Giulietta M. Riboldi
Alessio B. Di Fonzo
Christopher D. Stephen- 1Department of Neurology, The Marlene and Paolo Fresco Institute for Parkinson's and Movement Disorders, NYU Langone Health, New York, NY, United States
- 2Neurology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- 3Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
Editorial on the Research Topic
Genetic advances and translational applications in movement disorders
Despite recent advances in the field of genetics and translational medicine, many movement disorders still remain undiagnosed and difficult to treat. Genetic and genomic advances have led to the discovery of new genes and molecular pathways in movement disorders. Our Research Topic encompasses original works and literature reviews regarding the importance and challenges of genetic diagnosis, the pitfalls of atypical phenotypes, the benefit of leveraging interdisciplinary teams, and the potential for pathogenesis-directed therapies.
There are ongoing difficulties with clinic-genetic correlations in movement disorders (1, 2). Cesaroni et al. illustrate the importance of defining a genetic diagnosis with atypical symptoms. They describe a patient with a rare intellectual disability syndrome related to a pathogenic variant in FOXP1. Together with the classical phenotype, they describe paroxysmal dystonia and discuss the potential pathogenic role of FOXP1 in the basal ganglia, which may lead to movement disorders in this population.
In addition, Ando et al. describe the prevalence of RFC1 mutation carriers in a large cohort of patients with ataxia, who had a younger age of onset than previously described, in comparison to more typical late-onset presentations (3). As the causative role of intronic variants have been increasingly recognized as potentially common causes of genetic movement disorders, the inclusion of relevant intronic variants on gene panels and the assessment of repeat expansions are important to improve diagnosis (4).
More comprehensive tests, such as WES, are becoming more routine in the field of movement disorder as well. Zou et al. showed how WES allowed the identification of a new pathogenic variant in the PLA2G6 gene in two siblings allowing immediate management of the affected probands and counseling for the family.
Genetic counseling is a key principle of the management of rare neurogenetic disorders and this is particularly important in the fatal prion diseases. Appleby et al. in their review discuss the genetic associations in sporadic, acquired, and genetic prion diseases and present the intricacies of genetic testing during life or at autopsy, in addition to the thorny ethical quandaries for testing of at-risk family members. They discuss the possibility of future treatments targeting the PRNP gene.
Given the complexity of rare genetic disorders, there is increasing use of an interdisciplinary team-based approach, such as the Undiagnosed Disease Program (5, 6). In their paper, Huang et al. describe the important experience of the White Matter Rounds network, an international, collaborative platform where clinicians and scientists discuss challenging cases, promoting new understanding of these complex diseases and leveraging different expertise to aid in the diagnosis and facilitate research in white matter disorders leukodystrophies.
There are understandable challenges in the design and implementation of clinical trials in rare neurological disorders. Videnovic et al. highlight the lessons learned from clinical trials in pantothenate kinase-associated neurodegeneration, discussing successful strategies that can be applied to other rare and particularly metabolic movement disorders. They suggest multi-disciplinary engagement with experts and approaches concerning selection and recruitment of appropriate patients, trial endpoints and duration, special statistical considerations, and the importance of regulatory feedback.
Therefore, as genetic diagnosis become more relevant in the landscape of movement disorders, diagnostic, and therapeutic approaches need to be reshaped to include new discoveries in clinical practice and maximize implementation of integrative resources from the clinical and research settings.
Author contributions
GMR: Conceptualization, Writing—original draft, Writing—review and editing. ABD: Conceptualization, Writing—original draft, Writing—review and editing. CDS: Conceptualization, Writing—original draft, Writing—review and editing.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
GMR was supported by grants from Michael J Fox Foundation, Parkinson's Foundation, Department of Defense (PD210038), NIH (R01NS116006; 1R01NS133742-01), and received a previous research grant from Prevail Therapeutics. CDS has provided scientific advisory for SwanBio Therapeutics and his institution has received research funding from Sanofi-Genzyme for a study of video oculography in late-onset GM2 gangliosidosis. He has received financial support from SwanBio Therapeutics, Encora Therapeutics, Sanofi-Genzyme, Biogen and Biohaven for the conduct of clinical trials. He has received honoraria from the International Parkinson and Movement Disorders Society, the American Academy of Neurology/Continuum and Oakstone CME for the production of educational material. He has received grant support from the National Institutes of Health K23 NS118045-03.
The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
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References
1. Gannamani R, van der Veen S, van Egmond M, de Koning TJ, Tijssen MAJ. Challenges in clinicogenetic correlations: one phenotype – many genes. Mov Disord Clin Pract. (2021) 8:311–21. doi: 10.1002/mdc3.13163
2. Magrinelli F, Balint B, Bhatia KP. Challenges in clinicogenetic correlations: one gene - many phenotypes. Mov Disord Clin Pract. (2021) 8:299–310. doi: 10.1002/mdc3.13165
3. Cortese A, Simone R, Sullivan R, Vandrovcova J, Tariq H, Yau WY, et al. Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia. Nat Genet. (2019) 51:649–58. doi: 10.1038/s41588-019-0372-4
4. Beijer D, Fogel BL, Beltran S, Danzi MC, Németh AH, Züchner S, et al. Standards of NGS data sharing and analysis in ataxias: recommendations by the NGS working group of the ataxia global initiative. Cerebellum. (2023). doi: 10.1007/s12311-023-01537-1
5. Mühlbäck A, van Walsem M, Nance M, Arnesen A, Page K, Fisher A, et al. What we don't need to prove but need to do in multidisciplinary treatment and care in Huntington's disease: a position paper. Orphanet J Rare Dis. (2023) 18:19. doi: 10.1186/s13023-023-02622-8
Keywords: genetics, movement disorders, counseling, whole exome sequencing, clinical trials
Citation: Riboldi GM, Di Fonzo AB and Stephen CD (2023) Editorial: Genetic advances and translational applications in movement disorders. Front. Neurol. 14:1280958. doi: 10.3389/fneur.2023.1280958
Received: 21 August 2023; Accepted: 29 August 2023;
Published: 20 September 2023.
Edited and reviewed by: Huifang Shang, Sichuan University, China
Copyright © 2023 Riboldi, Di Fonzo and Stephen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Giulietta M. Riboldi, Z2l1bGlldHRhLnJpYm9sZGkmI3gwMDA0MDtueXVsYW5nb25lLm9yZw==