The parkin V380L variant is a genetic modifier of Machado-Joseph disease with impact on mitophagy.

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative spinocerebellar ataxia caused by a polyglutamine-coding CAG repeat expansion in the ATXN3 gene. While the CAG length correlates negatively with the age at onset, it accounts for approximately 50% of its variability only. Despite larger efforts in identifying contributing genetic factors, candidate genes with a robust and plausible impact on the molecular pathogenesis of MJD are scarce. Therefore, we analysed missense single nucleotide polymorphism variants in the PRKN gene encoding the Parkinson's disease-associated E3 ubiquitin ligase parkin, which is a well-described interaction partner of the MJD protein ataxin-3, a deubiquitinase. By performing a correlation analysis in the to-date largest MJD cohort of more than 900 individuals, we identified the V380L variant as a relevant factor, decreasing the age at onset by 3 years in homozygous carriers. Functional analysis in an MJD cell model demonstrated that parkin V380L did not modulate soluble or aggregate levels of ataxin-3 but reduced the interaction of the two proteins. Moreover, the presence of parkin V380L interfered with the execution of mitophagy-the autophagic removal of surplus or damaged mitochondria-thereby compromising cell viability. In summary, we identified the V380L variant in parkin as a genetic modifier of MJD, with negative repercussions on its molecular pathogenesis and disease age at onset.

A New Case Series Suggests That SCA48 (ATX/STUB1) Is Primarily a Monogenic Disorder.

BACKGROUND: Monoallelic, pathogenic STUB1 variants cause autosomal dominant cerebellar ataxia (ATX-STUB1/SCA48). Recently, a genetic interaction between STUB1 variants and intermediate or high-normal CAG/CAA repeats in TBP was suggested, indicating digenic inheritance or a disease-modifying role for TBP expansions. OBJECTIVE: To determine the presence and impact of intermediate or high-normal TBP expansions in ataxic patients with heterozygous STUB1 variants. METHODS: We describe 21 patients with ataxia carrying a heterozygous STUB1 variant and determined TBP repeat length. RESULTS: A total of 15 of 21 patients (71%) carried a normal TBP<40 allele, 4 (19%) carried an intermediate TBP41-42 allele, and two carried a high-normal TBP40 allele (9.5%). Five of six carriers (83%) of both STUB1 variants and TBP40-42 alleles showed marked cognitive impairment. CONCLUSIONS: SCA48 is predominantly a monogenic disorder, because most patients carried an isolated, heterozygous STUB1 variant and presented with the typical combined phenotype of ataxia and cognitive dysfunction. Still, co-occurrence of TBP41-42 or high-normal TBP40 alleles was relatively frequent and associated with marked cognitive defects (28.5%), suggesting a modifying effect on clinical expression in some cases. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Genetic Interventions for Spinocerebellar Ataxia and Huntington's Disease: A Qualitative Study of the Patient Perspective.

Background: For various genetic disorders characterized by expanded cytosine-adenine-guanine (CAG) repeats, such as spinocerebellar ataxia (SCA) subtypes and Huntington's disease (HD), genetic interventions are currently being tested in different clinical trial phases. The patient's perspective on such interventions should be included in the further development and implementation of these new treatments. Objective: To obtain insight into the thoughts and perspectives of individuals with SCA and HD on genetic interventions. Methods: In this qualitative study, participants were interviewed using semi-structured interview techniques. Topics discussed were possible risks and benefits, and logistic factors such as timing, location and expertise. Data were analyzed using a generic thematic analysis. Responses were coded into superordinate themes. Results: Ten participants (five with SCA and five with HD) were interviewed. In general, participants seemed to be willing to undergo genetic interventions. Important motives were the lack of alternative disease-modifying treatment options, the hope for slowing down disease progression, and preservation of current quality of life. Before undergoing genetic interventions, participants wished to be further informed. Logistic factors such as mode and frequency of administration, expertise of the healthcare provider, and timing of treatment are of influence in the decision-making process. Conclusions: This study identified assumptions, motives, and topics that require further attention before these new therapies, if proven effective, can be implemented in clinical practice. The results may help in the design of care pathways for genetic interventions for these and other rare genetic movement disorders.

Association of Body Mass Index and Parkinson Disease: A Bidirectional Mendelian Randomization Study.

BACKGROUND AND OBJECTIVES: The role of body mass index (BMI) in Parkinson disease (PD) is unclear. Based on the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in PD (Courage-PD) consortium, we used 2-sample Mendelian randomization (MR) to replicate a previously reported inverse association of genetically predicted BMI with PD and investigated whether findings were robust in analyses addressing the potential for survival and incidence-prevalence biases. We also examined whether the BMI-PD relation is bidirectional by performing a reverse MR. METHODS: We used summary statistics from a genome-wide association study (GWAS) to extract the association of 501 single-nucleotide polymorphisms (SNPs) with BMI and from the Courage-PD and international Parkinson Disease Genomics Consortium (iPDGC) to estimate their association with PD. Analyses are based on participants of European ancestry. We used the inverse-weighted method to compute odds ratios (ORIVW per 4.8 kg/m2 [95% CI]) of PD and additional pleiotropy robust methods. We performed analyses stratified by age, disease duration, and sex. For reverse MR, we used SNPs associated with PD from 2 iPDGC GWAS to assess the effect of genetic liability toward PD on BMI. RESULTS: Summary statistics for BMI are based on 806,834 participants (54% women). Summary statistics for PD are based on 8,919 (40% women) cases and 7,600 (55% women) controls from Courage-PD, and 19,438 (38% women) cases and 24,388 (51% women) controls from iPDGC. In Courage-PD, we found an inverse association between genetically predicted BMI and PD (ORIVW 0.82 [0.70-0.97], p = 0.012) without evidence for pleiotropy. This association tended to be stronger in younger participants (≤67 years, ORIVW 0.71 [0.55-0.92]) and cases with shorter disease duration (≤7 years, ORIVW 0.75 [0.62-0.91]). In pooled Courage-PD + iPDGC analyses, the association was stronger in women (ORIVW 0.85 [0.74-0.99], p = 0.032) than men (ORIVW 0.92 [0.80-1.04], p = 0.18), but the interaction was not statistically significant (p-interaction = 0.48). In reverse MR, there was evidence for pleiotropy, but pleiotropy robust methods showed a significant inverse association. DISCUSSION: Using an independent data set (Courage-PD), we replicate an inverse association of genetically predicted BMI with PD, not explained by survival or incidence-prevalence biases. Moreover, reverse MR analyses support an inverse association between genetic liability toward PD and BMI, in favor of a bidirectional relation.

Cognitive impairment in young adults following cerebellar stroke: Prevalence and longitudinal course.

INTRODUCTION: Cognitive impairment is a well-known result of a stroke, but for cerebellar stroke in young patients detailed knowledge on the nature and extent of cognitive deficits is limited. This study examined the prevalence and course of cognitive impairment in a large cohort of patients with cerebellar stroke. METHODS: Sixty young (18-49 years) cerebellar stroke patients completed extensive neuropsychological assessments in the subacute (<9 months post-stroke) and/or chronic phase (≥9 months post-stroke). Performance and course were assessed using standardized scores and Reliable Change Index analyses. Associations between cognitive deficits and lesion locations were explored using subtraction analyses, and associations with subjective cognitive complaints and fatigue were examined. RESULTS: Sixty patients (52% male) were included with a mean age at event of 43.1 years. Cognitive impairment was observed in 60.3% of patients in the subacute phase and 51.2% during the chronic phase. Deficits were most frequent for visuo-spatial skills and executive functioning (42.5-54.6%). Both improvement and decline were observed over time, in 17.9% and 41.0% of participants, respectively. Cognitive deficits seem to be associated with lesions in certain cerebellar regions, however, no distinct correlation was found for a specific subregion. Subjective cognitive complaints were present in the majority of participants (61-80.5%) and positively correlated with fatigue in both phases (ρ = -.661 and ρ = -.757, p < .001, respectively). DISCUSSION: Cognitive impairment in cerebellar stroke patients is common, with deficits most pronounced for visuo-spatial skills and executive functioning, as in line with the Cerebellar Cognitive Affective Syndrome. The course of cognitive performance was heterogenous, with cognitive decline despite the fact that no recurrent strokes occurred. No clear association between lesion location and cognitive deficits was observed. Subjective cognitive complaints and fatigue were prevalent and positively correlated. Clinicians could use this information to actively screen for and better inform patients about possible cognitive sequalae.

Generation of human induced pluripotent stem cell lines (LUMCi051-A,B and LUMCi052-A,B,C) of two patients with Spinocerebellar ataxia type 7.

Spinocerebellar Ataxia Type 7 (SCA7) is an autosomal dominantly inherited disorder, primarily characterized by cerebellar ataxia and visual loss. SCA7 is caused by a CAG repeat expansion in exon 3 of the ATXN7 gene. We generated human induced pluripotent stem cells (hiPSCs) from peripheral blood-derived erythroblasts from two SCA7 patients (LUMCi051-A,B and LUMCi052-A,B,C) using integration-free episomal vectors. All hiPSC clones express pluripotency factors, show a normal karyotype, and can differentiate into the three germ layers. These lines can be used for in vitro disease modeling and therapy testing.

Genotype-specific spinal cord damage in spinocerebellar ataxias: an ENIGMA-Ataxia study.

BACKGROUND: Spinal cord damage is a feature of many spinocerebellar ataxias (SCAs), but well-powered in vivo studies are lacking and links with disease severity and progression remain unclear. Here we characterise cervical spinal cord morphometric abnormalities in SCA1, SCA2, SCA3 and SCA6 using a large multisite MRI dataset. METHODS: Upper spinal cord (vertebrae C1-C4) cross-sectional area (CSA) and eccentricity (flattening) were assessed using MRI data from nine sites within the ENIGMA-Ataxia consortium, including 364 people with ataxic SCA, 56 individuals with preataxic SCA and 394 nonataxic controls. Correlations and subgroup analyses within the SCA cohorts were undertaken based on disease duration and ataxia severity. RESULTS: Individuals in the ataxic stage of SCA1, SCA2 and SCA3, relative to non-ataxic controls, had significantly reduced CSA and increased eccentricity at all examined levels. CSA showed large effect sizes (d>2.0) and correlated with ataxia severity (r<-0.43) and disease duration (r<-0.21). Eccentricity correlated only with ataxia severity in SCA2 (r=0.28). No significant spinal cord differences were evident in SCA6. In preataxic individuals, CSA was significantly reduced in SCA2 (d=1.6) and SCA3 (d=1.7), and the SCA2 group also showed increased eccentricity (d=1.1) relative to nonataxic controls. Subgroup analyses confirmed that CSA and eccentricity are abnormal in early disease stages in SCA1, SCA2 and SCA3. CSA declined with disease progression in all, whereas eccentricity progressed only in SCA2. CONCLUSIONS: Spinal cord abnormalities are an early and progressive feature of SCA1, SCA2 and SCA3, but not SCA6, which can be captured using quantitative MRI.

Smartphone applications for Movement Disorders: Towards collaboration and re-use.

BACKGROUND: Numerous smartphone and tablet applications (apps) are available to monitor movement disorders, but an overview of their purpose and stage of development is missing. OBJECTIVES: To systematically review published literature and classify smartphone and tablet apps with objective measurement capabilities for the diagnosis, monitoring, assessment, or treatment of movement disorders. METHODS: We systematically searched for publications covering smartphone or tablet apps to monitor movement disorders until November 22nd, 2023. We reviewed the target population, measured domains, purpose, and technology readiness level (TRL) of the proposed app and checked their availability in common app stores. RESULTS: We identified 113 apps. Most apps were developed for Parkinson's disease specifically (n = 82; 73%) or for movement disorders in general (n = 17; 15%). Apps were either designed to momentarily assess symptoms (n = 65; 58%), support treatment (n = 22; 19%), aid in diagnosis (n = 16; 14%), or passively track symptoms (n = 11; 10%). Commonly assessed domains across movement disorders included fine motor skills (n = 34; 30%), gait (n = 36; 32%), and tremor (n = 32; 28%) for the motor domain and cognition (n = 16; 14%) for the non-motor domain. Twenty-six (23%) apps were proof-of-concepts (TRL 1-3), while most apps were tested in a controlled setting (TRL 4-6; n = 63; 56%). Twenty-four apps were tested in their target setting (TRL 7-9) of which 10 were accessible in common app stores or as Android Package. CONCLUSIONS: The development of apps strongly gravitates towards Parkinson's disease and a selection of motor symptoms. Collaboration, re-use and further development of existing apps is encouraged to avoid reinventions of the wheel.