Huntington's Disease is a neurodegenerative disorder that progresses over time and can be passed down from parent to child. In uncontrolled motor activities, behavioural problems come into play, as well as progressive mental decline. The CAG triplet in the HTT gene found on chromosome 4 undergoes changes, leading to the production of a mutant protein called huntingtin, which consists of a bigger-than-normal polyglutamine tract that then undergoes misfolding and produces toxic oligomers and fibrillar deposits that can cause dysfunction in normal cell functioning and therefore in nerve cells as well. Although early research linked the pathophysiology of Huntington's disease primarily to mHTT aggregation, more recent research indicates broad protein-protein interaction networks that affect several cellular pathways. Systems biology approaches using tools such as STRING, BioGRID, and Cytoscape have provided evidence of interconnected networks that promote proteostasis, mitochondrial dynamics, energy metabolism, neuroinflammation, synaptic transmission, and transcriptional and epigenetic regulation. Important protein hubs, including HSP70, DRP1, NLRP3, and TFEB, act as central controls that bind those pathways. mHTT-mediated defect in the function of the ubiquitin-proteasome system promotes mitochondrial oxidative stress, which triggers the NLRP3 inflammasome, leading to synaptic dysfunction and specific loss of striatal medium spiny neurons. Investigations using various experimental techniques, which involve R6/2 and YAC128 mouse models, neurons derived from human iPS cells, and multi-omics studies, reveal that faulty neuroplasticity develops before the formation of visible protein aggregates. As for therapeutics targeting central components of neuronal networks, they have all demonstrated certain neuroprotective effects.

Growing interest in earlier and mechanism-targeted interventions for Huntington's disease (HD) has brought focus on biomarkers capable of informing trial design and regulatory pathways. This review discusses recent advances in fluid and neuroimaging biomarkers since the introduction of the HD-Integrated Staging System (HD-ISS), focusing on candidates with the most relevant evidence for regulatory applications.

Ataxia-telangiectasia (ATX-ATM) is a rare multisystem disorder caused by pathogenic variants in the ataxia-telangiectasia mutated (ATM) gene. The classic phenotype is characterized by childhood-onset progressive cerebellar ataxia and movement disorders, accompanied by telangiectasias, primary immunodeficiency, chronic pulmonary disease, endocrine abnormalities, and increased sensitivity to ionizing radiation, as well as a markedly elevated risk of malignancy. In contrast, variant ATX-ATM is associated with a milder and more heterogeneous phenotype, in which cerebellar ataxia may be absent, while dystonia and axonal sensorimotor neuropathy are common; immune and respiratory function are typically preserved, although the risk of malignancy remains increased. We report a 39-year-old man presenting with progressive ataxia, chorea, and telangiectasias, with two siblings exhibiting a similar phenotype. Notably, one sibling developed diffuse gastric adenocarcinoma and cutaneous melanoma, whereas his sister died from ovarian and colon cancer. Whole-exome sequencing identified compound heterozygous variants in the ATM gene in the two affected siblings: a pathogenic splice-site variant, c.2921 + 1G > A, and a heterozygous missense variant of uncertain significance, c.8083G > A; p.(Gly2695Ser). Segregation analysis confirmed that these variants were in trans, supporting the identification of a rare ATM variant associated with ATX-ATM in this family. The diagnosis of variant ATX-ATM remains challenging because of its marked phenotypic heterogeneity. Nevertheless, early recognition is essential given the substantially increased risk of malignancy and the need for appropriate oncologic surveillance and genetic counseling. The identification and reporting of ATM variants contribute to improved genotype-phenotype correlations and broaden the current understanding of disease variability.

Acquired hemichorea-hemiballismus, also termed diabetic striatopathy, is an uncommon but established complication of uncontrolled hyperglycemia in patients with diabetes. It typically presents as involuntary, unilateral choreiform movements secondary to nonketotic hyperglycemia with characteristic hyperdensities in the contralateral striatum on brain imaging. Here, we report the case of an 82-year-old female who presented with bilateral acquired chorea-ballismus with corresponding hyperdensities in both basal ganglia on imaging in the setting of diabetic ketoacidosis. Her presentation was also complicated by acute encephalopathy attributed to hyperglycemia and catheter-associated urinary tract infection. Her choreiform movements and encephalopathy improved with correction of hyperglycemia and resolution of ketoacidosis but only fully resolved when starting risperidone therapy. Brain imaging on hospital day 6 showed stable hyperdensities in the striata compared with admission despite improvement in symptoms. The patient re-presented to the hospital for unrelated reasons 3 months later and had sustained resolution of symptoms. This report highlights the variability of symptom presentation in diabetic striatopathy and confirms diabetic ketoacidosis as a setting for this rare complication.

The glymphatic system, the cerebrospinal fluid-based circulation and waste clearance system for the brain, is gaining increasing attention in Huntington's disease (HD) due to its potential role in neurodegeneration. Glymphatic dysfunction may contribute to progressive neuronal damage and key clinical features such as cognitive decline and sleep disturbances. This chapter explores the current neuroimaging techniques used to assess glymphatic function in HD, as well as emerging approaches applied in other neurodegenerative disorders, with an emphasis on magnetic resonance imaging and positron emission tomography. We discuss the biological specificity and methodological limitations of these imaging proxies, including the need for multimodal integration. Finally, we outline the clinical and translational implications of glymphatic imaging, including its potential use as a biomarker for early disease detection, longitudinal disease monitoring, and the development of targeted therapeutic strategies.

Sydenham chorea (SC) has been conventionally recognized as a movement disorder that occurs in 10%-50% of pediatric patients with acute rheumatic fever. In this article, we review the research on SC's psychiatric aspects and detail how physicians writing in English have grappled with questions of SC's psychological and somatic etiology and symptoms over the past 150 years. We demonstrate that the current neuropsychiatric understanding of SC in Anglophone contexts is the result of decades of scientific dialogue, with its mental, emotional, and behavioral symptoms now identified as a feature of organic pathology. This examination provides a valuable perspective on the challenges of interpreting and understanding the central nervous system manifestations of autoimmune illness caused by Group A Streptococcus.

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by vascular thrombosis and/or obstetric morbidity in the presence of persistent antiphospholipid antibodies. Chorea is an uncommon neurological manifestation, reported in approximately 1% of patients, and is not included among the clinical domains required for classification. We report the case of a 28-year-old woman who presented with acute left-sided sensorimotor deficits. Her only relevant history was an episode of chorea involving the left upper limb at 18 years of age, which resolved spontaneously after an incomplete etiological workup at another institution. Neuroimaging demonstrated a right frontal ischemic lesion, and cardioembolic and large-vessel causes were excluded. Prompted by the prior history of chorea, testing revealed persistently high-titer anticardiolipin IgG and anti-β2-glycoprotein I IgG antibodies, establishing a diagnosis of primary APS. She was started on warfarin and achieved functional independence without recurrent vascular events. This case illustrates that juvenile-onset chorea may represent the heralding manifestation of APS, preceding the qualifying thrombotic event by a decade. An isolated, self-limited chorea of undetermined cause should prompt antiphospholipid antibody testing, as early recognition may allow timely thromboprophylaxis and potentially prevent cerebrovascular events in young patients.

Postpump chorea is a rare hyperkinetic movement disorder following cardiac surgery with cardiopulmonary bypass. Although initially described in pediatric patients, postpump chorea is increasingly recognized in adults. We report the case of a 65-year-old woman who developed severe choreiform movements approximately 2 weeks after cardiac surgery. Extensive diagnostic workup including cerebrospinal fluid analysis revealed no alternative etiology. Notably, hypothermia had only been mild during cardiac surgery, and there were no characteristic basal-ganglia MRI abnormalities. Treatment with tiapride, a selective dopamine D2/D3 receptor antagonist with established antichoreic effects was followed by rapid neurological improvement and complete remission of symptoms. This is one of the first reports of tiapride in adult postpump chorea, supporting its role as a potentially useful symptomatic therapeutic option in this rare complication.