OBJECT:Glutamic acid decarboxylase antibody-associated neurological disease (GADAND) is a rare autoimmune disorder with elusive immunogenetic underpinnings. We aimed to investigate HLA associations with GADAND susceptibility in a Chinese cohort. METHODS:We performed HLA genotyping at the HLA-A, -B, -C, -DRB1, -DQA1, and -DQB1 loci in 62 Chinese patients with GADAND and compared them with 990 healthy controls. Haplotype frequencies were estimated using the expectation-maximization (EM) algorithm. Allele and haplotype associations with disease susceptibility and clinical phenotypes were assessed. RESULTS:We identified the HLA class I haplotype A*11:01 ~ B*40:01 ~ C*07:02 as a susceptibility haplotype for GADAND (OR = 10.22, 95% CI 3.86-25.57, padj = 0.003), and the association was stronger for the extended haplotype including DQA1*01:03 (OR = 25.61, 95% CI 4.99-89.11, padj < 0.001). Three haplotypes showed suggestive but non-significant associations: B*44:02 ~ C*05:01 (OR = 8.32, 95% CI 2.52-24.48, padj = 0.069), DQA1*01:03 ~ DQB1*06:01 ~ DRB1*08:03 (OR = 3.15, 95% CI 1.67-5.63, padj = 0.066), and DQA1*05:05 ~ DQB1*03:01, which showed a suggestive protective effect (OR = 0.15, 95% CI 0.018-0.556, padj = 0.088). T1DM risk haplotypes, including DQA1*03:01 ~ DQB1*03:02 ~ DRB1*04:03 (OR = 5.04, 95% CI 1.18-16.62, padj = 0.744) and DQA1*05:01 ~ DQB1*02:01 ~ DRB1*03:01 (OR = 2.50, 95% CI 1.07-5.24, padj = 0.829), were more frequent in GADAND patients, and A*11:01 ~ B*40:01 ~ C*07:02 was enriched in those with comorbid AITD. No statistically significant associations were identified between HLA haplotypes and clinical phenotypes. CONCLUSIONS:The haplotype A*11:01 ~ B*40:01 ~ C*07:02 was associated with GADAND susceptibility in the Chinese population, implicating T cell involvement. T1DM-associated haplotypes were overrepresented in GADAND, and A*11:01 ~ B*40:01 ~ C*07:02 was enriched in comorbid AITD, suggesting HLA as a shared immunogenetic basis for autoimmune comorbidities. No significant HLA associations with clinical phenotypes were identified, warranting validation in larger cohorts.

Background: Variants in anoctamin 3 (ANO3) are linked to autosomal dominant dystonia, commonly known as DYT-ANO3 (OMIM: #615034). While craniocervical dystonia constitutes the most frequently observed phenotype, its clinical manifestations display significant heterogeneity. Nevertheless, the data concerning the genetic characteristics, clinical features, and therapeutic outcomes of ANO3-related dystonia within Asian populations remain scarce. Methods: Whole-exome sequencing was conducted on 661 Chinese patients, comprising 356 individuals with dystonia and 305 individuals with non-dystonic movement disorders who served as an internal disease-control cohort. Candidate ANO3 variants were evaluated based on population frequency, predicted deleteriousness, ACMG criteria, and aggregate frequency analyses. A retrospective review was performed of clinical features and treatment responses. Results: Fifteen rare ANO3 missense variants were identified in 16 patients with dystonia and one non-dystonic individual, including one pathogenic variant, six likely pathogenic variants, and nine previously unreported variants. The rare ANO3 variants were significantly enriched in the dystonia cohort compared with the controls. ANO3-related dystonia exhibited broad clinical heterogeneity, with frequent cervical involvement (62.5%) and tremulous features (75%), and occasionally extended beyond classical isolated dystonia. Oral medication and botulinum toxin showed variable benefit, whereas deep brain stimulation was associated with marked improvement in selected medically refractory patients. Conclusions: This study broadens the genetic and clinical spectrum of ANO3-related movement disorders in a Chinese cohort. The findings support substantial clinical heterogeneity in DYT-ANO3 and suggest that deep brain stimulation, especially STN-DBS, may be considered in selected refractory cases, although further studies are needed.

INTRODUCTION:Blepharospasm (BSP) has a high spreading risk, and the most common condition is becoming blepharospasm-oromandibular dystonia (BOM). We aimed to identify the shared and specific changes in the brain cerebral blood flow (CBF) covariance network between BSP and BOM. METHODS:This single-center study enrolled 21 BSP patients, 21 BOM patients, and 20 healthy controls (HC). Clinical information and MRI imaging including arterial spin labeling, three-dimensional T1-weighted and conventional sequences were obtained. CBF data were preprocessed, and group-level CBF covariance networks were constructed. Intergroup differences of network connections and properties were compared using a permutation test, and for all network metrics, the statistical significance was defined as p < 0.01 (uncorrected, 5000 times). RESULTS:In both patient groups, hypoperfusion is mainly located in the bilateral frontal lobe and cingulate gyrus. The global properties were standard, and spatial covariance analysis revealed whole-brain reconfiguration. CBF connections in BSP patients were partially increased, whereas they were mostly decreased in BOM patients. Two groups shared lost hubs in the vermis 8, left putamen, right superior temporal gyrus, right cerebellum 4-5, and left thalamus. Compared with BSP, the BOM group showed more widespread decreased connections linking these lost hubs to the rest of the brain, especially for the left putamen, left thalamus and right superior temporal gyrus hub. CONCLUSIONS:Loss function in the vermis 8, left putamen, right superior temporal gyrus, right cerebellum 4-5, and left thalamus are important features for the pathophysiology of both patient groups. Among them, decreased connections in the left putamen, left thalamus, and right superior temporal gyrus mainly unveiled the specific pathophysiological differences between groups.

Background:Previous studies have indicated that non-motor symptoms are primary problems in focal dystonia, but limited data are available about cognitive function and their correlation with motor severity in generalized dystonia (GD). Methods:In the present study, we performed a case-control study and enrolled isolated genetic or idiopathic GD patients and age-, sex- and education-matched healthy controls (HC). Clinical characteristics, motor symptoms, psychiatric symptoms, and cognitive performance were assessed in both groups using various standardized rating scales and a comprehensive neuropsychological battery. Group comparisons, multiple linear regression analyses, and correlation analyses were performed, with adjustment for demographic and affective variables and correction for multiple comparisons. Results:Twenty patients with GD and matched healthy controls were enrolled and completed the assessments. Compared with HC, GD patients showed mild impairments, particularly in MoCA, executive function/attention, spatial ability, some tests in memory and similarities while other cognitive function did not differ between patients and HC. After adjustment and multiple comparison correction, MOCA, MOCA, executive function/attention and episodic memory remained the most consistent deficits. Several other cognitive differences were no longer significant after correction. No significant associations were found between cognitive performance and motor severity or disease duration. Cognitive performance did not differ between genetic and idiopathic subgroups or between medication groups. Conclusion:GD is associated with mild and heterogeneous cognitive impairments, with only a subset of deficits remaining robust after adjustment. Cognitive performance appears largely independent of motor severity, disease duration, medication use, and disease etiology.

Alacrima-achalasia-mental retardation syndrome(AAMR) is an extremely rare autosomal recessive genetic disorder caused by mutation in the GMPPA gene. Its pathogenesis is associated with congenital disorders of glycosylation. The clinical manifestations involve multiple system impairments, with alacrima, achalasia, and mental retardation as the core features. This article reports the diagnosis, treatment process and long-term follow-up outcomes after deep brain stimulation in one patient with AAMR complicated with dystonia, aiming to improve clinicians' understanding of this disease.

This study aims to evaluate a novel integrated teaching model for learning the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale Part III (MDS-UPDRS-III). The model combines self-directed video learning with case-based, in-person teaching. A total of 23 non-expertise neurology residents from Peking Union Medical College Hospital participated the study. The training program comprised four stages: video-based self-learning, a pre-training assessment (Case 1), expert-led offline instruction with case analysis, and a post-training assessment (Case 2). The rating accuracy and scoring errors for individual items were compared before and after the training. A subgroup analyses was conducted to assess the learning outcomes among physicians at different levels. The total scoring error decreased significantly after training (median score reduced from 13 to 12, P = 0.002). Significant improvements were observed in the accuracy of non-tremor items, such as speech, postural stability, and freezing of gait (p < 0.05), while the accuracy of certain tremor items declined due to increased case difficulty. Subgroup analysis indicated that participants with little or no prior MDS-UPDRS assessment experience, and junior physicians with 1–5 years of work experience demonstrated the most significant reduction in scoring errors (p < 0.05). In contrast, senior or highly experienced physicians showed no substantial improvement. The novel integrated teaching model that comprising self-directed video learning and case-based in-person sessions, enhances non-expertise neurology residents’ competency in MDS-UPDRS-III scoring. This approach is particularly beneficial for less experienced clinicians, allowing them to quickly master the scale, and has significant potential for widespread application in neurology training.

Lecanemab was widely used in China since June 2024 . Its real-world efficacy and safety profile have attracted significant attention. The aim of the study is to evaluate the clinical outcomes, adverse effects, and dynamic follow-up results of lecanemab in a Chinese population. The study enrolled AD patients treated with lecanemab at Peking Union Medical College Hospital (PUMCH), all confirmed by cerebrospinal fluid (CSF) and/or PET imaging (Aβ: AV45 or PiB; Tau: MK6240). Baseline assessments included demographic data collection, APOE genotyping, and comprehensive cognitive evaluations. MRI protocols comprised 3D T1, T2 FLAIR, SWI, T2, DWI, and DTI sequences. Adverse events were documented. At the 6-month follow-up, cognitive function, MRI, and Aβ-PET were reassessed (Centiloid quantification). Brain volumetrics were analyzed using United Imaging software (Z-scores derived). Plasma biomarkers (Aβ42, Aβ40, p -tau217, p -tau181) were measured quarterly via LUMIPULSE-G to track longitudinal trends. The cohort comprised 42 patients (M:F=12:30; age range 48-89 years [≤65:16; >65:26]). APOE ε4: wild-type (15), heterozygous (17), and homozygous (8). Baseline MMSE 8-29 (CDR 0.5-1). The safety outcomes include: ARIA-E (1 case), ARIA-H (1 case), ARIA-E+H (1 case) – all asymptomatic without treatment interruption; Infusion-related fever (6 cases, 14.3%); Other transient events (9 cases: insomnia, transient hypertension, headache); 1 central retinal vein occlusion and 1 elevated creatinine with unclear drug relationship. Efficacy in 20 Patients Completing 6-Month Follow-up was evaluated (Table 1). Cognitive Function remained stable (Table 2 + Figure 1). Aβ-PET Centiloid decreased significantly from 59.0±20.9 to 21.7±20.0 ( p <0.001, Figure 1). Significant reductions in total brain, gray/white matter volumes; ventricular/CSF volume expansion were found (Table 3 + Figure 2a). No significant DTI-ALSP changes found in 9 cases (Figure 2b). Among 19 tau-PET stratified patients (low burden:4; moderate-high:15), no differential treatment response was observed (possibly due to small sample size). Plasma biomarkers evaluation: Aβ42/Aβ40 ratio (baseline:0.0667 → 6mo:0.0708); p -tau217 (0.7801→ 0.762 pg/mL); p -tau181 (2.3426→ 2.1478 pg/mL). While statistical significance was not reached, improving trends were found. Six-month lecanemab treatment demonstrated Clinical stabilization with robust amyloid clearance, MRI brain volume reduction, preserved glymphatic function, promising biomarker trends requiring longer observation and favorable safety profile in Chinese patients.

Approximately 20% of dopa-responsive dystonia (DRD) cases remain genetically unresolved. Using whole-genome sequencing, we identified two TH variants in a young DRD patient, including a novel deep intronic variant. Minigene assays confirmed that this variant causes aberrant splicing. The patient exhibited an atypical disease progression compared with typical TH-associated DRD cases, presenting with generalized dystonia, episodic hypotonia, Parkinsonism, and oromandibular dyskinesias. These findings, including the first known documented deep intronic TH variant, expand our understanding of TH-associated DRD's phenotypic and genotypic spectrum, aiding clinical evaluation.

BACKGROUND:The safety and effectiveness of deep brain stimulation of the subthalamic nucleus (STN-DBS) for the treatment of dystonia lack high-level evidence-based medical support. This study aimed to clarify the efficacy and safety of STN-DBS and perform a post hoc analysis comparing it with DBS of the internal globus pallidus (GPi-DBS). METHODS:This multicentre, randomised, double-blind, controlled trial included 67 patients aged 6-60 years old diagnosed with genetic or idiopathic isolated generalised or segmental dystonia. They were enrolled from seven hospitals in China and randomly assigned to undergo GPi-DBS or STN-DBS. After surgery, they were randomised to receive either neurostimulation or sham stimulation for 3 months. At the 3-month follow-up, neurostimulation was also initiated in the sham stimulation group, and all patients were followed up for more than 3 years after treatment. The primary outcome was the Burke-Fahn-Marsden Dystonia Rating Scale movement (BFMDRS-M) score. RESULTS:In the STN group, the neurostimulation subgroup exhibited significant improvement (p<0.001), which is also superior to the sham stimulation subgroup (p=0.028) at 3-month follow-up. At the 6-month and >3-year follow-ups, all patients receiving STN-DBS showed a significant improvement in BFMDRS-M scores (p<0.001). Further post hoc analysis revealed that both STN-DBS and GPi-DBS could produce similar therapeutic effects on motor symptoms (P6 months=0.865, P>3 years=0.905). There were no ongoing serious adverse events throughout the study. CONCLUSIONS:For isolated generalised and segmental dystonia patients, the STN is a selectable DBS target with ensured safety and efficacy. STN-DBS and GPi-DBS may achieve comparable therapeutic effects on motor symptoms. TRIAL REGISTRATION NUMBER:NCT03017586.

BACKGROUND:DaxibotulinumtoxinA for injection (DAXI), the first long-acting botulinum toxin (BoNT) type A, is FDA approved for cervical dystonia (CD). DAXI's novel formulation, which includes a custom-engineered peptide, is designed to provide an extended duration of clinical benefit. OBJECTIVE:To evaluate the pooled efficacy and safety of DAXI for CD across two phase 3, multicenter, randomized, double-blind, placebo-controlled trials: ASPEN-1, conducted in North America and Europe, and ASPEN-1-CN, a similarly designed, smaller pivotal clinical trial, conducted in China. METHODS:Adults with moderate-to-severe CD were randomized (3:3:1) to receive DAXI 125U, DAXI 250U, or placebo. The primary endpoint was change from baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score averaged across weeks 4 and 6. A key secondary endpoint was duration, defined as time until loss of >80 % of peak effect. RESULTS:In all, 357 subjects were randomized and received DAXI 125U (n = 149), DAXI 250U (n = 154), or placebo (n = 54). DAXI 125U (-12.0) and DAXI 250U (-11.9) significantly improved the mean TWSTRS total score versus placebo (-4.6; P < 0.0001). Median (95 % CI) duration of effect was 24.1 (20.6-28.9) weeks for DAXI 125U and 22.0 (20.1-24.3) weeks for DAXI 250U. Rates of treatment-related dysphagia (125U: 4.7 %, 250U: 4.5 %) and muscle weakness (125U: 5.4 %, 250U: 4.5 %) were low for both active doses. CONCLUSIONS:This pooled analysis of two phase 3 trials demonstrates that DAXI is an effective, safe, and long-acting treatment for CD. Key adverse events occurred at rates lower than prior pivotal trials of BoNTs for CD.

Background IRF2BPL -related disorder ,also known as neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures, NEDAMSS, is a rare neurogenetic disorder. It typically presents with developmental delay or seizures as the initial symptoms. This report describes a case of IRF2BPL mutation with cervical dystonia as the initial symptom and further explores the treatment strategies for movement symptoms. Case Presentation: A 17-year-old female presented with involuntary leftward head rotation and mild lower limb tremors three years ago. She was diagnosed with cervical dystonia, and after receiving botulinum toxin injections, her symptoms completely resolved. In the following three years, the patient developed worsening lower limb tremors, diagnosed as myoclonic seizures based on EEG findings, along with dysarthria and ataxia. Whole-exome sequencing confirmed the IRF2BPL mutation, and the final diagnosis was IRF2BPL -related syndrome. The patient was treated with carbamazepine, which alleviated the tremor symptoms. Conclusion The treatment of IRF2BPL -related disorder primarily focuses on seizure control, while movement symptoms, such as dystonia, significantly affect the patient's quality of life but are often overlooked. In this case, botulinum toxin effectively controlled the patient's dystonia, providing a new approach to treating movement symptoms.

Background:The most common spread of blepharospasm (BSP) is to the oromandibular region, labeled as blepharospasm-oromandibular dystonia (BOM). We aimed to identify shared and different functional changes in BSP and BOM, trying to unveil the pathogenesis of these disorders and the mechanism of dystonic spread. Materials and methods:This single center study recruited 16 BSP patients, 16 BOM patients and 20 healthy controls (HC). Clinical information and resting-state fMRI images were collected. Dynamic amplitude of low-frequency fluctuations (dALFF) was calculated using the sliding window method. Intergroup differences in static ALFF (sALFF) and dALFF were examined. Using dALFF results, seed-based static and dynamic functional connectivity (FC) were constructed to compare connectivity changes in BSP and BOM networks. Correlations between dynamic parameters and disease severity scores were analyzed using Spearman partial correlation. Results:Compared with HC, BSP and BOM presented increased dALFF in the bilateral basal ganglia, bilateral supplementary motor area, right precentral gyrus, and bilateral cingulate gyrus. BOM further demonstrated decreased sALFF in the left cerebellum. Compared with HC, BOM patients had decreased sFC in the network involving the sensorimotor cortex, supplementary motor area, basal ganglia, cerebellum, and brainstem. In addition, decreased dFC strength was found between the right pallidum and cerebellum. Comparing with BSP patients, BOM patients showed decreased sFC and dFC strength in a similar but limited pattern. Clinical scores of BSP severity were significantly correlated with dALFF in some of these important regions. Conclusions:Our results demonstrated common brain regions with impaired functional activity in BSP and BOM patients. Further, BOM is featured with widespread connectivity reduction in the sensorimotor cortico-basal ganglia-brainstem-cerebellar network deriving from these key regions. These findings could help investigate mechanisms of dystonia spread and potentially facilitate disease-modifying therapies.

Hereditary spastic paraplegia (HSP) is a rare genetically heterogeneous neurodegenerative disorder. The most common type of HSP is caused by pathogenic variants in the SPAST gene. Various hypotheses regarding the pathogenic mechanisms of HSP-SPAST have been proposed. However, a single hypothesis may not be sufficient to explain HSP-SPAST. To determine the causative gene of autosomal dominant HSP-SPAST in a pure pedigree and to study its underlying pathogenic mechanism. A four-generation Chinese family was investigated. Genetic testing was performed for the causative gene, and a splice site variant was identified. In vivo and in vitro experiments were conducted separately. Western blotting and immunofluorescence were performed after transient transfection of cells with the wild-type (WT) or mutated plasmid. The developmental expression pattern of zebrafish spasts was assessed via whole-mount in situ hybridization. The designed guide RNA (gRNA) and an antisense oligo spast-MO were microinjected into Tg(hb9:GFP) zebrafish embryos, spinal cord motor neurons were observed, and a swimming behavioral analysis was conducted. A novel heterozygous intron variant, c.1004 + 5G > A, was identified in a pure HSP-SPAST pedigree and shown to cosegregate with the disease phenotypes. This intron splice site variant skipped exon 6, causing a frameshift mutation that resulted in a premature termination codon. In vitro, the truncated protein was evenly distributed throughout the cytoplasm, formed filamentous accumulations around the nucleus, and colocalized with microtubules. Truncated proteins diffusing in the cytoplasm appeared denser. No abnormal microtubule structures were observed, and the expression levels of α-tubulin remained unchanged. In vivo, zebrafish larvae with this mutation displayed axon pathfinding defects, impaired outgrowth, and axon loss. Furthermore, spast-MO larvae exhibited unusual behavioral preferences and increased acceleration. The adverse effects of premature stop codon mutations in SPAST result in insufficient levels of functional protein, and the potential toxicity arising from the intracellular accumulation of spastin serves as a contributing factor to HSP-SPAST.

BackgroundIntranasal transplantation of ANGE-S003 human neural stem cells showed therapeutic effects and were safe in preclinical models of Parkinson’s disease (PD). We investigated the safety and tolerability of this treatment in patients with PD and whether these effects would be apparent in a clinical trial.MethodsThis was a 12-month, single-centre, open-label, dose-escalation phase 1 study of 18 patients with advanced PD assigned to four-time intranasal transplantation of 1 of 3 doses: 1.5 million, 5 million or 15 million of ANGE-S003 human neural stem cells to evaluate their safety and efficacy.Results7 patients experienced a total of 14 adverse events in the 12 months of follow-up after treatment. There were no serious adverse events related to ANGE-S003. Safety testing disclosed no safety concerns. Brain MRI revealed no mass formation. In 16 patients who had 12-month Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) data, significant improvement of MDS-UPDRS total score was observed at all time points (p<0.001), starting with month 3 and sustained till month 12. The most substantial improvement was seen at month 6 with a mean reduction of 19.9 points (95% CI, 9.6 to 30.3; p<0.001). There was no association between improvement in clinical outcome measures and cell dose levels.ConclusionsTreatment with ANGE-S003 is feasible, generally safe and well tolerated, associated with functional improvement in clinical outcomes with peak efficacy achieved at month 6. Intranasal transplantation of neural stem cells represents a new avenue for the treatment of PD, and a larger, longer-term, randomised, controlled phase 2 trial is warranted for further investigation.

Objective To identify the pathogenic variants in 110 patients with essential tremor(ET).Methods Clinical data and peripheral blood samples of ET patients were collected from the Department of Neurology of Peking Union Medical College Hospital and then the genomic DNA was extracted.Dynamic mutation detection of NOTCH2NLC was performed in patients with essential tremor by triplet repeat primed PCR(TP-PCR).Since ET is as-sociated with multiple mechanisms of neuro-degeneration,the next generation sequencing(NGS)panel targeting neu-rodegenerative associating genes were performed to check pathogenic variants in additional genes.Results A total of 110 ET patients and 187 matched control individuals were recruited.The age of onset in the current ET group was(36.30±17.64)years,and 74.8%patients had a family history.No abnormal trinucleotide repeat expansion in NOTCH2NLC was identified.The repeat number of(GGC)n lied within normal ranges between 10－47(average 18.6±5.4).Variants burden analysis showed association of ET with PLA2G6.Three rare variants in four patients in PLA2G6 were identified with unknown significance.Conclusions Dynamic mutations of NOTCH2NLC are uncom-mon in ET patients and that suggests need of more researches for further exploring the genetic mechanism of ET.

Introduction The pedunculopontine nucleus (PPTg) is a vital interface between the basal ganglia and cerebellum, participating in modulation of the locomotion and muscle tone. Pathological changes of the PPTg have been reported in patients and animal models of dystonia, while its effect and mechanism on the phenotyping of dystonia is still unknown. Methods In this study, a series of behavioral tests focusing on the specific deficits of dystonia were conducted for mice with bilateral and unilateral PPTg excitotoxic lesion, including the dystonia-like movements evaluation, different types of sensory-motor integrations, explorative behaviors and gait. In addition, neural dysfunctions including apoptosis, neuroinflammation, neurodegeneration and neural activation of PPTg-related motor areas in the basal ganglia, reticular formations and cerebellum were also explored. Results Both bilateral and unilateral lesion of the PPTg elicited dystonia-like behaviors featured by the hyperactivity of the hindlimb flexors. Moreover, proprioceptive and auditory sensory-motor integrations were impaired in bilaterally lesioned mice, while no overt alterations were found for the tactile sensory-motor integration, explorative behaviors and gait. Similar but milder behavioral deficits were found in the unilaterally lesioned mice, with an effective compensation was observed for the auditory sensory-motor integration. Histologically, no neural loss, apoptosis, neuroinflammation and neurodegeneration were found in the substantia nigra pars compacta and caudate putamen (CPu) following PPTg lesion, while reduced neural activity was found in the dorsolateral part of the CPu and striatal indirect pathway-related structures including subthalamic nucleus, globus pallidus internus and substantia nigra pars reticular. Moreover, the neural activity was decreased for the reticular formations such as pontine reticular nucleus, parvicellular reticular nucleus and gigantocellular reticular nucleus, while deep cerebellar nuclei were spared. Conclusion In conclusion, lesion of the PPTg could elicit dystonia-like behaviors through its effect on the balance of the striatal pathways and the reticular formations.

Objective:To elucidate the clinical and genetic characteristics of PLA2G6-related parkinsonism. Methods:The clinical, imaging and genetic data of 6 patients with PLA2G6-related parkinsonism admitted to Peking Union Medical College Hospital from January 2015 to December 2022 were retrospectively collected and analyzed. The prognosis was followed up through phone call. Results:There were 3 male and 3 female patients, and the age of disease onset was (24.3±5.4) years. Phenotypically, 5 of them had dystonia-parkinsonism (DP) with obvious atrophy of cerebellum and 1 presented as early-onset Parkinson′s disease (EOPD) with no brain structural abnormality. Only 1 patient presented with abnormal brain iron deposition. All of the patients were partially responsive to levodopa. Three cases underwent levodopa challenge test with the objective levodopa responsiveness varied from 10.3% and 10.6% in 2 DP patients, to 77.0% in 1 EOPD patient. Levodopa-induced dyskinesias were present in 4 of them, and all appeared within the first year since the initiation of dopaminergic treatment. Two patients underwent bilateral deep brain stimulation (DBS) of subthalamic nucleus and globus pallidus internus respectively, albeit revealed poor outcome. Genetically, 8 PLA2G6 variants were identified. Two of them were found to be novel (c.1973A>G and exon2 heterozygous deletion), and the most frequent variant was the c.991G>T mutation which was detected in 4 patients. Conclusions:The phenotype of PLA2G6-related parkinsonism is complex. Cerebellar atrophy is a frequent magnetic resonance imaging feature. Levodopa responsiveness tends to depend on the clinical phenotype, and EOPD is better than DP. DBS might not be promising in DP patients with obvious cerebral atrophy. The c.991G>T mutation is the most frequent mutation, suggesting a common founder effect.

Objective:To summarize genotype-phenotype features and explore the long-term outcome of bilateral globus pallidus interna deep brain stimulation (DBS) in chorea-acanthocytosis (ChAc) patients.Methods:Seven patients who diagnosed with ChAc were included in this study from April 2016 to April 2018 at Peking Union Medical College Hospital. Whole-exome sequencing was used for gene analysis of the patients, and the genotype-phenotype features of these patients were recorded. All patients underwent the DBS surgery, and long term follow-up was conducted before surgery, 3 months, 6 months, 1 year, 3 years, and 5 years after surgery. Patients were scored using the Unified Huntington Disease Rating Scale (UHDRS) to evaluate the long-term efficacy of DBS surgery.Results:The main clinical manifestations in all 7 patients were oro-faciol-ingual dyskinesia, limb chorea, dystonia, and dysarthria. Genetic testing found that all patients had VPS13A gene pathogenic variation, but the type of variation was different. The UHDRS motor score before bilateral pallidal DBS surgery was 37.00±16.68, which significantly improved to 19.67±5.99 at 1 year post-surgery, with average improvement of 46.8% ( t=5.20, P=0.003), to 23.86±8.99 at 3 years post-surgery, with average improvement of 35.5% ( t=3.08, P=0.022), and to 29.00±14.97 at 5 years post-surgery, with average improvement of 21.6% ( t=1.41, P=0.217). The symptoms of patients were most significantly improved in limb chorea and oro-facio-lingual dyskinesia. However, at the 5-year follow-up, severe dystonia and gait difficulties reoccurred in 3/7 and 4/7 of the patients, respectively. The patient′s dysarthria had not been effectively improved. Conclusions:The clinical manifestations of patients with ChAc are relatively consistent, but there is significant genetic heterogeneity. Bilateral pallidal DBS therapy is effective for patients with ChAc, but the long-term efficacy decreases with disease progression.

Table S1 Overview of characteristics for 9 cases diagnosed with dystonia-deafness syndrome related to a mutation in the β-actin (ACTB) gene. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Objective . To explore the efficacy and safety of pramipexole sustained release (SR) versus pramipexole immediate release (IR) in treating nocturnal symptoms in levodopa-treated Chinese patients with advanced Parkinson’s disease (PD) and sleep disturbances. Method . SUSTAIN was an open-label, randomised, active-controlled parallel group exploratory pilot study (NCT03521635). A total of 98 patients were randomly allocated (1 : 1) to either pramipexole SR ( n  = 49) or pramipexole IR ( n  = 49) groups. The primary endpoint was a change from baseline in PD Sleep Scale 2 nd version (PDSS-2) total score at 18 weeks. A reduction in score represents improvement. Secondary endpoints included Nocturnal Hypokinesia Questionnaire, Scales for Outcomes in PD Sleep Scale, Early Morning Off (EMO), Epworth Sleepiness Scale, PD Questionnaire-8, and responder rates as measured by PDSS-2 total score (<18), EMO scores (≥1 point change), Clinical Global Impression Improvement scale, and Patient Global Impression-Improvement scale. Other endpoints included motor complications (MDS-UPDRS part IV) score. Adverse events were evaluated for each group. Results . The mean pramipexole dose for both groups was 1.5 mg/day at week 18, and the mean changes in PDSS-2 total score for pramipexole SR and IR were –13.7 (95% CI –16.0 to –11.4) and –14.4 (–16.8 to –12.0) (difference of 0.7; p = 0.688). Change from baseline for both groups achieved the minimal clinical important difference threshold (MCID = –3.44). No significant difference was observed in change from baseline for other measures of sleep-related disturbances or responder rates. For motor complications, a greater improvement in MDS-UPDRS part IV score was observed in pramipexole SR over IR (–3.4 vs –2.3; treatment group difference: –1.1; p = 0.036). Both groups had comparable safety profiles. Conclusion . In Chinese patients with advanced PD and sleep disturbances, pramipexole SR and IR have similar benefits in the treatment of nocturnal symptoms and safety, and an improvement from baseline in nocturnal symptoms was observed regardless of pramipexole formulation.