Search Results (703)

Background: Juvenile-onset Huntington disease (JoHD) is a rare form of Huntington disease characterized by symptom onset at or before 20 years of age. Early manifestations are often non-choreic and may be attributed to developmental, psychiatric, movement, metabolic, or epileptic disorders. We described three molecularly confirmed cases and examined early manifestations, diagnostic pathways, and epilepsy. Methods: We conducted a retrospective case series and a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 systematic review of PubMed, Scopus, and Web of Science Core Collection through 5 July 2026. The strict patient-level synthesis required attributable onset at or before 20 years, patient-specific molecular confirmation of a pathogenic HTT repeat expansion, and extractable clinical data. Complementary aggregate or linked reports using closely aligned JoHD criteria were retained for context but excluded from patient-level calculations. Results: The cases included childhood-onset JoHD with drug-resistant epilepsy, adolescent-onset JoHD with progressive motor-cognitive decline and epilepsy in a known Huntington disease pedigree, and childhood-onset JoHD without available family history, in whom status epilepticus prompted renewed diagnostic evaluation. Ninety-three reports were included; of these, 81 contributed 228 unique patients and 12 provided complementary data. Early manifestations were heterogeneous and broadly consistent with previously described childhood-onset JoHD phenotypes. Diagnostic delay was extractable in 180/228 patients; among 172 with point estimates, the median was 4.0 years. Definite epilepsy was reported in 60/145 patients with ascertainable seizure status and was descriptively more frequent in childhood-onset (<10 years) than adolescent-onset (10–20 years) JoHD (49/84 [58.3%] vs. 11/57 [19.3%]). Conclusions: JoHD should be considered in children and adolescents with progressive multisystem neurological involvement, particularly when epilepsy occurs with developmental regression, gait or speech deterioration, pyramidal or extrapyramidal signs, basal-ganglia abnormalities, or a compatible family history. Full article

Background: The cerebellum integrates sensory information to maintain balance and posture, allowing movement guidance. Perinatal damage to this brain region correlates with an increased incidence of Autism Spectrum Disorder (ASD), a major neurodevelopmental condition where poor motor performance in eye–hand coordination, balance and gait is observed. The cerebellum of ASD individuals is affected by reduced GABAergic signaling that leads to an excitatory/inhibitory imbalance. Methods: Motor coordination behavior were tested and Western blot essays performed to study the developmental expression of GABAergic signaling proteins, namely GABA_A receptor (α1, α2 and β1) subunits and glutamate decarboxylase 67 (GAD67), in CD1 mice prenatally exposed to valproic acid (VPA), a preclinical model of ASD. Results: The VPA group exhibited motor coordination deficits on postnatal day 30 (P30) compared to the control. The expression profiles for the control group revealed that GABA_A-α1 increased linearly, while GABA_A-β1 displayed the opposite pattern and GABA_A-α2 presented one peak of expression (P8). GAD67 decreased from embryonic day 16 (E16) to P8 but increased linearly after the first week of postnatal development (P8-P30). The developmental expression profile for all these proteins was disrupted by prenatal exposure to VPA. Conclusions: Motor coordination deficits correlate with a downregulated expression of GABA_A (α1, α2 and β1) subunits and GAD67 through cerebellar development in individuals that were prenatally exposed to VPA. Full article

Background/Objectives: Cerebral small vessel disease (CSVD) is an important contributor to motor impairment. Cortical cerebral microinfarct (CCMI) is an emerging imaging marker of CSVD. Although its association with cognitive impairment has been well established, its relationship with motor function remains unclear. We explored associations of CCMI with motor performance at baseline and 1-year follow-up in this secondary analysis of data from the China Imaging-based Biobank of Cerebral Small Vessel Diseases. Methods: CCMI was assessed on baseline brain magnetic resonance imaging. Motor function was assessed at baseline and at 1-year follow-up. Outcomes were gait speed, poor balance performance (Short Physical Performance Battery balance score ≤ 2), abnormal gait (Scale for the Assessment and Rating of Ataxia gait score ≥ 2), and repeated chair-stand time. Gait speed was the primary outcome and all other motor outcomes were secondary. Multivariable linear and logistic regression models were used, with Benjamini–Hochberg correction applied to secondary outcomes. Results: The analysis included 192 patients, of whom 74 had 1-year follow-up motor data. At baseline, 55 patients (28.65%) had CCMI. Compared with patients without CCMI, those with CCMI had lower gait speed [0.92 (0.75–1.12) vs. 1.05 (0.87–1.16) m/s]. They also had higher prevalences of poor balance performance (29.09% vs. 14.60%) and abnormal gait (63.64% vs. 36.50%). However, fully adjusted analyses provided no conclusive evidence of baseline associations. At 1-year follow-up, CCMI was associated with slower gait speed after adjustment for demographic factors, baseline gait speed, and total CSVD burden (adjusted β −0.16, 95% CI −0.24 to −0.08; p < 0.001). CCMI was also nominally associated with longer repeated chair-stand time (adjusted β 2.07, 95% CI 0.39–3.75; nominal p = 0.02; adjusted p = 0.06), but this association did not survive correction for multiple comparisons. Conclusions: CCMI was associated with slower gait speed at 1-year follow-up in patients with CSVD. This finding is hypothesis-generating and requires confirmation. Full article

Frailty syndrome and Alzheimer’s disease are prevalent conditions in the elderly that are associated with aging, decreased quality of life, and a significant healthcare burden. Evidence for a relationship between physical frailty and neurodegenerative decline is accumulating. This study analyzed two independent datasets, a frailty dataset based on gait and mobility parameters and an AD dataset with clinical, functional and lifestyle variables, in order to evaluate and compare their classification performance using machine learning. Features were optimized using dimensionality reduction techniques to keep predictors of clinical significance and hyperparameter optimized Random Forest models were built to develop the best model. Evaluation was performed with Accuracy, F1-score, Matthews Correlation Coefficient and Area Under the Curve. The results showed that the models constructed on the whole AD dataset achieved maximum predictive power with an accuracy of 0.946, which was slightly increased to an accuracy of 0.948 after the selection of significant features. Diagnostic models based on frailty were able to demonstrate an ACC predictive capacity of 0.6418, and in terms of feature selection, improvements appeared in all indicators. Regarding the features derived from Alzheimer’s disease associated with geriatric frailty, they managed to surpass the ACC frailty features of 0.741 alone, suggesting some intercalation mechanisms between neurodegeneration and physical vulnerability. These findings show that machine learning algorithms accompanied by feature selection improve clinical discrimination and prediction of frailty and neurodegenerative disorders, which offers a promising aspect for geriatric assessment. The frailty models analyzed demonstrated an ACC predictive capacity of 0.6418, even though feature selection improved all indicators. Alzheimer’s disease-derived features associated with frailty outperformed features in the frailty dataset with an ACC of 0.741, suggesting the mechanism of overlap between neurodegeneration and physical vulnerability. These results support the theory of a motor-cognitive aging continuum, indicating that algorithmic machine learning techniques coupled with feature selection mainly provide computational validation for the biological intersection of neurodegeneration and physical frailty, rather than forming an independent predictive clinical model. Using these algorithms the study highlights shared pathophysiological mechanisms, providing a significant insight into systemic geriatric deterioration. Full article

Population aging and the rising prevalence of motor disorders are driving demand for assistive lower-limb robotic systems capable of decoding user intention rather than merely providing mechanical support. We present CM-FuseNet, an attention-augmented hybrid Brain–Computer–Muscle Interface (BCMI) that simultaneously fuses cortical concentration indices extracted from electroencephalography (EEG) and lower-limb intention patterns derived from electromyography (EMG) to adaptively control a 4-DOF assistive lower-limb exoskeleton. To eliminate the burden of human-subject ethics review and to ensure reproducibility of the proposed methodology, all validation is performed exclusively on (i) permissively licensed open-access biomedical datasets, (ii) high-fidelity OpenSim 4.5 and MuJoCo 3.1 musculoskeletal–exoskeleton co-simulation, and (iii) limited self-experimentation by the corresponding author with non-invasive consumer-grade devices. Three components are introduced: (i) a log-tanh normalized concentration index CI in (0, 1) derived from the $(P_{SMR}+P_{Mid-Beta})/P_{Theta}$ ratio; (ii) a bidirectional Cross-Modal Transformer (CMT) with eight-head self- and cross-attention; and (iii) a Soft Actor-Critic (SAC) reinforcement-learning controller that adaptively tunes four servo PID gains using a concentration-weighted state. Experiments on the PhysioNet EEGMMIDB, Ninapro DB2/DB7, HuMoD and WAY-EEG-GAL datasets (combining N = 162 trial sessions, 47,520 windows, and five-fold cross-validation) yield a gait-phase classification accuracy of 96.84 ± 1.18%, torque-tracking RMSE of 0.072 ± 0.008 N·m, information transfer rate of 38.6 bits/min, end-to-end latency of 9.4 ms, and a 27.4% reduction in simulated metabolic cost over an EMG-only PID baseline (one-way ANOVA: F(4, 75) = 47.83, p < 0.001; Tukey HSD: p < 0.01 against all baselines). Under high cognitive load, CM-FuseNet preserves accuracy with only a 4.63 percentage-point degradation versus 13.22 percentage points for the EMG-only baseline. Full article

Gait analysis is increasingly used as a dynamic functional biomarker for computer-aided diagnosis (CADx), although strong internal performance alone does not establish clinical utility. This targeted narrative review examines Parkinson’s disease (PD) and knee osteoarthritis (KOA) as its primary clinical contexts while treating fall risk and other mobility disorders as contextual extensions. A structured literature search and source-verification process covered studies available through 31 July 2026. The review corpus comprised 118 sources spanning clinical evidence, measurement validation, datasets, algorithmic architectures, and methodological guidance. This review critically compares sensing modalities, public and proprietary datasets, feature-based models, CNN/RNN architectures, graph neural networks, Transformers, state-space models, and trust-supporting approaches, including explainable artificial intelligence, automated machine learning, federated learning, and multimodal fusion. Using an explicit coverage rule, a common validation audit was applied to 15 empirical or measurement-validation studies. The audited evidence did not demonstrate mature independent multisite validation for disease-focused gait CADx. Formal probability calibration and quantitative testing of explanation stability were also absent, while publicly available KOA-specific multimodal benchmarks remained scarce. Based on these findings, this review proposes a six-level validation-readiness ladder in which independent external evidence at Level 3 represents the minimum threshold for initiating a supervised clinical pilot. The framework prioritizes subject-level separation, leakage control, calibration, clinically meaningful reference standards, and prospective workflow evaluation. Full article

Background and Objectives: Angular and rotational lower limb alignment concerns are a frequent reason for paediatric consultations. In most children, these findings reflect physiological developmental patterns that resolve spontaneously, but unilateral, progressive, or symptomatic cases may indicate pathology and require specialist assessment. Materials and Methods: This narrative review summarizes clinically relevant developmental norms, key elements of history and physical examination, common differential diagnoses, and practical indications for imaging and referral, with the objective of offering a structured clinical guidance framework for primary care and paediatric practitioners. Results: Physiological coronal plane lower limb alignment typically progresses from infant genu varum to neutral alignment by around 2 years, followed by transient genu valgum between 3 and 6 years, and stabilizes by approximately 7–8 years. Rotational alignment changes predictably with growth and most commonly presents as in-toeing due to femoral anteversion, internal tibial torsion, or metatarsus adductus. Out-toeing is less often physiological and should prompt careful evaluation for underlying disorders, including slipped capital femoral epiphysis. Clinical assessment should prioritize gait observation, foot progression angle, hip rotation, and thigh–foot angle, while imaging should be reserved for atypical presentations, asymmetry, progression, pain, or suspected systemic or neuromuscular disease. Conclusions: Most paediatric lower limb alignment “abnormalities” represent normal variants and require reassurance and observation. Recognizing age-appropriate patterns and red flags enables paediatricians to limit unnecessary interventions while ensuring timely referral and treatment for pathological conditions. Full article

Background: Robot-assisted gait training is increasingly used in pediatric neurorehabilitation, but its effects on the full time-course of gait kinematics remain insufficiently understood. This study aimed to determine whether intensive gait training with the automated PRODROBOT device could improve frontal- and transverse-plane kinematic profiles in children with neurological disorders and shift them toward the gait pattern of healthy peers. Methods: A prospective single-arm pre–post study was conducted in 10 children with cerebral palsy aged 8–13 years who underwent 20 PRODROBOT training sessions over 4 weeks. A control group comprised 18 healthy age-matched children. Three-dimensional gait analysis was performed before intervention (KF1) and after intervention (KF2). The primary outcome was the similarity of full frontal- and transverse-plane kinematic waveforms of the hip, knee, and ankle/foot relative to pre–post changes and to the healthy reference profiles, assessed using the difference factor (f1) and similarity factor (f2). Results: Only two within-group pre–post comparisons met both similarity criteria: hip rotation KF2 versus KF1 (f1 = 13.9%, f2 = 83.7) and ankle rotation KF2 versus KF1 (f1 = 4.1%, f2 = 67.4). These findings indicate similarity between the pre- and post-intervention profiles within the intervention group, rather than normalization relative to the control group. In comparisons with healthy controls, most variables retained elevated f1 values, indicating persistent quantitative deviation from the reference gait pattern. Conclusions: PRODROBOT-assisted gait training was associated with partial reorganization of selected kinematic waveforms rather than full normalization of gait. The intervention appeared more effective in improving waveform consistency and selected transverse-plane features than in correcting persistent distal and rotational deviations linked to more complex structural or neuromuscular factors. Full article

Background/Objectives: Wolfram syndrome is an ultra-rare, progressive multisystem disorder in which endocrine and sensory manifestations coexist with neurological involvement. Quantitative magnetic resonance imaging (MRI) may help characterize central nervous system involvement in this condition; however, evidence derived from small imaging cohorts requires cautious interpretation. This study aimed to examine the relationships between different MRI-derived attributes and neurological symptoms in Wolfram syndrome, with the goal of identifying exploratory imaging patterns that may suggest the involvement of specific neural systems. Methods: We analyzed a Spanish cohort of 45 genetically confirmed patients with Wolfram syndrome. A homogeneous subset of 15 patients with standardized 3-Tesla multimodal MRI and adequate image quality was included in the quantitative imaging analysis. T1-weighted MRI, T2-weighted/fluid-attenuated inversion recovery (FLAIR) imaging, and diffusion tensor imaging (DTI) were processed using a standardized workflow for brain extraction, anatomical segmentation, cortical reconstruction, and quantitative feature extraction. A total of 172 MRI-derived features were examined in relation to neurological phenotypes, including dysphagia, ataxia, gait instability, and cognitive impairment. Analyses included principal component analysis, exploratory factor analysis, correlation analyses, and symptom-specific group comparisons. Given the small MRI sample size and the high feature-to-subject ratio, all analyses were considered exploratory and hypothesis-generating, and the findings should be interpreted cautiously pending validation in larger, independent cohorts. Results: Multimodal MRI-derived features showed distributed associations with neurological manifestations. The most recurrent exploratory imaging correlates involved the thalamus, lateral geniculate nucleus, cerebellum, brainstem, ventricular system, corpus callosum, posterior cortical regions, and white-matter pathways. FLAIR-derived signal heterogeneity in the thalamus and lateral geniculate nucleus appeared repeatedly across several clinical manifestations. Dysphagia was associated with a distributed pattern involving cortical thinning, thalamic and brainstem volume reduction, reduced cerebellar white-matter integrity, increased FLAIR heterogeneity, and ventricular enlargement. Ataxia and gait instability showed overlapping but partially distinct imaging profiles, whereas cognitive impairment was associated with broader cortical, subcortical, callosal, cerebellar, and ventricular alterations. Conclusions: In this exploratory pilot study, multimodal MRI-derived features showed clinically plausible associations with neurological manifestations in Wolfram syndrome. The findings support a distributed model of neurological involvement affecting cerebello-thalamo-cortical circuits, visual relay structures, brainstem pathways, and long-range white-matter connections. These results should be interpreted as exploratory MRI-derived attributes rather than as validated biomarkers, prognostic indicators, or clinically applicable imaging signatures. Confirmation in future longitudinal, multicenter studies with harmonized imaging protocols and external validation will be required. Full article

Hereditary neuromuscular disorders in dogs can be difficult to classify since variants in different genes can result in similar clinical signs or variable phenotypes can be associated with the same DNA sequence variant. A disorder known for many years as Dancing Doberman Disease, suspected to be neuropathy or neuromyopathy, is characterized by repeated lifting and shifting of the pelvic limbs while standing and frequent sitting. More recently, Doberman Pinschers have been identified with a different and more severe phenotype characterized by a crouched stance and bunny hopping gait in the pelvic limbs that is termed duck walking. Dogs with both phenotypes show pelvic limb weakness, muscle atrophy, and fatigue, and clinical signs can progress to involve the thoracic limbs. These distinct phenotypes were evaluated clinically, histologically, and by whole-genome sequencing and genotyping a large cohort of affected and unaffected Doberman Pinschers. The same homozygous missense variant in AGRN (Dog 10K Boxer Tasha chr5:56,346,611,G>A; p.R1710H, XP 038377340.1) was associated with both disorders. AGRN encodes Agrin, an essential synaptic protein, that mediates clustering of acetylcholine receptors on the post-synaptic membrane at the neuromuscular junction. Variants in AGRN are associated with a congenital myasthenic syndrome (CMS) in humans. This is the first report of a CMS in dogs associated with an AGRN variant and expands the spectrum of known CMS genetic risk factors in this species. This study also highlights the importance of whole-genome sequencing (WGS) to accurately classify neuromuscular diseases as forms of CMS, which is not possible based on clinical presentation alone. Full article

Parkinson’s Disease (PD) is the second most diagnosed neurological disorder globally, affecting millions of people worldwide. Oxidative stress is implicated in the progression of PD, yet its direct effects on motor function, particularly in the context of synucleinopathy, are not fully understood. Here, we investigated the effects of the loss of the antioxidant regulatory transcription factor NRF2 in the A53TSyn mouse model of synucleinopathy. Motor function was evaluated in separate cohorts of A53TSyn mice without NRF2 (A53TSyn/NRF2KO), as well as A53TSyn mice expressing NRF2 (A53TSyn/NRF2+) and healthy wild-type (WT) mice at four, six, and eight months of age. The overall mobility decreased in A53TSyn/NRF2KO mice relative to WT mice at all ages. Significant alterations in gait were also apparent in A53TSyn/NRF2KO mice compared to A53TSyn mice without NRF2 deletion. Expression of tyrosine hydroxylase (TH) was also quantified in the brains of those mice. While there were no differences in cortical pSyn expression between A53TSyn/NRF2+ and A53TSyn/NRF2KO mice, a reduction in TH abundance in the striatum was evident in A53TSyn/NRF2KO mice at all ages. In summary, our data suggest that NRF2 plays a role in maintaining mobility and gait in the context of synucleinopathy and may represent a therapeutic target to mitigate mobility decline in PD-affected individuals. Full article

Gait symmetry analysis has emerged as an important tool in rehabilitation engineering and neurological disorder assessment, as it provides clinically relevant indicators of mobility impairment and gait abnormalities. The proposed framework integrates gait symmetry variability, statistical gait features and Dynamic Time Warping (DTW)-based temporal alignment to enhance robustness against gait variations and irregular walking patterns. A hybrid feature vector comprising DTW similarity scores, the hybrid gait symmetry index (GSI), and statistical gait descriptors was employed to classify gait patterns into five categories: normal, slow, medium, fast, and abnormal. The system was implemented as a wearable edge-computing platform using an NI myRIO device equipped with a tri-axial Inertial Measurement Unit (IMU) mounted on the subject’s body. The onboard FPGA performs real-time signal preprocessing, GSI computation, feature extraction, constrained DTW matching, and gait classification using fixed-point streaming architectures and BRAM-based buffering. Meanwhile, the embedded ARM processor manages TCP/IP communication and transmits real-time gait information to a remote monitoring workstation via a WiFi interface for visualization and analysis. Operating at a clock frequency of 100 MHz, the complete architecture achieves an end-to-end processing latency of approximately 4 ms. The proposed FPGA-based implementation provides low-latency, energy-efficient, and real-time gait analysis, making it well suited for wearable rehabilitation systems, assistive healthcare devices, and continuous mobility monitoring applications. Full article

Background: Pathogenic variants in genes that cause skeletal dysplasias may, instead of producing classic findings, present in children with a phenotype whose hip radiographs resemble bilateral Legg-Calvé-Perthes disease (LCPD). Objectives: This study aims to investigate the efficacy of genetic diagnosis in children with waddling gait or joint pain and radiological evidence of hip dysplasia mimicking bilateral LCPD. Methods: Forty children with bilateral femoral head dysplasia from 36 families were included in the study. Exome sequencing was performed, and all identified variants were confirmed within the families by Sanger sequencing. Results: Twelve pathogenic or likely pathogenic variants were identified: six in COL2A1, two in COL9A1, and one each in RPL13, EIF2AK3, DNAJC21, and ARSK; six are novel. The diagnostic yield was 33.3% (12/36) in 12 families. Additionally, variants of uncertain significance (VUS), proposed as causative, were detected in five families (5/36:13.9%): two in COL11A1 and one each in COL9A3, COL11A2, and ARSK. Based on bilateral epiphyseal dysplasia of the femoral head, it was observed that seven families may be compatible with mild spondyloepiphyseal dysplasia and six families may have Stickler syndrome. Notably, among these, three children carrying closely localized pathogenic/likely pathogenic variants in COL2A1 shared a novel phenotype characterized by short stature and bilateral irregular femoral heads. In four families, EIF2AK3, DNAJC21, and ARSK were also responsible for the ultra-rare disorders Wolcott-Rallison syndrome, bone marrow failure syndrome 3, and mucopolysaccharidosis 10, respectively. Conclusions: This study, for the first time, investigated the frequency of associated genes in a pediatric cohort with bilateral hip dysplasia resembling LCPD, providing important information for pathogenesis and differential diagnosis. Full article

Background and Clinical Significance: Alien hand syndrome (AHS) is a rare disorder of agency and complex motor control characterized by involuntary, apparently purposeful limb movements experienced as outside voluntary control. Pontine hemorrhage is an uncommon substrate, and its manifestations may overlap with sensory ataxia and other post-stroke movement disorders. Case Presentation: An 86-year-old right-handed man developed right-sided alien hand phenomena after a left pontine hemorrhage. Examination showed dysarthria, limited left gaze, diplopia, preserved muscle strength, marked right-sided proprioceptive impairment, a thalamic-hand-like posture, impaired spatial control, involuntary levitation, intermanual conflict, and purposeful-appearing rubbing movements when distracted. The diagnosis was based on loss of agency and autonomous limb behavior that could not be explained by sensory ataxia alone. Serial CT demonstrated an interval reduction in the size of the pontine hemorrhage; a representative thalamic level CT showed no evident thalamic hemorrhage or gross structural lesion, although a small CT occult ischemic lesion could not be excluded. Repeat MRI was not completed because of severe claustrophobia and anesthesia risk. EEG, formal neuropsychological testing, and standardized functional scales were unavailable. The NIHSS, assessed 15 days after admission to our hospital, was 6 points. No specific pharmacological treatment was initiated. Cognitive-behavioral rehabilitation was recommended, but transportation difficulties prevented regular attendance. Approximately three months after discharge, physician relatives reported resolution of abnormal movements and improved independent gait; no formal post-discharge examination was performed. Conclusions: Pontine hemorrhage may rarely be associated with mixed AHS phenomenology. Disruption of ascending proprioceptive and sensorimotor pathways is plausible, but the absence of advanced imaging and neurophysiological assessment precludes definitive anatomical or causal conclusions. Full article

Falls remain the leading cause of injury-related death among older adults, with turning accident often producing the most severe consequences, such as hip fractures and a resulting decline in independence. Despite curved-path walking accounting for the majority of daily locomotion, most interventions insufficiently target the coordinated action of lower limb, pelvic and trunk muscles underlying safe turning. This leaves a large proportion of older adults and patients with motricity problems and movement disorders at heightened risk of life-altering injuries. Addressing this gap requires innovative strategies that proactively build on recent physiological research and improve turning strength and neuromuscular control of steering. Gait problems have often been addressed through the use of linear treadmills, which emphasise the symmetry and automaticity of walking but ignore the fact that more than half of daily locomotion involves deviations from the trajectory. In this perspective article, we review the differences between linear and curved walking. We also put forward the hypothesis that a turntable rotating parallel to the horizontal plane represents a potential solution. Such a device could allow individuals to step in place while the surface moves beneath them, simulating the natural rotation of legs, pelvis, and trunk involved in turning. The exercise is designed to train the muscle synergies and proprioceptive responses critical for turning, while minimising stress on vestibular systems, and enhancing task-specific neuroplasticity and proprioception. Full article