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Hyperkinetic Movement Disorders
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Morales-Briceno Hugo, Victor S.C. Fung, Annu Aggarwal, Philip Thompson
GNAL-related dystonia (DYT25): Autosomal dominant isolated dystonia.Onset in the fourth decade but can present earlier.Cervical involvement at onset.Can also involve upper limbs.Often remains focal or segmental.
Immune-Related Adverse Events from Cancer Immunotherapy
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
Much of the translational research in this field has investigated the potential relationship between irAEs and blood biomarkers as well as cellular repertoire found in irAE tissue histology. Study of the blood and serum have yielded findings regarding the correlation between irAEs and circulating cells, autoantibody presence, and peripheral cytokines and chemokines. Peripheral neutrophil-to-lymphocyte ratios and peripheral eosinophilia at time of event have been associated with ICI toxicities, with the latter closely correlated with dermatologic-irAEs.64 Additionally, peripheral blood gene expression profiling of cases with melanoma and ICI-colitis yielded high levels of CD177 and CEACAM1, two neutrophil-activation markers.65 Regarding the relationship between irAEs and autoantibodies, a systematic review assessing autoantibodies in relation to irAEs found the highest association with ICI-endocrinopathies, dermatologic irAEs, and irAEs affecting the musculature, such as those for myositis / myocarditis / myasthenia gravis.44 A retrospective analysis of patients with non-small-cell lung cancer and PD-1 inhibitor therapy revealed a significant association with “any pre-existing antibody” with that of irAEs and progression-free survival (antibody panel included rheumatoid factor, antinuclear antibody [ANA], antithyroglobulin, and antithyroid peroxidase antibodies).66 In this same vein, there has been notable correlation between pre-ICI anti-GNAL and anti-ITM2B antibodies with that of ICI-hypophysitis as well as pre-ICI anti-CD74 positivity and ICI-pneumonitis.67 A hypothesis-generating proteomic microarray analysis identified an association between severe any-type irAEs and distinct pre-ICI or baseline serum antibody profiles that corresponded to certain immune pathways such as TNF-α signaling or toll-like receptor signaling.68
New approaches to discovering drugs that treat dystonia
Published in Expert Opinion on Drug Discovery, 2019
Sarah Pirio Richardson, H. A. Jinnah
In isolated dystonia, six genes have been identified, which are estimated to account for a very small percentage (around 2%) of cases overall [40,41]. The first described among the isolated dystonias was the TOR1A gene (DYT1), encoding a protein chaperone, torsinA [42]. DYT1 dystonia typically presents as a childhood onset and lower-limb onset dystonia, which generalizes throughout the body. Although within families with DYT1, the clinical presentation can vary, including incomplete penetrance and dystonia focal in its onset and persistence [43]. The THAP1 gene, encoding the Thanatos-associated protein domain containing apoptosis-associated protein 1, presents as focal or segmental dystonia mostly in the upper limbs, neck or face [44]. More recently, there have been four other genes described: 1) the CIZ1 gene linked to familial cervical dystonia [45]; 2) the ANO3 gene with a clinical presentation of familial tremor-dominant cervical dystonia [46]; 3) the GNAL gene linked with familial dystonia with onset in the head and neck [47]; 4) the TUBB4 gene associated with whispering dysphonia and inherited in an autosomal dominant manner [48]. The range of abnormal proteins produced from these gene mutations from torsinA to a G-protein involved in neuronal signaling to a protein that bears homology to a chloride channel illustrates the potential heterogeneity in disease pathophysiology but also opens the door to new potential targets that may be wide-ranging.
Current challenges in the pathophysiology, diagnosis, and treatment of paroxysmal movement disorders
Published in Expert Review of Neurotherapeutics, 2021
Cécile Delorme, Camille Giron, David Bendetowicz, Aurélie Méneret, Louise-Laure Mariani, Emmanuel Roze
Other hyperkinetic movement disorders have been associated with a dysregulation of the cAMP turnover. Pathogenic loss-of-function variants of GNAL, encoding for the alpha subunit Gαolf, cause dystonia[88–91] (Figures 1(a, b)). In LID occurring in Parkinson’s disease, the level of cAMP is increased in the striatum lacking dopaminergic input, particularly in the striato-nigral SPNs baring D1 receptors (Figure 1a). Selective upregulation of the Gαolf-cAMP-PKA pathway in direct SPNs, through an increase in Gαolf levels and a decrease in PDEs activity, plays a key role in the pathogenesis of levodopa-induced dyskinesia[92–98] (Figure 1a). PET-Imaging studies in patients with Huntington disease, another hyperkinetic movement disorder, show a decrease in PDE10A and D2 receptor, which would both be leading to an increase of cAMP concentration[99–101] (Figures 1(a, b)). Decreased levels of PDE10A and PDE1B were also found in the brain of Huntington’s disease patients and in an Huntington’s disease mice model [102,103]. In indirect SPNs, activation of adenosine A2A receptor, coupled to Golf, leads to the increase of cAMP production through the activation of AC5 (Figure 1(b)). The role of the A2AR in LID has been suggested (Figure 1(b)). PET-imaging studies suggested that dyskinesia might involve adenosine A2AR. Studies in patients with PD demonstrated that the putaminal density of adenosine A2AR was increased in patients with dyskinesia and that there was no significant difference between de novo PD patients and normal controls [104–106]. Istradefylline, an A2AR antagonist, has been reported to reduce LID in PD patients [107].
Hypophysitis related to immune checkpoint inhibitors: An intriguing adverse event with many faces
Published in Expert Opinion on Biological Therapy, 2021
Maria V Deligiorgi, Charis Liapi, Dimitrios T Trafalis
In the setting of ir hypophysitis, investigation of alterations in autoantibody expression revealed increased autoantibodies against the guanine nucleotide-binding protein G(olf) subunit alpha (GNAL) and the integral membrane protein 2B (ITM2B) in 8 patients with melanoma, prostate cancer, and renal cell carcinoma. Recently, autoantibody profiling on serial samples from 2 patients with ir hypophysitis ‒one patient receiving ipilimumab and another one receiving pembrolizumab‒ identified presence of common autoantibodies against the zinc finger CCHC-type containing 8 (ZCCHC8) protein. This result laid the groundwork for demonstration of ZCCHC8 expression in pituitary tissue [32].