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Background Cerebellar ataxias comprise sporadic and genetic etiologies. Ataxia may also be a presenting feature in hereditary spastic paraplegias (HSPs).

Background and purpose: Hereditary spastic paraplegias (HSPs) comprise a group of inherited neurodegenerative disorders characterized by progressive spasticity and weakness. Botulinum toxin has been approved for lower limb spasticity following stroke and cerebral palsy, but its effects in HSPs remain underexplored. We aimed to characterize the effects of botulinum toxin on clinical, gait, and patient‐reported outcomes in HSP patients and explore the potential of mobile digital gait analysis to monitor treatment effects and predict treatment response. Methods: We conducted a prospective, observational, multicenter study involving ambulatory HSP patients treated with botulinum toxin tailored to individual goals. Comparing data at baseline, after 1 month, and after 3 months, treatment response was assessed using clinical parameters, goal attainment scaling, and mobile digital gait analysis. Machine learning algorithms were used for predicting individual goal attainment based on baseline parameters. Results: A total of 56 patients were enrolled. Despite the heterogeneity of treatment goals and targeted muscles, botulinum toxin led to a significant improvement in specific clinical parameters and an improvement in specific gait characteristics, peaking at the 1‐month and declining by the 3‐month follow‐up. Significant correlations were identified between gait parameters and clinical scores. With a mean balanced accuracy of 66%, machine learning algorithms identified important denominators to predict treatment response. Conclusions: Our study provides evidence supporting the beneficial effects of botulinum toxin in HSP when applied according to individual treatment goals. The use of mobile digital gait analysis and machine learning represents a novel approach for monitoring treatment effects and predicting treatment response. [ABSTRACT FROM AUTHOR]

Background and purpose: White matter (WM) damage is the main target of hereditary spastic paraplegia (HSP), but mounting evidence indicates that genotype‐specific grey matter (GM) damage is not uncommon. Our aim was to identify and compare brain GM and WM damage patterns in HSP subtypes and investigate how gene expression contributes to these patterns, and explore the relationship between GM and WM damage. Methods: In this prospective single‐centre cohort study from 2019 to 2022, HSP patients and controls underwent magnetic resonance imaging evaluations. The alterations of GM and WM patterns were compared between groups by applying a source‐based morphometry approach. Spearman rank correlation was used to explore the associations between gene expression and GM atrophy patterns in HSP subtypes. Mediation analysis was conducted to investigate the interplay between GM and WM damage. Results: Twenty‐one spastic paraplegia type 4 (SPG4) patients (mean age 50.7 years ± 12.0 SD, 15 men), 21 spastic paraplegia type 5 (SPG5) patients (mean age 29.1 years ± 12.8 SD, 14 men) and 42 controls (sex‐ and age‐matched) were evaluated. Compared to controls, SPG4 and SPG5 showed similar WM damage but different GM atrophy patterns. GM atrophy patterns in SPG4 and SPG5 were correlated with corresponding gene expression (ρ = 0.30, p = 0.008, ρ = 0.40, p < 0.001, respectively). Mediation analysis indicated that GM atrophy patterns were mediated by WM damage in HSP. Conclusions: Grey matter atrophy patterns were distinct between SPG4 and SPG5 and were not only secondary to WM damage but also associated with disease‐related gene expression. Clinical trial registration no. NCT04006418. [ABSTRACT FROM AUTHOR]

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Background Hereditary or familial spastic paraplegias (SPG) comprise a group of genetically and phenotypically heterogeneous diseases characterized by progressive degeneration of the corticospinal tracts. The complicated forms evolve with other various neurological signs and symptoms, including movement disorders and ataxia.

ABSTRACT Hereditary spastic paraplegias (HSP) are a group of genetic diseases characterized by lower limb spasticity with or without additional neurological features. Swallowing dysfunction is poorly studied in HSP and its presence can lead to significant respiratory and nutritional complications. Objectives: The aim of this study was to evaluate the frequency and clinical characteristics of dysphagia in different types of HSP. Methods: A two-center cross-sectional prevalence study was performed. Genetically confirmed HSP patients were evaluated using the Northwestern Dysphagia Patient Check Sheet and the Functional Oral Intake Scale. In addition, self-perception of dysphagia was assessed by the Eat Assessment Tool-10 and the Swallowing Disturbance Questionnaire. Results: Thirty-six patients with spastic paraplegia type 4 (SPG4), five with SPG11, four with SPG5, four with cerebrotendinous xanthomatosis (CTX), three with SPG7, and two with SPG3A were evaluated. Mild to moderate oropharyngeal dysphagia was present in 3/5 (60%) of SPG11 and 2/4 (50%) of CTX patients. A single SPG4 (2%) and a single SPG7 (33%) patient had mild oropharyngeal dysphagia. All other evaluated patients presented with normal or functional swallowing. Conclusions: Clinically significant oropharyngeal dysphagia was only present in complicated forms of HSP Patients with SPG11 and CTX had the highest risks for dysphagia, suggesting that surveillance of swallowing function should be part of the management of patients with these disorders.

Objective To investigate the clinical phenotype and genotype manifestations of autosomal recessive hereditary spastic ataxia 2 (SPAX2), to help physicians recognize this disease. Methods and Results A 35-year-old male patient presented with postural tremors, ataxia, hyperreflexia and then got worse progressively. Sanger sequencing found a homozygous missense mutation in the exon 13 c.1089T > G (p.Ile363Met) of KIF1C gene. It came from his parents respectively and was consistent with the autosomal recessive genetic law. The patient was clearly diagnosed as SPAX2, and his family was diagnosed as SPAX2 pedigree. Conclusions KIF1C-related SPAX2 may be considered as a candidate diagnosis for adolescent patients with postural tremor, ataxia and hyperreflexia. DOI: 10.3969/j.issn.1672-6731.2019.06.008

The L1 cell adhesion molecule (L1) has demonstrated a range of beneficial effects in animal models of spinal cord injury, neurodegenerative disease, and ischemia; however, the role of L1 in TBI has not been fully examined. Mutations in the L1 gene affecting the extracellular domain of this type 1 transmembrane glycoprotein have been identified in patients with L1 syndrome. These patients suffer from hydrocephalus, MASA (mental retardation, adducted thumbs, shuffling gait, aphasia) symptoms, and corpus callosum agenesis. Clinicians have observed that recovery post-traumatic brain injury (TBI) varies among the population. This variability may be explained by the genetic differences present in the general population. In this study, we utilized a novel mouse model of L1 syndrome with a mutation at aspartic acid position 201 in the extracellular domain of L1 (L1-201). We assessed the impact of this specific single nucleotide polymorphism (SNP) localized to the X-chromosome L1 gene on recovery outcomes following TBI by comparing the L1-201 mouse mutants with their wild-type littermates. We demonstrate that male L1-201 mice exhibit significantly worse learning and memory outcomes in the Morris water maze after lateral fluid percussion (LFP) injury compared to male wild-type mice and a trend to worse motor function on the rotarod. However, no significant changes were observed in markers for inflammatory responses or apoptosis after TBI.

Motor and somatosensory pathway dysfunction due to degeneration of long tracts in hereditary spastic paraplegias (HSP) indicates that postural abnormalities may be a relevant disease feature. However, balance assessments have been underutilized to study these conditions. How does the static balance of individuals with HSP with eyes open and closed differ from healthy controls, and how does it relate to disease severity? This cross-sectional case-control study assessed the static balance of 17 subjects with genetically confirmed HSP and 17 healthy individuals, evaluating the center of pressure (COP) variables captured by a force platform. The root-mean-square of velocities and mean of displacements amplitudes in mediolateral and anteroposterior axes were correlated with disease severity. All COP parameters' performances were significantly impaired in HSP subjects compared to controls (p < 0.001 for all comparisons). COP with eyes open and closed differed for all variables within the HSP group, whereas in the control group, differences were observed only for anteroposterior velocity and amplitude. Spastic Paraplegia Rating Scale presented moderate direct correlations with the most COP variables (Rho =  - 0.520 to - 0.736). HSP individuals presented significant postural instability with eyes open and to a greater extent with eyes closed, corroborating the clinical findings of somatosensorial and proprioceptive pathways dysfunction. The degrees of proprioceptive and motor impairments are mutually correlated, suggesting that similar pathophysiological mechanisms operate for the degeneration of these long tracts. COP parameters can be seen as disease severity biomarkers of HSP, and they should be assessed in future clinical trials., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: ALS2-related disorder involves retrograde degeneration of the upper motor neurons of the pyramidal tracts, among which autosomal recessive Infantile-onset ascending hereditary spastic paralysis (IAHSP) is a rare phenotype. In this study, we gathered clinical data from two Chinese siblings who were affected by IAHSP. Our aim was to assess the potential pathogenicity of the identified variants and analyze their clinical and genetic characteristics., Method: Here, Whole-exome sequencing (WES) was performed on proband to identify the candidate variants. Subsequently, Sanger sequencing was used to verify identified candidate variants and to assess co-segregation among available family members. Utilizing both silico prediction and 3D protein modeling, an analysis was conducted to evaluate the potential functional implications of the variants on the encoded protein, and minigene assays were performed to unravel the effect of the variants on the cleavage of pre-mRNA., Results: Both patients were characterized by slurred speech, astasia, inability to walk, scoliosis, lower limb hypertonia, ankle clonus, contracture of joint, foot pronation and no psychomotor retardation was found. Genetic analysis revealed a novel homozygous variant of ALS2, c.1815G > T(p.Lys605Asn) in two Chinese siblings. To our knowledge, it is the first confirmed case of a likely pathogenic variant leading to IAHSP in a Chinese patient., Conclusion: This study broadens the range of ALS2 variants and has practical implications for prenatal and postnatal screening of IAHSR. Symptom-based diagnosis of IAHSP is frequently difficult for medical practitioners. WES can be a beneficial resource to identify a particular disorder when the diagnosis cannot be determined from the symptoms alone., (© 2024. The Author(s).)

Background: Papaya (Carica papaya) is a tropical fruit of great economic and nutritional importance, loved for its sweet and delicious flesh. However, papaya cultivation faces serious challenges in the form of Begomovirus attacks. Begomoviruses are a group of viruses that pose a serious threat to plants worldwide. Including papaya, Begomovirus has become a significant threat to papaya production in various parts of the world and has been identified in several regions in Indonesia., Methods: DNA was extracted from seven samples representing different papaya growing areas using a Plant Genomic DNA Mini Kit. Genomic DNA from the samples was subjected to PCR using universal primers of AC2, AC1, SPG1 and SPG2. The PCR products then sequenced using the dideoxy (Sanger) approach. The obtained sequence then compared to the gene bank using BLAST software available at NCBI. Multiple sequence alignment and phylogenetic tree construction were analyzed using the MEGA11 program., Results: Detection based on viral nucleic acid in papaya plants in Pesawaran, Lampung Province with seven sampling points using universal primers SPG1/SPG2 showed positive results for Begomovirus infection with visible DNA bands measuring ± 900 bp. Direct nucleotide sequencing using SPG1/SPG2 primers for the AC2 and AC1 genes of the Begomovirus and confirmed by the BLAST program showed that papaya samples were infected with Ageratum yellow vein virus (AYVV). The phylogenetic results show that AYVV from papaya samples has a close relationship with the AYVV group from several other countries, with 98% homology., Conclusion: In the papaya cultivation area in Pesawaran, Lampung province, it was identified as Begomovirus, Ageratum yellow vein virus (AYVV) species and is closely related to the AYVV group from several other countries. Overall, our study further suggests that Ageratum acts as an alternative host and reservoir for Begomovirus., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

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., (© 2023. The Author(s).)

ARL6IP1 is implicated in hereditary spastic paraplegia (HSP), but the specific pathogenic mechanism leading to neurodegeneration has not been elucidated. Here, we clarified the molecular mechanism of ARL6IP1 in HSP using in vitro and in vivo models. The Arl6ip1 knockout (KO) mouse model was generated to represent the clinically involved frameshift mutations and mimicked the HSP phenotypes. Notably, in vivo brain histopathological analysis revealed demyelination of the axon and neuroinflammation in the white matter, including the corticospinal tract. In in vitro experiments, ARL6IP1 silencing caused cell death during neuronal differentiation and mitochondrial dysfunction by dysregulated autophagy. ARL6IP1 localized on mitochondria-associated membranes (MAMs) to maintain endoplasmic reticulum and mitochondrial homeostasis via direct interaction with LC3B and BCl2L13. ARL6IP1 played a crucial role in connecting the endoplasmic reticulum and mitochondria as a member of MAMs. ARL6IP1 gene therapy reduced HSP phenotypes and restored pathophysiological changes in the Arl6ip1 KO model. Our results established that ARL6IP1 could be a potential target for HSP gene therapy., (© 2023 Lim et al.)