Medicine and Pharmacology

Abstract: Background: Parkinson's disease (PD) diagnostic approaches have evolved substantially over the past two centuries in parallel with advances in clinical neurology, neuropathology, neuroimaging, genetics, and biomarker science. Recent developments, particularly α-synuclein(αSyn)-based biomarkers, have challenged traditional symptom-based definitions and enabled biologically driven disease classification. Objective: To review the historical evolution of PD diagnostic criteria and compare their conceptual foundations, diagnostic approaches, strengths, limitations, and future implications. Methods: A narrative review of major PD diagnostic frameworks published between 1817 and 2024 was conducted. Included systems comprised the original clinical description by James Parkinson, the UKPDSBB, Calne, Larsen, and Gelb criteria, EFNS/MDS-ES recommendations, MDS Clinical Diagnostic Criteria, MDS Prodromal Criteria and their update, and the SynNeurGe and NSD-ISS frameworks. Results: The evolution of PD diagnosis occurred across four major eras: descriptive clinical diagnosis, clinicopathological criteria, probabilistic and biomarker-supported diagnosis, and biological classification. Early criteria emphasized motor manifestations, exclusion of alternative diagnoses, and responsiveness to dopaminergic therapy. Later frameworks introduced diagnostic certainty levels, ancillary investigations, and Bayesian risk estimation for prodromal disease. The recently proposed SynNeurGe and NSD-ISS frameworks represent a paradigm shift by incorporating biomarkers of αSyn pathology, neurodegeneration, and genetics as disease-defining elements. Conclusions: PD diagnostic criteria have progressively evolved from phenotype-based recognition toward biologically defined classification and staging. Emerging biomarker-based frameworks may enable earlier diagnosis, improved patient stratification, and future precision medicine approaches.

Abstract: Aim: Vascular cognitive impairment (VCI), which affects many people, is important to distinguish from other types of cognitive impairment because vascular risk factors can slow the onset and progression of the disease. In our study, we aimed to determine the most appropriate cognitive screening tool. Methods: The study included 110 patients with minor VCI and a control group of 90 volunteers aged over 55 and was conducted between July 2024 and September 2025. The diagnosis of mild VCI was determined according to DSM-5 criteria. The Montreal Cognitive Assessment (MoCA), the Standardized Mini-Mental State Examination (MMSE), and the Addenbrooke's Cognitive Examination Test (ACE-R) were administered to all participants. Results: Our findings demonstrate that all three screening tools significantly differentiate patients with mild VCI from healthy controls. ACE-R had the highest area under the curve (AUC=0.967) and showed 90% sensitivity and 100% specificity at a cutoff point of 68.5. MoCA also showed relatively high sensitivity (86.4%) and specificity (91.1%), with high diagnostic accuracy (AUC = 0.946). In contrast, MMSE showed slightly lower diagnostic performance (AUC=0.926) but still had high specificity (92.2%). Conclusion: Our study shows that ACE-R is the most accurate screening tool for detecting mild vascular cognitive impairment, closely followed by MoCA, while MMSE, though useful, may be less sensitive in the early stages. Further studies involving larger, multicenter cohorts and different subtypes of vascular cognitive impairment are needed.

Abstract: Critical-period accounts of autism spectrum disorder (ASD) represent developmental plasticity as a quantity. On these accounts a critical period may open early or late, last longer or shorter, admit more or less plasticity, or fail to open or close — but plasticity itself remains a scalar that is raised or lowered. We argue that this representation cannot accommodate the best-characterized structural finding in ASD neuropathology. Postmortem ASD cortex shows increased dendritic spine density arising from reduced developmental pruning, correlated with mTOR hyperactivation and impaired autophagy; in Tsc2 haploinsufficient mice, autophagy enables spine elimination with no effect on spine formation, and rapamycin restores pruning and social behavior in an autophagy-dependent manner. This is not less plasticity. It is the selective loss of one arm of a bidirectional process while the opposing arm is spared. We show that filial imprinting in the domestic chick, where the same signaling pathway has been manipulated during a defined encoding window, independently establishes that developmental encoding is signed and that its two arms are separably controlled: imprinting reduces thin spines and increases mushroom spines, and mTOR inhibition blocks the increase without blocking the decrease. We therefore propose that the appropriate formal object for developmental encoding is a direction vector rather than a scalar gain, and that ASD is better modeled as a rotation of that vector than as a reduction of plasticity. The proposal generates a three-way partition among phenotypically convergent presentations — encoding-direction failure, progressive loss of social input, and absence of input under intact machinery — which we map onto idiopathic ASD, the prospective infant-sibling literature, and deprivation-related quasi-autism respectively. We identify an existing direct comparison between deprivation-related and community autism as a test already conducted, note that the reported sex distributions align with the partition, and argue on framework-internal grounds that the maternal hypothyroxinemia–autism association should be assigned to architecture rather than to the encoding gate. Predictions, boundary conditions, and the principal weaknesses of the proposal are stated.

Abstract: Bahrain has the clinical infrastructure, specialist services and patient volumes of a modern Gulf health system, yet the maturity of its hospital-based research ecosystem remains less visible than its service capacity would predict. This narrative health-policy analysis argues that Bahrain's challenge is best understood as compositional rather than simply volumetric: national medical publication output is real and has grown, but publication volume does not by itself demonstrate a hospital research system capable of producing registries, pragmatic trials, implementation studies, health-economic evidence, transparent dashboards and policy-changing local data. The paper applies a health-research-systems lens to Bahrain's public and quasi-public clinical institutions, drawing on published bibliometric evidence, regulatory and ethical guidance, recent Bahrain clinical-trials evidence, and selected Gulf Cooperation Council examples. It distinguishes academic-sector productivity from hospital-based research maturity, identifies the clinical-service-to-research conversion gap, and proposes a sequenced reform agenda mapped to stewardship, financing, resources, and production and use of research. Priority actions include annual hospital research dashboards, professionalised research and ethics committees, pilot research offices or clinical-trial-unit-equivalent structures, registry governance aligned with data-protection and demographic realities, protected clinician-scientist time, responsible metrics, workforce-equity monitoring, public and patient engagement, sustainable funding, and affordable publishing support. Bahrain's compact scale should be treated as a design advantage. By the end of 2027, progress should be visible in public dashboards, audited research assets, named priority registries, functioning research-support units, and documented outputs beyond declarations alone.

Abstract: Background: Inflammatory demyelinating diseases of the central nervous system, including multiple sclerosis (MS), aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG-positive NMOSD), seronegative NMOSD, myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), recurrent optic neuritis, longitudinally extensive transverse myelitis (LETM), and pediatric acquired demyelinating syndromes, are increasingly recognized across the Gulf Cooperation Council (GCC) countries. Regional evidence remains fragmented, retrospective, disease-specific and unevenly distributed across Bahrain, Saudi Arabia, the United Arab Emirates, Kuwait, Qatar and Oman. Existing data suggest expanding recognition of MS and related demyelinating disorders, but the region lacks a unified prospective platform capable of capturing diagnostic criteria version, antibody testing, imaging, treatment access, longitudinal disability, visual outcomes, pediatric development, real-world treatment safety, pharmacovigilance, health-service equity and precision-management variables across public and private care pathways.Objectives: This strategic framework proposes a unified GCC Demyelinating Disease Registry to transform fragmented evidence into a prospective, interoperable, ethically governed and policy-relevant learning health-system platform for precision neuroimmunology across the Arabian Gulf.Proposed design: The registry would use a modular architecture incorporating a core minimum dataset and disease-specific modules for MS, NMOSD, MOGAD, optic neuritis, LETM, pediatric acquired demyelination, imaging, antibody testing, treatment, relapse, disability, visual outcomes, quality of life, pregnancy, vaccination, infection and long-term safety. Optional extended modules would support approved studies of immunopathology, genetic susceptibility, gene-environment interaction, pharmacogenomics, biomarkers, health economics and therapy response. The technical design should use a pragmatic hybrid model: REDCap or an equivalent electronic case-report form for clinical data entry, an Observational Medical Outcomes Partnership-compatible analytical backend, FAIR-aligned metadata, standardized vocabulary mapping, Observational Health Data Sciences and Informatics-compatible analytics, and privacy-preserving federated reporting. Governance would require national coordinating hubs, hospital registry nodes, pediatric and laboratory-imaging panels, a FAIR-OMOP technical board, transparent publication rules, patient and family input, and explicit protection of national data sovereignty.Expected scientific and clinical impact: A unified GCC registry would enable accurate disease ascertainment, antibody-testing harmonization, diagnostic reclassification, real-world treatment evaluation, pediatric outcome tracking, pharmacovigilance, clinical-trial readiness, health-economic analysis, clinical decision-support development and policy decision-making. It would address GCC-specific challenges, including multinational coordination, expatriate mobility, variable laboratory access, cultural considerations, data sovereignty, shared and partially overlapping ancestral and environmental backgrounds, and equity in biologic treatment access. If adopted across all six member states, the registry could plausibly enroll several thousand patients within five years and, with mature national coverage including expatriate residents, could over the longer term approach the majority of the region's prevalent demyelinating-disease population.Conclusion: A unified GCC Demyelinating Disease Registry would provide the region with a practical, prospective and interoperable infrastructure for surveillance, real-world treatment evaluation, pharmacovigilance, pediatric outcome tracking, clinical decision support and precision-neuroimmunology research. By building on prior Gulf registry experience without duplicating disease-specific initiatives, the proposed framework could transform fragmented national evidence into a coordinated GCC-wide learning health-system platform and a scalable model for other Middle Eastern and North African health systems.

Abstract: Chronic pain imposes a significant burden on global healthcare systems, and existing pharmacological interventions often provide inadequate pain management. Long-term opioid therapy for chronic pain has contributed to the ongoing global opioid crisis, and its utilization is restricted by severe adverse effects including tolerance, addiction risks, and fatal respiratory suppression. However, recent preclinical studies have shown that peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) has the potential to provide effective chronic pain management and to suppress adverse outcomes of chronic opioid therapy. PGC-1α acts by coordinating mitochondrial renewal, redox balance, and neuroinflammation within neural pathways. Its suppression drives mitochondrial dysfunction and pain chronification. Available evidence highlights the role of oxidative damage and impaired mitochondrial function in chronic pain across musculoskeletal, neuropathic, cancer, and opioid-induced pain models. Therefore, advancing research into the role of PGC-1α in chronic pain management could uncover effective therapeutic interventions with safer clinical outcomes. However, comprehensive reviews that integrate mechanistic evidence on PGC-1α from multiple chronic pain models with drug-repurposing implications remain limited in the literature. This narrative review synthesizes evidence on PGC-1α involvement in chronic pain and examines potential therapeutic interventions through the modulation of PGC-1α as a novel neuroprotective target. Activation of PGC-1α has been shown to attenuate mitochondrial abnormalities and pain hypersensitivity in several preclinical models. Natural compounds, repurposed drugs, and synthetic small-molecule compounds targeting PGC-1α have shown promise as bioactive agents for modulating mitochondrial dysfunction, oxidative stress, and neuroinflammation. However, most available data are preclinical and highlight a translational gap between experimental findings and clinical application across various nociceptive models. Therefore, additional investigation is required to clarify tissue-specific pathways, optimize PGC-1α pharmacological activators, and establish the safety and translational relevance of modulating PGC-1α in chronic pain.

Abstract: Objective: To establish whether the published epidemiological record can support or refute the proposition that chronic migraine is a modifiable midlife contributor to Alzheimer’s dementia, and to specify the studies that would settle the question. Background: Migraine is repeatedly reported as a dementia risk factor and has been proposed for addition to the list of modifiable risks. A route from recurrent cortical spreading depolarization through perivascular clearance failure to amyloid aggregation, and onward through pannexin-1–HMGB1–toll-like-receptor transduction to sustained neuroinflammation, is biologically coherent. Whether the epidemiology actually tests that route has not been examined. Methods: Narrative review. PubMed, Google Scholar and CrossRef were searched from January 2020 to August 2026, with hand-searching for seminal earlier work. Following an internal audit, every quantitative claim was re-derived from the source record rather than from an earlier draft, and claims that could not be so derived were removed. Results: The association declines monotonically as control over ascertainment improves. For primary headache the odds ratio is 1.49 (95% CI 1.20–1.85) in case-control studies, 1.35 (1.25–1.45) in retrospective cohorts and 0.82 (0.74–0.92) in prospective cohorts, the last significantly below the null. Heterogeneity falls from I2 85.9% undivided to 9.2%, 61.9% and 26.9% within design strata, and small-study effects appear only in the middle stratum. Attack frequency has never been related to dementia incidence in any cohort; the one study that measured frequency directly reported no direct association with its brain-age gap, alongside a positive indirect path through segmented brain volume in a design with a truncated exposure range. Chronicity has never been stratified against episodic migraine. No adequate aura-stratified evidence exists, so aura supports neither the model nor its negation. Across pain phenotypes migraine ranks fifth of six, below trigeminal neuralgia and fibromyalgia, neither of which involves depolarization, and the source authors attribute their own top-ranked estimate to depression. Risk attenuates with time since the first diagnostic code and remains elevated beyond ten years. Conclusion: These findings share one cause: exposure is recorded as a diagnosis and not measured as disease activity, so the coded date marks clinical contact and not disease onset, and the interval between the two differs systematically across phenotypes and designs. The proposition is untested, not refuted. A falsifiable prediction follows, together with a cross-sectional plasma-biomarker comparison that would substantially weaken the hypothesis if null and open the frequency question if positive, at a fraction of the cost of an imaging program. Plain Language Summary: Migraine has been named as a possible cause of dementia in later life, but no long-term study has asked whether people with more attacks go on to develop it. We reviewed the evidence and found the link weakens, then reverses, in the studies that follow patients most closely. These studies record a diagnosis and not the illness itself, so the question stays open; one blood test study would go a long way toward answering it.

Abstract: Background/Objectives: Cognitive impairment in neuromyelitis optica spectrum disorder (NMOSD) is increasingly recognized, but its profile and clinical correlates remain uncertain. This study sought to describe cognitive performance in individuals with NMOSD and to explore its associations with disease activity, disability level, and immunosuppressive treatment. Methods: This exploratory cross-sectional study characterized cognitive performance in 36 AQP4-IgG–positive individuals with NMOSD and 18 healthy volunteers using domain-level cognitive scores adjusted for age, education, and visual acuity. Results: Cognitive impairment was present in at least one domain in 27 participants, most frequently affecting memory (36%), praxis (33%), and information processing speed (IPS; 31%). IPS was the only domain significantly impaired in NMOSD compared with controls in unadjusted analyses (p = 0.007), but no domain remained significantly different after adjustment, despite a medium-to-large effect for IPS. Higher disability burden was associated with worse IPS (p = 0.011) and with lower scores on a clinically sensitive cognitive composite integrating memory, IPS, and executive function (β = –0.125, p = 0.040). Among clinical activity measures, annualized relapse rate showed a positive association only with executive function (β = 0.282, p = 0.007), whereas neither relapse count nor immunosuppressive treatment was associated with cognitive performance. Conclusions: These findings indicate a heterogeneous cognitive profile in NMOSD strongly influenced by demographic and sensory factors, with disability burden emerging as the main clinical correlate of cognitive performance.

Abstract: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by α-synuclein (αSyn) aggregation, dopaminergic neuronal loss within the substantia nigra (SN), and widespread involvement of multiple neurotransmitter systems. The recognition of prodromal and preclinical disease stages has accelerated efforts to develop biomarkers capable of identifying underlying pathology before the onset of motor symptoms, improving diagnostic accuracy, enabling biological staging, monitoring disease progression, and facilitating disease-modifying clinical trials. Neuroimaging has emerged as a central component of this effort by providing in vivo assessment of molecular, structural, and functional alterations across the PD continuum. This narrative review summarizes current and emerging neuroimaging biomarkers, including dopaminergic imaging with DAT SPECT, fluorodopa, and VMAT2 PET, metabolic network imaging with FDG-PET, and novel molecular imaging approaches targeting cholinergic dysfunction, autonomic denervation, neuroinflammation, synaptic integrity, noradrenergic and serotonergic pathways, glutamatergic signaling, adenosine A2A receptors, opioid receptors, and αSyn pathology. Advanced MRI techniques, including neuromelanin-sensitive MRI, nigrosome-1 imaging, QSM, FW imaging, and functional MRI, are also reviewed. Current evidence suggests that multimodal imaging approaches integrating molecular and structural biomarkers may improve diagnostic performance, prognostication, biological staging, and patient stratification compared with individual modalities. We additionally discuss applications in prodromal PD and clinical trials, as well as challenges related to standardization, harmonization, and regulatory qualification. Future advances in αSyn imaging, artificial intelligence–assisted image analysis, and integration with fluid and genetic biomarkers are expected to accelerate the transition toward biologically defined and precision medicine approaches in PD.

Abstract: Alzheimer’s disease (AD) is one of the most prevalent causes of dementia, with both genetic and environmental factors influencing its progression. The role of phagocytosis and its relationship to AD-associated neuroinflammation has recently garnered considerable attention in the field. For this systematic review, Scopus and PubMed databases were searched to identify studies examining how peripheral immune signaling and systemic metabolic alterations modulate microglial phagocytic function within the context of dementia pathogenesis. Twenty-two full-text original articles, published within the last decade and exclusively in English, were selected for inclusion. Neurodegeneration is a continuous process of barrier breakdown and disruption of cellular homeostasis, during which phagocytosis, a cellular process continuously shaped by peripheral signals, becomes dysregulated, rendering it ineffective and, in certain contexts, neurotoxic. Peripheral stressors such as metabolic stress, systemic infections, and circulating cytokines converge on shared signaling pathways that collectively alter microglial function. The current literature supports a multi-system, multi-hit model in which the central and the peripheral nervous systems engage in continuous bidirectional crosstalk, culminating in the maladaptive remodeling of microglial function upon sustained exposure to peripheral stressors.

Abstract: Purpose. To develop a proband-level five-tier outcome classification for trio genome sequencing (GS) in neurodevelopmental disorders (NDD), and, in a small subgroup, to explore what is associated with a full versus partial phenotype match to a candidate gene’s disease spectrum. Methods. A rule-based five-tier framework integrating ACMG/AMP classification, ClinGen gene-disease validity, phenotype concordance, and orthogonal validation was applied to 40 probands with unresolved NDD (36 after exclusions); two reviewers assigned tiers by consensus. Phenotype matching used clinician-documented Human Phenotype Ontology terms, characterised against documentation-derived metrics. Results. Of 36 probands, 7 (19.4%; 95% CI 8.2–36.0%) received a confirmed diagnosis (Tier 1) and 5 (13.9%) a high-priority, unvalidated candidate (Tier 3); none were Tier 2 (Provisional). The remainder had a low-priority candidate (22, 61.1%) or no candidate (2, 5.6%). Among 12 probands with strong disease-association evidence, a full phenotype match was associated with richer documentation than a partial match, not a higher similarity score (p = 0.005); this preliminary finding warrants replication. All confirmed diagnoses involved variant types detectable by exome sequencing (ES), not genome-specific findings like deep intronic variants. Conclusion. The five-tier framework resolves the diagnostic intermediate collapsed by binary solved/unsolved reporting. Comprehensive, disease-specific phenotyping is the practical lever for framework performance.

Abstract: Background: Glutamatergic overactivity mediated by metabotropic glutamate receptor 5 (mGluR5) is implicated in levodopa-induced dyskinesia (LID) in Parkinson’s disease (PD). Mavoglurant (AFQ056), a selective mGluR5 antagonist, has shown inconsistent efficacy across clinical trials. We conducted a systematic review and meta-analysis to evaluate its efficacy and safety in PD patients with LID. Methods: Randomized controlled trials (RCTs) comparing mavoglurant with placebo in patients with PD and LID were systematically identified. Outcomes were pooled using random-effects models. Primary outcome was dyskinesia severity measured by the modified Abnormal Involuntary Movement Scale (mAIMS). Secondary outcomes included daily OFF-time, ON-time without troublesome dyskinesia, Lang-Fahn Activities of Daily Living Dyskinesia Scale (LFADLDS), Unified Parkinson’s Disease Rating Scale (UPDRS) Parts III and IV, and safety outcomes. PROSPERO (CRD420261446524). Results: Four publications reporting six RCTs involving 485 participants were included. Mavoglurant significantly improved mAIMS scores compared with placebo (MD −2.43, 95% CI −3.79 to −1.07; p < 0.001). No significant benefits were observed for daily OFF-time (MD −0.27 h/day, 95% CI −0.79 to 0.24), ON-time without troublesome dyskinesia, total ON-time, LFADLDS, UPDRS Part III, or total UPDRS-IV (MD −0.33, 95% CI −0.70 to 0.04). Improvement was observed for UPDRS-IV Item 32 (duration of dyskinesia) (MD −0.35, 95% CI −0.66 to −0.04). Conclusion: Mavoglurant provides modest improvement in dyskinesia severity as measured by the mAIMS but does not consistently improve motor fluctuations, motor function, or overall dyskinesia-related disability. Its limited efficacy and increased adverse-event risk suggest restricted clinical utility for LID management in PD.

Abstract: Background/Objectives: PLA2G6-associated neurodegeneration (PLAN) is an autosomal recessive neurodegenerative spectrum encompassing infantile, juvenile/atypical, and adult-onset phenotypes. Juvenile PLAN may initially resemble autism spectrum disorder or nonspecific developmental regression, delaying diagnosis. Case Presentation: We describe a 14-year-old boy and his 9-year-old sister, both with initially normal early development followed by progressive gait impairment, speech and cognitive regression, epilepsy, contractures, and loss of independent ambulation. Brain MRI in both siblings demonstrated marked symmetric cerebellar atrophy, susceptibility-weighted hypointensity of the globus pallidus and substantia nigra compatible with iron accumulation, and bilateral optic nerve thinning. Electroneurography showed selective motor axonal involvement. Molecular testing identified the same two heterozygous PLA2G6 findings in both children: c.1934G>A (p.Arg645Gln) and an exon 4–7 copy-number gain. Parental testing was unavailable; therefore, the phase of the findings could not be established, and it remains unknown whether they are in trans or in cis. Conclusions: The shared clinical, neuroimaging, and electrophysiological phenotype is strongly consistent with juvenile PLAN and provides additional phenotypic evidence regarding p.Arg645Gln. However, unresolved phase and incomplete structural characterization of the copy-number gain preclude definitive molecular attribution. These cases emphasize the diagnostic value of susceptibility-weighted MRI, deletion/duplication analysis, and family segregation studies in children with progressive neurodevelopmental regression.

Abstract: Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) and the wider family of RFC1-related diseases are among the most common causes of adult-onset hereditary ataxia, yet diagnosis is frequently delayed by decades. This Patient Perspective combines the historical evolution of clinical understanding with a first-person patient account to illustrate why the disorder is so often missed, and to offer a structured, clinically usable approach to recognition, investigation and multidisciplinary management. We argue that no single symptom is diagnostic; rather, the diagnosis emerges from recognising phenotypic patterns, which in the case of CANVAS are sensory ganglionopathy, bilateral vestibular hypofunction and cerebellar impairment. This triad may accumulate over many years and is often attributed by patients and clinicians alike to unrelated, more common conditions. A chronic cough generally predates the onset of the other features. Practical diagnostic pearls, a stepwise investigation algorithm and a multidisciplinary management framework are presented alongside the patient’s own account of a three-decade diagnostic journey, to help shorten the path to diagnosis for future patients.

Abstract: Pathogenic variants in ADPRS, encoding ADP-ribosylhydrolase 3 (ARH3), cause stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS; OMIM: 618170), an ultra-rare autosomal recessive disorder with fewer than 61 reported cases worldwide. Here we report a previously undiagnosed 36-year-old who we analysed using trio exome sequencing analysis. We identified a homozygous pathogenic ADPRS variant (NM_017825.3:c.1004T>G; p.Val335Gly), bringing to an end to a 33-year diagnostic odyssey. The patient presented with neurological features consistent with CONDIAS including childhood-onset gait instability, distal sensory-motor axonopathy, and later-emerging cerebellar ataxia with consistently normal brain MRI. However, he also showed with severe primary hypogonadism, including markedly reduced testosterone, elevated gonadotropins, microorchidism, and secondary osteopenia. Although neurological features are well-characterised in CONDSIAS, endocrine involvement has not been emphasized as part of the clinical phenotype. We conducted a literature review of CONDSIAS and report an update on the mutation and clinical spectrum. Our review highlights that endocrine involvement can be part of the phenotype in CONDSIAS . The patient described here has the most severe gonadal phenotype reported to date. Treatment of the patient with testosterone replacement precipitated neurological deterioration on two separate occasions, suggesting that sex hormone supplementation should be carefully considered for ARH3-deficient individuals.

Abstract: Background: Nicotine has been proposed as a potential therapeutic agent in Parkinson's disease (PD) based on epidemiologic and preclinical evidence, but clinical findings remain inconsistent. This systematic review and meta-analysis evaluated the efficacy and safety of nicotine-based interventions in PD. Methods: Randomized controlled trials comparing nicotine-based interventions with placebo or control in patients with PD were systematically reviewed. Outcomes included motor severity, activities of daily living, quality of life (QoL), levodopa equivalent daily dose (LEDD), and adverse events. Random-effects meta-analyses were performed, and certainty of evidence was evaluated using the GRADE framework (PROSPERO CRD420261442440). Results: Six randomized trials involving 389 participants were included. Nicotine did not significantly improve motor outcomes (SMD −0.16, 95% CI −0.76 to 0.43), activities of daily living (MD −0.65, 95% CI −1.77 to 0.47), or LEDD (MD −114.40 mg/day, 95% CI −258.82 to 30.02). A small but significant improvement in QoL was observed (SMD −0.26, 95% CI −0.44 to −0.07). Serious adverse events were not significantly increased (RR 1.39, 95% CI 0.56-3.49), whereas overall adverse events were more common with nicotine (RR 1.51, 95% CI 1.23-1.86), particularly gastrointestinal symptoms. Substantial heterogeneity was present for motor outcomes and LEDD. Conclusions: Current evidence does not support the routine use of nicotine as symptomatic therapy for PD. Although a modest improvement in QoL was observed, it was accompanied by a higher burden of adverse events and no significant benefit in motor outcomes. Larger, adequately powered trials are needed.

Abstract: Background: Persistent postural-perceptual dizziness (PPPD) is a chronic functional neuro-otologic disorder marked by persistent dizziness, unsteadiness, and visual dependence. Its electrophysiological mechanisms remain unclear. This study examined resting-state EEG spectral power and functional connectivity in PPPD and their associations with postural stability and clinical symptoms. Methods: Forty patients with PPPD and 40 age- and sex-matched healthy controls were studied with an eyes-closed resting state EEG recording. Static postural stability was measured with Pro-Kin system. Spectral power was calculated for delta, theta, alpha, beta, and gamma bands. Functional connectivity was assessed using weighted phase lag index. Results: Static posturography showed impaired postural stability in patients with PPPD compared with healthy controls，especially under eyes-closed conditions. Spectral power analysis showed increased theta-band relative power over the frontal and right parieto-occipital regions. Connectivity analysis showed increased prefrontal–temporal and decreased temporal–occipital connectivity in the theta band, increased fronto-parieto-occipital and decreased parietal -temporal connectivity in the alpha band, and decreased cerebellar and temporal, central connectivity in the gamma band. Frontal spectral power was positively correlated with HAMA scores in the PPPD group. Conclusions: PPPD was associated with frequency-specific alterations in resting-state cortical oscillations and functional connectivity involving cognitive-affective, visual, and sensorimotor networks. Resting-state EEG may help characterize network-level abnormalities in PPPD.

Abstract: Approximately 75% of individuals with neurodevelopmental disorders (NDD) remain without a molecular diagnosis after first-tier genetic testing, and a substantial share of that gap reflects the pace of gene-disease discovery rather than sequencing technology alone (Stefanski et al., 2021). Here we report trio genome sequencing in 36 probands with NDD or epilepsy who remained molecularly unsolved despite prior genetic testing. Likely pathogenic variants were identified in thirteen probands (36%): eight confirmed diagnoses and five high-priority findings pending Sanger validation, including a deep intronic PPP2R5C variant that extends the gene's recognised mutational spectrum. A further 19 candidate genes without an established disease association were prioritised by evidence score, including PRKAR1B, identified independently as a de novo duplication in two unrelated probands but not counted as a diagnosis pending clarification of its disease mechanism. Grouping all 34 findings by functional theme showed genes involved in transcription and chromatin regulation as the largest category. Only 9% of findings were in genome regions inaccessible to exome sequencing, indicating that most diagnostic value reflected thorough, trio-based analysis rather than access to genome-specific sequence. These findings support genome sequencing as a second-tier diagnostic step after negative prior testing, while showing that reassessing gene-disease validity, not sequencing technology, accounted for part of this yield.

Abstract: SHANK3-related disorder within the Phelan-McDermid syndrome spectrum is clinically heterogeneous and commonly includes severe expressive language impairment, hypotonia, motor coordination difficulties, sensory features, sleep disturbance, reduced pain expression, and regression in a subset of affected individuals. However, a potential dystonic contribution to expressive language impairment, orofacial dysfunction, other motor abnormalities, and illness-associated functional deterioration has not been systematically examined. Case Presentation: We report a 7-year-old girl whose early presentation was dominated by severe expressive language delay. Receptive communication, social reciprocity and practical problem-solving appeared substantially stronger than expressive output suggested. Longitudinal features included fine-motor incoordination, toe walking, intermittent atypical hand movements, sensory reactivity, overload-associated dysregulation and prolonged mouthing/oral exploration of objects. During febrile illness in March 2025, she developed painful gait deterioration, continuous toe walking, dystonic hand posturing and worsening orofacial motor function. Low-dose levodopa was initiated because dopa-responsive dystonia or a related dopaminergic disorder was clinically considered. Following initiation of levodopa, improvements were observed across several functional domains that had shown only slow progress or prolonged plateau phases during the preceding years. Short-read whole-genome sequencing identified a heterozygous pathogenic SHANK3 frameshift variant, NM_001372044.2:c.3904dup, with the predicted protein consequence NP_001358973.1:p.(Ala1302fs). With continued levodopa and later trihexyphenidyl, further gains were observed across gait stability, orofacial control, spoken language output, sensory tolerance and functional participation; the previously persistent mouthing/oral exploration was no longer observed after dopaminergic treatment had been established. Conclusion: Across neurodevelopmental disorders of diverse genetic aetiology and across age groups, the co-occurrence of marked expressive language impairment, orofacial dysfunction, and fine- or gross-motor abnormalities should prompt targeted assessment for dystonia or another movement disorder. Such motor manifestations may represent a convergent and potentially modifiable component of the clinical phenotype, including previously unrecognized impairment of speech-motor control. The multidomain improvement observed following initiation of levodopa in this case of SHANK3-related disorder was clinically meaningful and hypothesis-generating and warrants prospective investigation.

Abstract: Background: Fibromyalgia syndrome (FMS) is a chronic pain disorder characterized by widespread musculoskeletal pain, fatigue, sleep disturbances, cognitive dysfunction, and psychological symptoms. Despite its considerable prevalence and clinical burden, the biological mechanisms underlying FMS remain incompletely understood, and no validated biomarkers are currently available for its diagnosis, prognosis, or clinical monitoring. Objective: This narrative review aimed to synthesize and critically examine the available evidence on inflammatory, immune-related, and neurobiological biomarkers associated with FMS. Methods: A narrative review of the scientific literature was conducted. Relevant studies published between 1999 and 2026 were identified through searches of PubMed, Scopus, and Web of Science using terms related to fibromyalgia, biological biomarkers, inflammation, immune dysregulation, neuroinflammation, neuroplasticity, and neural injury. Original studies examining molecular, inflammatory, immune-related, or neurobiological biomarkers in individuals with FMS were considered. The available evidence was narratively synthesized according to the biological functions of the biomarkers, the biological samples analyzed, their associations with clinical manifestations, and their potential diagnostic, prognostic, or therapeutic relevance. Results: The literature has examined a wide range of biomarkers in blood, serum, plasma, saliva, cerebrospinal fluid, skin biopsies, and peripheral blood cells. Findings regarding classical inflammatory biomarkers, including C-reactive protein, tumor necrosis factor-α, interleukins, and chemokines, have been heterogeneous and, in some cases, contradictory. Nevertheless, several emerging biomarkers, such as triggering receptor expressed on myeloid cells-1, colony-stimulating factor-1, interleukin-31, interleukin-33, glial fibrillary acidic protein, and neurofilament light chain, have shown potentially relevant alterations in individuals with FMS. Biomarkers associated with neuroplasticity, glial activation, and neural injury, including brain-derived neurotrophic factor and matrix metalloproteinases, have also displayed abnormal concentrations, although the evidence remains inconsistent. Several biomarkers have been associated with pain severity, fatigue, sleep disturbances, cognitive impairment, anxiety, and depression, suggesting relationships between biological alterations and the heterogeneous clinical manifestations of FMS. Conclusions: The available evidence supports the involvement of inflammatory, immune, and neurobiological processes in the pathophysiology of FMS. However, methodological variability, small and heterogeneous samples, differences in biological specimens and analytical procedures, and the limited replication of individual biomarkers currently preclude their clinical application. FMS should therefore be understood as a multifactorial and heterogeneous condition involving complex interactions among immune dysregulation, neuroinflammation, glial activation, and maladaptive neuroplasticity. Future longitudinal and multicenter studies integrating inflammatory, immune-related, and neurobiological biomarkers with detailed clinical phenotyping are needed to identify clinically meaningful subgroups and facilitate the development of personalized diagnostic and therapeutic strategies.