Gordon Holmes syndrome (GHS, MIM 212840) is an autosomal recessive disorder with a clinical manifestation of cerebellar ataxia, dementia and hypogonadotropic hypogonadism. To describe the clinical and genetic profile of patients with GHS reported worldwide with genotype-phenotype correlation. This is a review of reported cases of GHS based on the different genetic variant worldwide. We report 2 patients of GHS due to variant in the RNF216 gene. There was total 29 reported cases of GHS with RNF216 variants, 9 cases with PNPLA6 variants, and 5 with STUB1 variant. There was male predominance in the RNF216 and PNPLA6 variants. The median age at onset was lower and duration of illness was longer in STUB1 variants. Cerebellar ataxia and dysarthria were seen in all variants. Dementia, chorea and psychiatric disturbances were common in RNF216 variants. Seizures were seen only in STUB1 variants. Hypogonadotrophic hypogonadism were seen in all variants. Brain magnetic resonance imaging showed signal changes in the white matter apart from the cerebellar and cerebral atrophy in RNF216 variants. Missense, frameshift and non-sense variants were common in RNF216 and missense variants were common in PNPLA6 and STUB1. The phenotypic and genotypic presentation of GHS is heterogeneous with variants in the RNF216 representing majority of GHS cases.

Chromosome 16p11.2 deletion syndrome is a genetic syndrome that includes difficulties in speech, language, and motor coordination. Arbaclofen, a selective GABA-B receptor agonist, has improved motor functioning and memory in mouse models. Prior clinical trials of arbaclofen in fragile X syndrome and autism spectrum disorder suggested benefit for social communication. L16hthouse (NCT04271332) is a multi-site, double-blind, randomized, placebo-controlled phase 2 trial to evaluate safety, efficacy, and tolerability of arbaclofen compared in 60 youths with 16p11.2 deletion syndrome (5 to 17:11 years) randomized on a 1:1 ratio. Primary outcomes included speech articulation, measured by the Goldman Fristoe Test of Articulation 3 (GFTA-3). Secondary outcomes included objective dysarthria indices, memory, motor control, and cognitive function, assessed with both standardized clinical measures and novel, computer-based assessments with automated scoring. Exploratory outcomes included attention, autism traits, and electrophysiological responses. L16hthouse is the first randomized trial in 16p11.2 deletion syndrome and uses an array of novel outcome measures to assess potential benefit in this population. In addition to providing potential insights about the safety, efficacy, and tolerability of arbaclofen, L16hthouse will provide an initial assessment of how these developmental outcome measures perform in a clinical trial across a broad age range.Clinical trial registration number: NCT04271332; 2020-02-13.

Deep brain stimulation (DBS) effectively treats motor symptoms in movement disorders but often compromises speech through incompletely defined mechanisms. We conducted a PROSPERO-registered systematic review and meta-analysis of publications through August 2024 (CRD42024527738). Among 2726 screened records, we included 184 studies: 131 in Parkinson's disease (PD), 32 in essential tremor (ET), and 21 in dystonia, assessing perceptual, acoustic, and patient-reported speech outcomes. Meta-analyses showed that subthalamic nucleus DBS in PD resulted in poorer speech intelligibility compared with best medical treatment (effect size -0.24; 95% confidence interval: -0.46 to -0.03; P = 0.027), with state-dependent decline under active stimulation on longitudinal analysis (Unified Parkinson's Disease Rating Scale Part III item 18 monthly change: medication on +0.016, P < 0.001; medication off +0.002, P = 0.50). In ET, DBS consistently suppressed vocal tremor but increased the risk of dysarthria, particularly with bilateral stimulation. Dystonia outcomes showed greater heterogeneity. Across disorders, sustained phonation measures improved, whereas connected speech performance worsened, indicating selective vulnerability of complex motor tasks. Neuroanatomical mapping identified two nonexclusive mechanisms: current spread to corticobulbar fibers producing spastic speech features and to the cerebellothalamocortical pathway producing ataxic features. Hypokinetic and stuttering-like phenotypes also occurred but likely reflect network-level interactions rather than tract-specific spread. These tract-mediated and network-level alterations appear to interact with hemispheric lateralization, medication state, and longer-term plasticity to produce complex clinical phenotypes. We outline a clinical framework integrating systematic screening, phenotype identification, and targeted programming adjustments. Enhanced speech assessment, precise field mapping, and adaptive DBS paradigms may promote individualized care that optimizes speech and motor function in precision DBS therapy. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Spinocerebellar ataxias (SCAs) are a group of neurodegenerative diseases characterized by progressive cerebellar dysfunction, which leads to impaired coordination, dysarthria, oculomotor disorders, and subsequently to a marked reduction in quality of life and high disability. In addition to the main motor symptoms, patients often suffer from cerebellar cognitive-affective syndrome, depression, and sleep disturbances. Despite advances in understanding the molecular and genetic underpinnings of SCAs, there are currently no disease-modifying therapies approved by the FDA (U.S. Food and Drug Administration) or EMA (European Medicines Agency), and management remains largely symptomatic, focusing on improving quality of life and functional independence. Recent systematic reviews and clinical guidelines emphasize a combination of pharmacological, non-pharmacological, and novel gene and cell therapies that are currently under investigation, with varying levels of evidence for their efficacy. The transition to precision medicine and early intervention at the pre-ataxic stage are essential for effectively combating neurodegeneration. This review summarizes the latest data on the treatment of SCA, including existing and new treatments, their effectiveness, limitations, and future prospects.

SLC52A3-related Brown-Vialetto-Van Laere syndrome (BVVL) is a rare neurodegenerative disorder characterized by progressive motor and sensory impairment, with high mortality rate if left untreated. We hereby report the largest cohort with SLC52A3-related BVVL from the Arabian Peninsula. A total of 23 patients, 16 females and 7 males, with genetically confirmed BVVL diagnosis at two tertiary centers from the region were retrospectively reviewed. Most patients were clinically ascertained (13/23), while 10 patients were diagnosed pre-symptomatically. 20 patients were homozygous for SLC52A3: c.634C>T (p.Arg212Cys) variant and 3 patients were homozygous for SLC52A3: c.1325_1326del. Facial diplegia was the commonest clinical feature (12/13), while moderate to severe hearing loss and dysarthria were seen in (10/13) patients. Symptomatic patients were treated with riboflavin doses ranging between 15 and 100 mg/Kg/day, with a median of 26 mg/Kg/day. Pre-symptomatic patients were treated with doses lower than that (as low as 5 mg/Kg/day). Patients were followed for 6 months to 12 years, with a median of 4 years. Most patients have shown significant or near-total recovery with residual symptoms (11/13), while 9/10 patients diagnosed pre-symptomatically remained symptom-free, and 2 symptomatic patients showed complete resolution of symptoms. The study emphasizes the significant interfamilial and intrafamilial variability of BVVL, and it stresses the impact of early treatment with riboflavin in the prevention of morbidity and mortality associated with this condition. The study also provides the longest cumulative follow-up of pre-symptomatically treated patients reported to date, providing preliminary evidence for the role of riboflavin in the prevention of morbidities associated with this condition.

Dysarthria secondary to acquired brain injury (ABI) is a motor speech disorder characterised by impaired coordination of the respiratory, phonatory and articulatory subsystems, with a negative impact on communication and quality of life. Previous studies have largely examined these components separately, which limits understanding of their functional interactions. An integrated approach combining respiratory and acoustic-articulatory measures may improve the characterisation of dysarthria and support the identification of objective markers of severity. The aim of this study is to jointly analyse respiratory function and speech acoustic parameters in adults with ABI and to examine their association with the presence and severity of dysarthria.

History A 76-year-old man presented to the emergency department with a 1-month history of worsening binocular diplopia on left horizontal gaze, along with 1 week of progressive dysarthria and dizziness. Additionally, he had a chronic history of right-sided cervicobrachialgia related to degenerative disk disease, which had been improving with oral analgesia. The patient's past medical history included hypertension, dyslipidemia, insomnia, and hypothyroidism. He also had postpolio syndrome affecting the right lower limb. He reported no fever, chills, cough, shortness of breath, abdominal pain, or chest pain. There was no history of rash, intravenous drug use, immunosuppressive medication use, or documented congenital abnormalities. He reported no recent or recurrent bacterial or viral infections. At clinical examination, the patient appeared tired and had a decreased level of alertness. He was hypertensive (165/91 mm Hg) but had a normal body temperature. Other vital signs were unremarkable. Neurologic assessment revealed left abducens nerve palsy, right lower facial palsy, horizontal nystagmus during right eye adduction, and right lower limb paresis with ipsilateral patellar hyperreflexia. Brain MRI performed the day after admission showed imaging abnormalities (Figs 1-3). Laboratory testing showed an elevated C-reactive protein level (135 mg/L; upper limit of normal, 1 mg/L); other blood tests were within normal limits. Extensive additional diagnostic workup-including serologic testing for anti-aquaporin-4 antibody, anti-DNA antibody, lupus anticoagulant, antinuclear antibody, anti-cardiolipin antibody, and rheumatoid factor-yielded negative results. Lumbar puncture revealed a normal cerebrospinal fluid opening pressure (18 cm H2O; upper limit of normal, 25 cm H2O). The cerebrospinal fluid was clear, with a normal total nucleated cell count (3.75/mm3; reference range, 0-5/mm3), normal glucose level (53 mg/dL [2.9 mmol/L]; reference range, 50-77 mg/dL [2.8-4.3 mmol/L]), and elevated total protein level (750 mg/L; reference range, 100-450 mg/L). Cerebrospinal fluid oligoclonal bands were positive.

We present the case of a lady in her early 20s who developed over a few weeks progressive appendicular and limb ataxia and dysarthria. She was found to have a high titer of voltage-gated calcium channel antibodies (VGCCAs) and was started on immunosuppressive and immunomodulating therapy with no further worsening of her neurological status. Subsequent testing revealed that she was also TG6 antibody-positive, and a gluten-free diet was added to her management, following which improvement in cerebellar N-acetyl-aspartate (NAA) concentration (an index of neuronal health/integrity) was noted on magnetic resonance spectroscopy (MRS), while her clinical picture remained static.

Myasthenia gravis (MG) is a rare autoimmune disorder characterized by muscle weakness and fatigue, caused by autoantibodies produced by B-cells that target proteins in the postsynaptic membrane of the neuromuscular junction. Clinical manifestations are heterogeneous and may include diplopia, ptosis, dysarthria, dysphagia, and limb muscle weakness, with severity ranging from mild symptoms to life-threatening myasthenic crisis. Despite advances in diagnostic approaches and the availability of immunomodulatory and biological therapies, there remains a need for an improved understanding of the disease mechanisms and biomarker development in MG. Blood-derived exosomes are small extracellular vesicles that carry proteins, lipids, nucleic acids, and glycoconjugates, and are involved in intercellular communication and the transfer of biological material between cells. Circulating exosomes may reflect aspects of cellular and immune status and have been proposed as a minimally invasive source of biomarkers in various diseases. In this review, we summarize current evidence on the potential role of exosomes in MG, with a focus on their involvement in disease-associated processes and their possible utility as biomarkers, as well as directions for future research.

X-linked adrenoleukodystrophy (X-ALD) is a genetic peroxisome disorder linked to ABCD1 mutation, characterized by rapid and complex clinical symptoms. We here report a case of X-ALD manifesting solely as dysarthria, associated with an undefined mutation in the ABCD1 gene, underscoring the necessity of atypical clinical symptoms in X-ALD diagnosis.

Cardiac papillary fibroelastomas are rare benign primary cardiac tumors that predominantly involve the endocardium. Despite their benign histological nature, they have a high embolic potential and may present as ischemic stroke, making their identification particularly relevant in the context of cryptogenic stroke. We report the case of a 52-year-old woman who presented to the emergency department with sudden-onset right-sided hemiplegia and dysarthria. Computed tomography angiography revealed occlusion of the M1 segment of the left middle cerebral artery, and she underwent intravenous thrombolysis followed by mechanical thrombectomy, with favorable clinical evolution. During the etiological workup, transthoracic echocardiography revealed an image suggestive of a mass on the posterior leaflet of the mitral valve, later confirmed by transesophageal echocardiography, raising suspicion of a papillary fibroelastoma. The patient subsequently underwent cardiac surgery, which confirmed the diagnosis. The aim of this report is to describe a rare case of ischemic stroke in association with a mitral valve papillary fibroelastoma and to highlight the importance of comprehensive etiological investigation in patients with presumed cryptogenic stroke.