This systematic review synthesised evidence on the acoustic and perceptual characteristics of voice tremor (VT) in the adult population, the speech tasks used in VT evaluations, and the impact of VT on quality of life (QoL). Following PRISMA guidelines, 58 studies were included and assessed for risk of bias. Acoustically, VT is consistently characterised by rhythmic modulation of frequency and amplitude. Secondary acoustic measures, including jitter, shimmer, noise, and cepstral measures, demonstrate fluctuations in VT, but are not defining features. Perceptually, listeners show greater sensitivity to the extent of modulation than to the rate of frequency and amplitude. There were no definitive aetiology-specific patterns. Sustained vowel phonation best captures VT, whereas connected speech tends to mask modulation despite providing ecological validity. A significant gap was identified in QoL evaluations, limiting the holistic understanding of VT. Overall, the included studies show a moderate to low risk of bias.

Essential Tremor (ET) is a highly heterogeneous movement disorder with a strong genetic basis. However, the etiology of ET is unclear, largely due to its clinical heterogeneity and frequently observed comorbidities. We conducted a three-part study to investigate the genetic basis of ET in relation to co-occurring phenotypes, aiming to assess causal directionality and to clarify phenotypic heterogeneity. First, we used Mendelian Randomization (MR) to test for directional, causal relationships between ET and common co-occurring traits. We then identified pleiotropic single nucleotide polymorphisms (SNPs) shared between ET and these traits, mapped them to genes, and performed gene ontology enrichment analyses. Finally, we applied genomic structural equation modeling (g-SEM) to group traits by shared genetic variance and evaluate their influence on ET. MR analyses did not reveal causal relationships, likely due to high genetic pleiotropy. Gene enrichment analyses of shared SNPs suggested involvement of certain pathways, but these signals were driven by limited gene overlap. SEM identified a well-fitting latent model of shared genetic architecture, but it explained only ~2% (±9%) of ET variance. Our findings suggest that ET and its comorbidities may share complex genetic architecture not captured by common variants alone. The limited variance explained by MR and SEM highlights the need for rare variant and multi-omics studies to better understand the biological mechanisms underlying ET and its heterogeneity.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting carriers of premutation expansions (55-200 CGG repeats) in the fragile X messenger ribonucleoprotein 1 (FMR1) gene. Despite its clinical significance, FXTAS currently lacks reliable molecular markers for disease monitoring and evaluation of therapeutic efficacy.

Background and Objectives: Parkinson's disease (PD) is a neurodegenerative disorder marked by bradykinesia, rigidity, and tremor. While deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) effectively alleviates motor symptoms, the potential of targeting the substantia nigra pars reticulata (SNr) is less understood. This study investigates the effects of mid-term DBS of the SNr on motor function and neuroplasticity in a 6-hydroxydopamine (6-OHDA) rat model of PD. Methods: Adult male Sprague-Dawley rats (280-300 g) were divided into healthy control (n = 10), PD (n = 9), sham-DBS (n = 7), and SNr-DBS (n = 7) groups. Bilateral striatal 6-OHDA lesions induced PD. High-frequency (130 Hz, 60 µs) SNr-DBS was delivered for 14 days. Locomotor activity (open-field), gait (footprint method), and motor coordination (rotarod) were assessed. Tyrosine hydroxylase (TH) expression in the SN and c-Fos and BDNF expression in the cerebellum, prefrontal cortex (PFC), and ventrolateral thalamus were analyzed histologically. Results: SNr-DBS significantly improved ambulation and horizontal activity compared to the PD group (p < 0.05). Gait analysis showed significant improvements in forelimb/hindlimb stride length and stance width, while rotarod performance indicated enhanced motor coordination (p < 0.05). Histology revealed increased TH expression in the SN and elevated c-Fos and BDNF levels in the cerebellum, PFC, and thalamus in the SNr-DBS group vs. PD rats (p < 0.05). Conclusions: Mid-term SNr-DBS produced significant functional gains in motor activity and coordination in a 6-OHDA PD model, together with molecular evidence of dopaminergic enhancement and neuroplastic activation. These translational findings suggest that targeting the SNr may offer a clinically relevant alternative for patients with PD, particularly for those who may not optimally respond to conventional STN or GPi stimulation.

Background and objectives: Movement disorders are an underrecognized phenomenon in Myelin Oligodendrocyte Glycoprotein-Associated Disease (MOGAD). The aim of this paper was to summarize all movement disorders previously described in MOGAD. Materials and Methods: We conducted a systematic literature search in PubMed, Web of Science, and Scopus in English, focusing on patients with MOGAD exhibiting a movement disorder, i.e., ataxia, tremor, dystonia, parkinsonism, chorea, athetosis, myoclonus, ballism, tics, stereotypies, dyskinesia. Results: We included 58 studies, with a total of 91 patients with MOGAD and a movement disorder (45.6% male, 54.4% female). Movement disorders had a mean latency of 2.1 years (±6.9, 0-42) after MOGAD onset; however, they could be the presenting feature (in approximately 70% of cases), especially in pediatric patients. Cerebellar ataxia was the most common movement disorder, occurring in 77 patients (84.6%). Tremor, postural and/or kinetic, was the second most common movement disorder (15%). Dystonia was reported in 8.8%, presenting as cervical, or limb dystonia or stereotyped dystonic episodes. Myoclonus and hypokinetic movement disorders were rare. Subcortical (in 60%), brainstem and cerebellar lesions (in 50% respectively) were the most common imaging findings. The most common accompanying symptoms were encephalopathy, fever and headache. Approximately half of the patients made a full recovery, and the other half showed a significant improvement in the movement disorder after immunomodulatory treatment, most commonly steroids. Conclusions: The new onset of a movement disorder, especially ataxia, in a young patient should prompt the search for MOGAD or can indicate a relapse in patients with an established diagnosis.

Background: Parkinson's disease (PD) is clinically heterogeneous, yet the genetic architecture underlying this heterogeneity remains incompletely understood. We examined the genetic correlates of four complementary PD subtyping frameworks: the clinical motor subtype (tremor-dominant [TD] vs. postural instability/gait difficulty [PIGD]), alpha-synuclein seed amplification assay status (SAA+ vs. SAA-), the pathological subtype (brain-first vs. body-first, based on the presence of REM sleep behavior disorder), and the data-driven subtype (diffuse malignant [DM] vs. mild-motor predominant [MMP] vs. intermediate [IM]). Methods: We analyzed 1390 PD patients from the Parkinson's Progression Markers Initiative (PPMI) with genotypes available for seven PD-associated genes (LRRK2, GBA1, SNCA, PRKN, PINK1, PARK7, VPS35), including specific variant resolutions (LRRK2 G2019S, R1441G/C/H; GBA1 N409S, severe variants; SNCAA53T), and APOE (ε2/ε3/ε4 alleles). Genetic variant frequencies were compared across subtypes using chi-square or Fisher's exact tests with the Benjamini-Hochberg false discovery rate (FDR) correction. Effect sizes were quantified using Cramér's V. multivariable logistic regression estimated adjusted odds ratios with Wald-based 95% confidence intervals. Results: Among genotyped PD patients, LRRK2 carriers constituted 13.7% (190/1390; 170 G2019S, 18 R1441G/C/H), GBA1 8.6% (119/1390; 96 N409S, 23 severe), and SNCA 2.0% (28/1390; all A53T). APOE ε4 carriers comprised 23.4% (323/1380). SAA-negative patients were markedly enriched for LRRK2 variants (37.1% vs. 10.2%, p = 3.7 × 10-19, q < 0.001, V = 0.25), specifically G2019S (28.5% vs. 9.6%, p = 4.9 × 10-11, q < 0.001) and R1441G/C/H (7.9% vs. 0.5%, p = 2.7 × 10-12, q < 0.001). Body-first PD was enriched for GBA1 carriers (12.3% vs. 6.7%, p = 0.004, q = 0.021) and had less LRRK2 carriers (7.9% vs. 15.0%, p = 0.002, q = 0.013). The DM subtype had the highest GBA1 frequency (14.0% vs. MMP 5.9%, p < 0.001, q = 0.003). After FDR correction, 10 out of 48 univariate tests remained significant. Clinical subtypes (TD vs. PIGD) showed only nominal LRRK2 differences that did not survive FDR correction. The APOE genotype did not differ across any framework. Conclusions: PD subtypes defined by alpha-synuclein pathology (SAA), pathological onset pattern (brain-first/body-first), and data-driven classification (DM/MMP/IM) show distinct genetic profiles that survive multiple comparison correction. LRRK2 variants strongly associate with SAA negativity (V = 0.25); GBA1 variants associate with the severe body-first onset and the diffuse malignant subtype.

BACKGROUND Kennedy disease, also known as spinal and bulbar muscular atrophy (SBMA), is a rare and incurable X-linked neuromuscular disorder mainly affecting men aged 30 to 60 years. Polymyositis can present similarly, but can be excluded by measuring muscle enzymes, performing muscle imaging, and electromyography. This report describes the case of a 52-year-old man with a 10-year history of progressive limb weakness due to Kennedy disease, established by genetic testing. CASE REPORT A 52-year-old man presented with a 10-year history of gradually progressive proximal limb weakness and persistently elevated creatine kinase levels ranging from 808-2300 U/L (normal 39-308 U/L). One year prior to this admission, the limb weakness had worsened, but initial electromyography, neuroimaging, and muscle biopsy showed no specific abnormalities. Despite a trial of immunosuppressive therapy due to suspected polymyositis, there was no clinical improvement. Neurological examination later revealed gynecomastia, proximal muscle atrophy, and bilateral tongue atrophy with tremor. Electromyography showed chronic neurogenic changes and reduced sensory nerve action potentials. Repeat expansion analysis identified a hemizygous pathogenic CAG repeat expansion in exon 1 of the androgen receptor gene using a short-read next-generation sequencing-based repeat detection algorithm (ExpansionHunter), with an estimated repeat number of 51 (range 50-53). At 6-month follow-up, the patient demonstrated mild progression of motor symptoms but remained functionally stable. CONCLUSIONS This report presents a rare case of Kennedy disease, initially diagnosed as polymyositis, and highlights the importance of follow-up with genetic testing when neurological and electromyography investigations are not typical for polymyositis. Early identification of Kennedy disease helps avoid unnecessary immunosuppressive treatments.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, affecting nearly 0.3% of the global population. Its pathology is primarily linked to dopaminergic neuronal loss in the substantia nigra, leading to hallmark motor impairments such as tremor, rigidity, and bradykinesia. A defining molecular feature of PD is the aberrant aggregation of α-synuclein, alongside dysregulation of proteins such as MAO-B, COMT, and LRRK2, which collectively contribute to disease progression. Within the current research, these proteins were designated as docking targets to explore the enzyme-modulating activity and the therapeutic promise of steroidal alkaloid candidates from the genus Fritillaria, a taxon long recognized in traditional medicine for its neuroprotective properties. Docking analyses revealed that among 70 compounds analysed, compound 65 exhibited strong MAO-B inhibitory activity (binding energy - 11 kcal/mol), compound 5 demonstrated pronounced COMT inhibition (- 9 kcal/mol), and compound 42 emerged as a promising dual-acting agent capable of targeting both enzymes. Favorable physicochemical attributes, including optimal lipophilicity, low polar surface area, and blood-brain barrier permeability, further support their suitability. These findings identify preliminary computational leads that warrant further experimental validation for potential future development.