phenotypic expression of this disorder is highly heterogeneous. Our findings expand the phenotypic spectrum of CLCN2-related leucoencephalopathy by adding prominent seizures, severe spastic paraplegia and developmental delay.

[Improvement of the treatment of patients with spastic movement disorder after stroke]. / Verbesserung der Versorgung von Patientinnen und Patienten mit spastischer Bewegungsstörung nach Schlaganfall.

BACKGROUND: Spastic movement disorder (SMD) develops in up to 43% of cases as a sequela of stroke. In the event of a functionally relevant or daily life impairing SMD or to avoid an impending complication, the medicinal treatment of a focal, multifocal and segmental increase in muscle tone with botulinum neurotoxin A (BoNT-A) is recommended; however, treatment data reveal a lack of guideline-conform treatment with BoNT­A in Germany. OBJECTIVE: The aim of the reported expert meeting was to discuss solutions to the incorrect treatment and undertreatment of patients with SMD and to formulate consensus recommendations to improve the care situation. METHODS: At a consensus meeting held in April 2022, eight experts from the fields of neurology, physical medicine and rehabilitation discussed the causes for the incorrect treatment and undertreatment and formulated consensus solution approaches. RESULTS: Possible reasons for the current incorrect treatment and undertreatment in SMD management in Germany include insufficient awareness of SMD among physicians, a lack of treatment capacities, a lack of information transfer in discharge management as well as staff shortages in the specialized inpatient and outpatient SMD treatment centers. The committee therefore recommended a patient pathway in which affected patients with SMD are provided with correctly implemented BoNT­A treatment in combination with physical measures. CONCLUSION: The recommended treatment pathway for use in stroke patients is intended to close gaps in care and thus ensure guideline-conform treatment of post-stroke SMD.

Clinical and genetic keys to cerebellar ataxia due to FGF14 GAA expansions.

BACKGROUND: SCA27B caused by FGF14 intronic heterozygous GAA expansions with at least 250 repeats accounts for 10-60% of cases with unresolved cerebellar ataxia. We aimed to assess the size and frequency of FGF14 expanded alleles in individuals with cerebellar ataxia as compared with controls and to characterize genetic and clinical variability. METHODS: We sized this repeat in 1876 individuals from France sampled for research purposes in this cross-sectional study: 845 index cases with cerebellar ataxia and 324 affected relatives, 475 controls, as well as 119 cases with spastic paraplegia, and 113 with familial essential tremor. FINDINGS: A higher frequency of expanded allele carriers in index cases with ataxia was significant only above 300 GAA repeats (10.1%, n = 85) compared with controls (1.1%, n = 5) (p < 0.0001) whereas GAA250-299 alleles were detected in 1.7% of both groups. Eight of 14 index cases with GAA250-299 repeats had other causal pathogenic variants (4/14) and/or discordance of co-segregation (5/14), arguing against GAA causality. We compared the clinical signs in 127 GAA≥300 carriers to cases with non-expanded GAA ataxia resulting in defining a key phenotype triad: onset after 45 years, downbeat nystagmus, episodic ataxic features including diplopia; and a frequent absence of dysarthria. All maternally transmitted alleles above 100 GAA were unstable with a median expansion of +18 repeats per generation (r2 = 0.44; p < 0.0001). In comparison, paternally transmitted alleles above 100 GAA mostly decreased in size (-15 GAA (r2 = 0.63; p < 0.0001)), resulting in the transmission bias observed in SCA27B pedigrees. INTERPRETATION: SCA27B diagnosis must consider both the phenotype and GAA expansion size. In carriers of GAA250-299 repeats, the absence of documented familial transmission and a presentation deviating from the key SCA27B phenotype, should prompt the search for an alternative cause. Affected fathers have a reduced risk of having affected children, which has potential implications for genetic counseling. FUNDING: This work was supported by the Fondation pour la Recherche Médicale, grant number 13338 to JLM, the Association Connaître les Syndrome Cérébelleux - France (to GS) and by the European Union's Horizon 2020 research and innovation program under grant agreement No 779257 ("SOLVE-RD" to GS). DP holds a Fellowship award from the Canadian Institutes of Health Research (CIHR). SK received a grant (01GM1905C) from the Federal Ministry of Education and Research, Germany, through the TreatHSP network. This work was supported by the Australian Government National Health and Medical Research Council grants (GNT2001513 and MRFF2007677) to MB and PJL.

Brainstem Infarction in Immunodeficiency Identified as Adenosine Deaminase 2 Deficiency: Case Report.

PURPOSE: We present the case of a 24-year-old male with CNS granulomatosis due to an immunodeficiency syndrome which was identified as deficiency of adenosine deaminase 2 (DADA2) as a cause of brainstem infarction. METHODS: Case report and detailed description of the clinical course of diagnosis and treatment. CASE: The patient's medical history consisted of an unknown immunodeficiency syndrome. Based on former findings, common variable immunodeficiency (CVID) was diagnosed. The patient suffered from three consecutive brainstem strokes of unknown etiology within 3 years. An MRI scan detected gadolinium-enhancing, granulomatous-suspect lesions in the interpeduncular cistern, temporal lobe, and tegmentum. Laboratory analysis was compatible with CVID, with leukopenia and immunoglobulin deficiency. Because granulomatous CNS inflammation was suspected, the patient received methylprednisolone immunosuppressive therapy, which led to partially regressive MRI lesions. However, in contrast to imaging, the patient showed a progressive cerebellar syndrome, indicating plasma exchange therapy and immunoglobulin treatment, which led to rapid symptom amelioration. After a relapse and a further stroke, expanded analysis confirmed DADA2 (and not CVID) as the inflammatory cause for recurrent stroke. After starting the therapy with immunoglobulins and adalimumab, no further strokes occurred. CONCLUSION: We present the case of a young adult with diagnosis of DADA2 as a cause for recurrent strokes due to vasculitis. This stroke etiology is rare but should be considered as a cause of recurrent stroke of unknown origin in young patients to avoid a disabling disease course by disease-specific treatment options.

Fast and reliable detection of repeat expansions in spinocerebellar ataxia using exomes.

Usually, molecular diagnosis of spinocerebellar ataxia is based on a step-by-step approach with targeted sizing of four repeat expansions accounting for most dominant cases, then targeted sequencing of other genes. Nowadays, genome sequencing allows detection of most pathogenic variants in a single step. The ExpansionHunter tool can detect expansions in short-read genome sequencing data. Recent studies have shown that ExpansionHunter can also be used to identify repeat expansions in exome sequencing data. We tested ExpansionHunter on spinocerebellar ataxia exomes in a research context as a second-line analysis, after exclusion of main CAG repeat expansions in half of the probands. First, we confirmed the detection of expansions in seven known expansion carriers and then, after targeted analysis of ATXN1, 2, 3 and 7, CACNA1A, TBP, ATN1, NOP56, AR and HTT in 498 exomes, we found 22 additional pathogenic expansions. Comparison with capillary migration sizing in 247 individuals and confirmation of all expanded alleles detected by ExpansionHunter demonstrated that for these loci, sensitivity and specificity reached 100%. ExpansionHunter detected but underestimated the repeat size for larger expansions, and the normal alleles distribution at each locus should be taken into account to detect expansions. Exome combined with ExpansionHunter is reliable to detect repeat expansions in selected loci as first-line analysis in spinocerebellar ataxia.

Intermediate repeat expansions of TBP and STUB1: Genetic modifier or pure digenic inheritance in spinocerebellar ataxias?

PURPOSE: CAG/CAA repeat expansions in TBP>49 are responsible for spinocerebellar ataxia (SCA) type 17 (SCA17). We previously detected cosegregation of STUB1 variants causing SCA48 with intermediate alleles of TBP in 2 families. This cosegregation questions the existence of SCA48 as a monogenic disease. METHODS: We systematically sequenced TBP repeats in 34 probands of dominant ataxia families with STUB1 variants. In addition, we searched for pathogenic STUB1 variants in probands with expanded alleles of TBP>49 (n = 2) or intermediate alleles of TBP≥40 (n = 47). RESULTS: STUB1 variants were found in half of the TBP40-49 cohort. Mirroring this finding, TBP40-49 alleles were detected in 40% of STUB1 probands. The longer the TBP repeat length, the more likely the occurrence of cognitive impairment (P = .0129) and the faster the disease progression until death (P = .0003). Importantly, 13 STUB1 probands presenting with the full SCA48 clinical phenotype had normal TBP37-39 alleles, excluding digenic inheritance as the sole mode. CONCLUSION: We show that intermediate TBP40-49 alleles act as disease modifiers of SCA48 rather than a STUB1/TBP digenic model. This distinction from what has been proposed before has crucial consequences for genetic counseling in SCA48.

ADHD-associated PARK2 copy number variants: A pilot study on gene expression and effects of supplementary deprivation in patient-derived cell lines.

Recent studies show an association of Parkin RBR E3 ubiquitin protein ligase (PARK2) copy number variations (CNVs) with attention deficit hyperactivity disorder (ADHD). The aim of our pilot study to investigate gene expression associated with PARK2 CNVs in human-derived cellular models. We investigated gene expression in fibroblasts, hiPSC and dopaminergic neurons (DNs) of ADHD PARK2 deletion and duplication carriers by qRT PCR compared with healthy and ADHD cell lines without PARK2 CNVs. The selected 10 genes of interest were associated with oxidative stress response (TP53, NQO1, and NFE2L2), ubiquitin pathway (UBE3A, UBB, UBC, and ATXN3) and with a function in mitochondrial quality control (PINK1, MFN2, and ATG5). Additionally, an exploratory RNA bulk sequencing analysis in DNs was conducted. Nutrient deprivation as a supplementary deprivation stress paradigm was used to enhance potential genotype effects. At baseline, in fibroblasts, hiPSC, and DNs, there was no significant difference in gene expression after correction for multiple testing. After nutrient deprivation in fibroblasts NAD(P)H-quinone-dehydrogenase 1 (NQO1) expression was significantly increased in PARK2 CNV carriers. In a multivariate analysis, ubiquitin C (UBC) was significantly upregulated in fibroblasts of PARK2 CNV carriers. RNA sequencing analysis of DNs showed the strongest significant differential regulation in Neurontin (NNAT) at baseline and after nutrient deprivation. Our preliminary results suggest differential gene expression in pathways associated with oxidative stress, ubiquitine-proteasome, immunity, inflammation, cell growth, and differentiation, excitation/inhibition modulation, and energy metabolism in PARK2 CNV carriers compared to wildtype healthy controls and ADHD patients.

SARS-CoV-2, COVID-19 and Neurodegeneration.

The COVID-19 pandemic continues to affect many areas of our daily life [...].

Inertial Gait Sensors to Measure Mobility and Functioning in Hereditary Spastic Paraplegia: A Cross-Sectional Multicenter Clinical Study.

BACKGROUND AND OBJECTIVES: Hereditary spastic paraplegia (HSP) causes progressive spasticity and weakness of the lower limbs. As neurological examination and the clinical Spastic Paraplegia Rating Scale (SPRS) are subject to potential patient- and clinician-dependent bias, instrumented gait analysis bears the potential to objectively quantify impaired gait. The aim of the present study was to investigate gait cyclicity parameters by application of a mobile gait analysis system in a cross sectional cohort of HSP patients and a longitudinal fast progressing subcohort. METHODS: Using wearable sensors attached to the shoes, HSP patients and controls performed a 4x10 meters walking test during regular visits in three outpatient centers. Patients were also rated according to the SPRS and in a subset, questionnaires on quality of life and fear of falling were obtained. An unsupervised segmentation algorithm was employed to extract stride parameters and respective coefficients of variation. RESULTS: Mobile gait analysis was performed in a total of 112 ambulatory HSP patients and 112 age and gender matched controls. While swing time was unchanged compared to controls, there were significant increases in the duration of the total stride phase and the duration of the stance phase, both regarding absolute values and coefficients of variation values. While stride parameters did not correlate to age, weight or height of the patients, there were significant associations of absolute stride parameters to single SPRS items reflecting impaired mobility (|r| > 0.50), to patients' quality of life (|r| > 0.44), and notably to disease duration (|r| > 0.27). Sensor-derived coefficients of variation, on the other hand, were associated with patient-reported fear of falling (|r| > 0.41) and cognitive impairment (|r| > 0.40). In a small 1-year follow-up analysis of patients with complicated HSP and fast progression, absolute values of mobile gait parameters had significantly worsened compared to baseline. DISCUSSION: The presented wearable sensor system provides parameters of stride characteristics which appear clinically valid to reflect gait impairment in HSP. Due to the feasibility with regard to time, space and costs, the present study forms the basis for larger scale longitudinal and interventional studies in HSP.

Adult-Onset Alexander Disease: New Causal Sequence Variant in the GFAP Gene.

Objectives: Alexander disease (AD) is a rare disorder of the CNS. Diagnosis is based on clinical symptoms, typical MRI findings, and mutations in the glial fibrillary acid protein (GFAP) gene. In this case study, we describe a new mutation (p.L58P) in GFAP that caused a phenotype of adult-onset AD (AOAD). Methods: In our outpatient clinic, a patient presented with cerebellar and bulbar symptoms after brain concussion. We used MRI and performed next-generation exome sequencing (NGS) to find mutations in GFAP to diagnose AD. The mutation was then transfected into HeLa cell lines to prove its pathogenicity. Results: The brain MRI finding showed typical AD alterations. The NGS found a heterozygous variant of unknown significance in GFAP (c.173T>C; p.L58P). After transfecting HeLa cell lines with this mutation, we showed that GFAP-L58P formed pathogenic clusters of cytoplasmic aggregates. Discussion: We have found a new mutation that causes AOAD. We recommend that AOAD is included in the diagnostic workup in adult patients with gait ataxia and cerebellar and bulbar symptoms in association with a traumatic head injury.

CNS-associated T-lymphocytes in a mouse model of Hereditary Spastic Paraplegia type 11 (SPG11) are therapeutic targets for established immunomodulators.

Pharmacological targeting of neuroinflammation in distinct models of genetically mediated disorders of the central nervous system (CNS) has been shown to attenuate disease outcome significantly. These include mouse models mimicking distinct subtypes of neuronal ceroid lipofuscinoses (NCL, CLN diseases) as well as hereditary spastic paraplegia type 2 (HSP/SPG2). We here show in a model of another, complicated HSP form (SPG11) that there is neuroinflammation in distinct compartments of the diseased CNS. Using a proof-of-principle experiment, we provide evidence that genetically targeting the adaptive immune system dampens disease progression including gait disturbance, demonstrating a pathogenic impact of neuroinflammation. Translating these studies into a clinically applicable approach, we show that the established immunomodulators fingolimod and teriflunomide significantly attenuate the neurodegenerative phenotype and improve gait performance in the SPG11 model, even when applied relatively late during disease progression. Particularly abnormalities in gait coordination, representing ataxia, could be attenuated, while features indicative of reduced strength during walking did not respond to treatment. Our study identifies neuroinflammation by the adaptive immune system as a robust and targetable disease amplifier in a mouse model of SPG11 and may thus pave the way for a translational approach in humans implicating approved immunomodulators.

SARS-CoV-2, COVID-19 and Parkinson's Disease-Many Issues Need to Be Clarified-A Critical Review.

Neurological manifestations during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic are of interest, regarding acute treatment and the so-called post-COVID-19 syndrome. Parkinson's disease (PD) is one of the most common neurodegenerative movement disorders worldwide. Hence, the influence of SARS-CoV-2 and the COVID-19 syndrome on PD patients has raised many questions and produced various publications with conflicting results. We reviewed the literature, with respect to symptoms, treatment, and whether the virus itself might cause PD during the SARS-CoV-2 pandemic in SARS-CoV-2-affected symptomatic PD patients (COVID-19 syndrome). In addition, we comment on the consequences in non-symptomatic and non-affected PD patients, as well as post-COVID syndrome and its potential linkage to PD, presenting our own data from our out-patient clinic.

Blood-based biomarker in Parkinson's disease: potential for future applications in clinical research and practice.

The clinical presentation of Parkinson's disease (PD) is both complex and heterogeneous, and its precise classification often requires an intensive work-up. The differential diagnosis, assessment of disease progression, evaluation of therapeutic responses, or identification of PD subtypes frequently remains uncertain from a clinical point of view. Various tissue- and fluid-based biomarkers are currently being investigated to improve the description of PD. From a clinician's perspective, signatures from blood that are relatively easy to obtain would have great potential for use in clinical practice if they fulfill the necessary requirements as PD biomarker. In this review article, we summarize the knowledge on blood-based PD biomarkers and present both a researcher's and a clinician's perspective on recent developments and potential future applications.

Monogenetic Forms of Parkinson's Disease - Bridging the Gap Between Genetics and Biomarkers.

The therapy of neurodegenerative diseases such as Parkinson's disease (PD) is still limited to the treatment of symptoms and primarily aimed at compensating for dopaminergic hypofunction. Numerous disease-modifying therapies currently in the pipeline attempt to modify the underlying pathomechanisms. In recent decades, the results of molecular genetics and biomarker research have raised hopes of earlier diagnosis and new neuroprotective therapeutic approaches. As the disease-causing processes in monogenetic forms of PD are better understood than in sporadic PD, these disease subsets are likely to benefit first from disease-modifying therapies. Recent studies have suggested that disease-relevant changes found in genetically linked forms of PD (i.e., PARK-LRRK2, PARK-GBA) can also be reproduced in patients in whom no genetic cause can be found, i.e., those with sporadic PD. It can, therefore, be assumed that as soon as the first causal therapy for genetic forms of PD is approved, more patients with PD will undergo genetic testing and counseling. Regarding future neuroprotective trials in neurodegenerative diseases and objective parameters such as biomarkers with high sensitivity and specificity for the diagnosis and course of the disease are needed. These biomarkers will also serve to monitor treatment success in clinical trials. Promising examples in PD, such as alpha-synuclein species, lysosomal enzymes, markers of amyloid and tau pathology, and neurofilament light chain, are under investigation in blood and CSF. This paper provides an overview of the opportunities and current limitations of monogenetic diagnostic and biomarker research in PD and aims to build a bridge between current knowledge and association with PD genetics and biomarkers.

De Novo and Dominantly Inherited SPTAN1 Mutations Cause Spastic Paraplegia and Cerebellar Ataxia.

BACKGROUND: Pathogenic variants in SPTAN1 have been linked to a remarkably broad phenotypical spectrum. Clinical presentations include epileptic syndromes, intellectual disability, and hereditary motor neuropathy. OBJECTIVES: We investigated the role of SPTAN1 variants in rare neurological disorders such as ataxia and spastic paraplegia. METHODS: We screened 10,000 NGS datasets across two international consortia and one local database, indicative of the level of international collaboration currently required to identify genes causative for rare disease. We performed in silico modeling of the identified SPTAN1 variants. RESULTS: We describe 22 patients from 14 families with five novel SPTAN1 variants. Of six patients with cerebellar ataxia, four carry a de novo SPTAN1 variant and two show a sporadic inheritance. In this group, one variant (p.Lys2083del) is recurrent in four patients. Two patients have novel de novo missense mutations (p.Arg1098Cys, p.Arg1624Cys) associated with cerebellar ataxia, in one patient accompanied by intellectual disability and epilepsy. We furthermore report a recurrent missense mutation (p.Arg19Trp) in 15 patients with spastic paraplegia from seven families with a dominant inheritance pattern in four and a de novo origin in one case. One further patient carrying a de novo missense mutation (p.Gln2205Pro) has a complex spastic ataxic phenotype. Through protein modeling we show that mutated amino acids are located at crucial interlinking positions, interconnecting the three-helix bundle of a spectrin repeat. CONCLUSIONS: We show that SPTAN1 is a relevant candidate gene for ataxia and spastic paraplegia. We suggest that for the mutations identified in this study, disruption of the interlinking of spectrin helices could be a key feature of the pathomechanism. © 2022 International Parkinson and Movement Disorder Society.

Association of Essential Tremor With Novel Risk Loci: A Genome-Wide Association Study and Meta-analysis.

Importance: Essential tremor (ET) is one of the most common movement disorders, affecting 5% of the general population older than 65 years. Common variants are thought to contribute toward susceptibility to ET, but no variants have been robustly identified. Objective: To identify common genetic factors associated with risk of ET. Design, Setting, and Participants: Case-control genome-wide association study. Inverse-variance meta-analysis was used to combine cohorts. Multicenter samples collected from European populations were collected from January 2010 to September 2019 as part of an ongoing study. Included patients were clinically diagnosed with or reported having ET. Control individuals were not diagnosed with or reported to have ET. Of 485 250 individuals, data for 483 054 passed data quality control and were used. Main Outcomes and Measures: Genotypes of common variants associated with risk of ET. Results: Of the 483 054 individuals included, there were 7177 with ET (3693 [51.46%] female; mean [SD] age, 62.66 [15.12] years), and 475 877 control individuals (253 785 [53.33%] female; mean [SD] age, 56.40 [17.6] years). Five independent genome-wide significant loci and were identified and were associated with approximately 18% of ET heritability. Functional analyses found significant enrichment in the cerebellar hemisphere, cerebellum, and axonogenesis pathways. Genetic correlation (r), which measures the degree of genetic overlap, revealed significant common variant overlap with Parkinson disease (r, 0.28; P = 2.38 × 10-8) and depression (r, 0.12; P = 9.78 × 10-4). A separate fine-mapping of transcriptome-wide association hits identified genes such as BACE2, LRRN2, DHRS13, and LINC00323 in disease-relevant brain regions, such as the cerebellum. Conclusions and Relevance: The results of this genome-wide association study suggest that a portion of ET heritability can be explained by common genetic variation and can help identify new common genetic risk factors for ET.

Anti-GFAP-antibody positive postinfectious acute cerebellar ataxia and myoclonus after COVID-19: a case report.

We present a case of acute cerebellar ataxia and myoclonus with detected anti-GFAP-antibodies in a patient recently recovered from COVID-19. Main symptoms consisted of acute gait and limb ataxia and myoclonus. The patient improved considerably upon treatment with high-dose intravenous (IV) steroids. While cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) findings were unremarkable, anti-GFAP-antibodies were detected in the patient's serum and disappeared upon clinical remission at a 3-month follow-up. This case suggests that anti-GFAP-antibodies might be associated with some of the increasingly observed cases of postinfectious acute cerebellar ataxias in COVID-19 patients and aid in the diagnosis of this autoimmune complication. We recommend searching for these antibodies in serum and CSF in suspected cases. Early steroid treatment may prove beneficial for these patients.