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.

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.

Votoplam is a novel, orally bioavailable, small molecule HTT gene splicing modifier that is being developed for the treatment of Huntington's disease. A single-dose, open-label, three-dose level (5, 10, 20 mg), parallel group ethnicity study was conducted to evaluate the pharmacokinetics and safety of votoplam in healthy Caucasian versus Japanese participants. Six participants per ethnic group were enrolled at each dose (12 participants per dose level overall). Thirty-five participants (N = 18 Japanese; N = 17 Caucasian) completed the study. Study results showed slightly higher exposure for Japanese participants at all dose levels. AUC0-last increased by 1.27-, 1.17-, and 1.29-fold, and Cmax increased by 1.58-, 1.19-, and 1.61-fold for 5, 10, and 20 mg, respectively, for Japanese compared with Caucasian participants. Doses proportionality was observed for both ethnicities. Few mild and moderate TEAEs were reported and were comparable between Japanese and Caucasian participants. In summary, votoplam pharmacokinetics and safety profiles are similar between healthy Japanese and Caucasian participants when administered in the single dose range of 5, 10, and 20 mg. Therefore, it is expected that dose adjustments should not be necessary in future clinical studies enrolling Japanese participants.

Physicians evaluating pediatric movement disorders, especially chorea, should consider a broad differential diagnosis, including vascular etiologies such as moyamoya disease. Prompt recognition, appropriate neuroimaging, and early diagnosis are crucial for guiding management and optimizing patient outcomes.

Huntington's disease (HD) is a rare, autosomal dominant neurodegenerative disorder characterized by progressive movement disturbances, psychiatric symptoms, and cognitive impairment. The disease is caused by an increased number of repeats of the cytosine-adenine-guanine (CAG) base sequence in the HTT gene, leading to the production of a huntingtin protein with toxic gain-of-function properties and the accumulation of protein aggregates in neurons, resulting in neurodegeneration. The prevalence of HD has previously been reported to be low in Iceland compared with other European countries. However, recent studies indicate an increased prevalence, likely due to improved diagnostic capabilities and greater use of genetic testing. Diagnosis is based on clinical evaluation, family history, and confirmation by genetic testing. Currently, no disease-modifying treatment is available, but symptomatic management and a multidisciplinary approach can improve patients' functional abilities and quality of life. This review article discusses the epidemiology, genetics, clinical manifestations, diagnosis, and treatment of Huntington's disease, with particular emphasis on recent Icelandic research findings and future prospects.

Chorea is a hallmark of Huntington's disease (HD), yet its clinical assessment is of limited reliability, impairing our ability to sensitively evaluate its progression. We evaluated passive monitoring for estimating the two-year evolution of upper limb chorea in HD. Across four studies, 1025 participants collected smartwatch accelerometer data during their everyday life. We developed a machine learning model anchored to in-clinic upper limb chorea and trained cross-sectionally on disease-relevant features. The final model, selected using nested cross-validation, allowed estimating the longitudinal evolution of chorea. The resulting digital passive monitoring chorea score shows a progression of 0.13 points per year (95% CI: [0.08, 0.17]), and a robust sensitivity to change across studies, avoiding biases related to in-clinic measurements. High-resolution accelerometer data collected passively during daily life can improve the measurement of chorea in HD. Clinical Trial Registry Name: ClinicalTrials.gov; Study IDs: NCT03761849 registered 2018-11-30 and NCT03664804 registered 2018-09-07.

A 71-year-old woman presented with late-onset behavioural change initially diagnosed as bipolar disorder, followed 4 years later by generalised chorea and weight loss. Examination showed hyperkinetic movements with frontal and oculomotor features. An MR scan of the brain showed bilateral striatal T2 FLAIR hyperintensities. Serum and cerebrospinal fluid were positive for anticollapsin response mediator protein 5/CV2 and anti-neuronal nuclear antibody type 1/Hu antibodies, and imaging identified an underlying thoracic malignancy. She did not respond to immunotherapy and died shortly afterwards. This case highlights paraneoplastic striatal encephalitis as an important cause of late-onset chorea. Psychiatric symptoms may precede neurological features by several years, and red flags such as subacute progression, systemic symptoms and characteristic MR imaging changes should prompt early investigation for neuronal antibodies and malignancy.

Alzheimer's disease (AD) and Huntington's disease (HD) share neuroinflammatory mechanisms, yet their specific immune microenvironments remain poorly understood. Integrating transcriptomic profiles of peripheral blood and frontal cortex tissues with 2,160 immune-related genes, we analysed their shared immunopathology. Differential analysis identified 64 peripheral and 159 central consistently dysregulated immune genes, intersecting to isolate 10 co-expressed all-immune genes. Functional enrichment highlighted neutrophil and monocyte activation, alongside IL-17 and T-cell receptor signalling pathways. Machine learning (LASSO and Boruta) robustly pinpointed MMP9 as the core shared immune hub gene. External validation revealed MMP9 exhibited modest diagnostic performance in peripheral blood (AD AUC = 0.616; HD AUC = 0.619) but stronger predictive accuracy in brain tissues (AD AUC = 0.825; HD AUC = 0.876). Furthermore, MMP9 expression positively correlated with neutrophil and M0 macrophage infiltration. While modest peripheral accuracy limits its standalone diagnostic utility, this cross-tissue analysis establishes MMP9 as a consistently upregulated candidate molecular indicator of shared neuroinflammation, offering a valuable target for future mechanistic research.

Background: In Parkinson's disease (PD), changes in the brain begin before clinical symptoms. We have previously shown that VGF precursor levels were reduced in a presymptomatic PD animal model. Objectives: In the present study, we investigated whether two VGF precursor-derived products, namely NAPP-129 protein and TLQP-62 peptide, also exhibit alterations using the same PD animal model. Methods: Specifically, rats were unilaterally injected in the substantia nigra with a viral vector overexpressing green fluorescent protein (N = 12) or α-synuclein (N = 13), the latter resulting in mild dopaminergic alterations without overt motor deficits. Results: NAPP-129 and TLQP-62 were investigated in the substantia nigra, striatum, and plasma by Western blotting or immunoassays using specific antibodies against NAPP and TLQP sequences, alongside other NERP-1- and AQEE-related products. Plasma samples of a Huntington's disease mouse model were also analyzed. We found reductions in NAPP-129 and TLQP-62 levels in the substantia nigra along with a decrease in NAPP- and TLQP-like plasma immunoreactivity in α-synuclein-overexpressed rats, while the striatum was not affected. NERP-1- and AQEE-related products were not altered. No changes were found in the Huntington's disease model. Conclusions: These findings indicate that NAPP-129 and TLQP-62 may enhance the sensitivity and specificity of biomarker-based strategies for PD.

A woman in her 50s with genetically confirmed Huntington's disease presented with right-sided arm sensory symptoms that evolved over days and persisted for at least 1 month. Neurological examination revealed mild right arm hypoesthesia and mild generalised choreiform movements. Brain MRI demonstrated multiple supratentorial and infratentorial lesions suggestive of demyelination, along with a short-segment, contrast-enhancing cervical spinal cord lesion. Cerebrospinal fluid analysis revealed type 2 IgG-restricted and type 4 IgM-restricted oligoclonal bands. Comprehensive testing for infectious, paraneoplastic, metabolic and other autoimmune aetiologies yielded negative results. A diagnosis of relapsing-remitting multiple sclerosis was established, based on the 2024 McDonald criteria and after exclusion of alternative diagnoses. Dimethyl fumarate was initiated, with neither adverse effects nor new clinical relapses or MRI lesions. This case highlights the need to remain alert to subjective neurological symptoms in patients with Huntington's disease, ensuring that new manifestations are not automatically attributed to a single disease process.

Sydenham chorea (SC) is the major neurologic manifestation of rheumatic fever. It is defined by characteristic involuntary movements and frequently associated with neuropsychiatric symptoms that may develop weeks or months following a Group A beta hemolytic streptococcal (GAS) infection.