Current challenges in the pathophysiology, diagnosis, and treatment of paroxysmal movement disorders

ABSTRACT

Introduction

Paroxysmal movement disorders mostly comprise paroxysmal dyskinesia and episodic ataxia, and can be the consequence of a genetic disorder or symptomatic of an acquired disease.

Areas covered

In this review, the authors focused on certain hot-topic issues in the field: the respective contribution of the cerebellum and striatum to the generation of paroxysmal dyskinesia, the importance of striatal cAMP turnover in the pathogenesis of paroxysmal dyskinesia, the treatable causes of paroxysmal movement disorders not to be missed, with a special emphasis on the treatment strategy to bypass the glucose transport defect in paroxysmal movement disorders due to GLUT1 deficiency, and functional paroxysmal movement disorders.

Expert opinion

Treatment of genetic causes of paroxysmal movement disorders is evolving towards precision medicine with targeted gene-specific therapy. Alteration of the cerebellar output and modulation of the striatal cAMP turnover offer new perspectives for experimental therapeutics, at least for paroxysmal movement disorders due to selected causes. Further characterization of cell-specific molecular pathways or network dysfunctions that are critically involved in the pathogenesis of paroxysmal movement disorders will likely result in the identification of new biomarkers and testing of innovative-targeted therapeutics.

KEYWORDS:

• ADCY5
• ATP1A3
• cAMP
• cerebellum
• episodic ataxia
• ketogenic diet
• paroxysmal dyskinesia
• PRRT2
• SLC2A1
• triheptanoin

Article Highlights

• Paroxysmal dyskinesia could be seen as a network disorder, in which either primary striatal dysfunction or aberrant cerebellar output conveyed to the striatum results in the phenotype.

• Striatal cAMP turnover is a critical molecular pathway involved in various hyperkinetic disorders and its alteration can result in paroxysmal movement disorders.

• The main treatable causes of paroxysmal movement disorders not to be missed include functional disorders, demyelinating (multiple sclerosis, neuromyelitis optica spectrum disorder), metabolic (dysthyroidism, hypoglycemia, hypocalcemia), immune-mediated (anti-LGI1 antibodies) and vascular disorders (limb shaking transient ischemic attack); and genetic disorders such as GLUT1-deficiency, PRRT2- or ADCY5-related paroxysmal dyskinesia, CACNA1A-related episodic ataxia, and paroxysmal dystonia due to GCH1 mutations.

• Dietary strategies used for bypassing the GLUT1 transporter defect comprise classical ketogenic diet, novel variant ketogenic diets, and triheptanoin. These strategies are obviously effective, but their current use is only based on uncontrolled and often retrospective studies. There is no study directly comparing these various approaches.

• The most reliable clues to the diagnosis of functional paroxysmal movement disorders include the presence of a paroxysmal tremor, unresponsiveness during attacks, movement incongruency with known movement disorders and/or consistent with a particular ‘functional’ motor pattern, abnormal interictal examination with functional signs, distractibility, and/or entrainment of the movements or their induction/cessation by suggestion or placebo, and a waxing and waning pattern within a single episode.

Declaration of interest

E Roze served on scientific advisory boards for Orkyn, Aguettant, Merz-Pharma; received honoraria for speeches from Orkyn, Aguettant, Merz-Pharma, Everpharma, International Parkinson and Movement disorders Society; received research support from Merz-Pharma, Orkyn, Aguettant, Elivie, Ipsen, Everpharma, Fondation Desmarest, AMADYS, Fonds de Dotation Brou de Laurière, Agence Nationale de la Recherche; received travel grant from Vitalair, PEPS development, Aguettant, Merz-Pharma, Ipsen, Merck, Orkyn, Elivie, Adelia Medical, Dystonia Medical Research Foundation, International Parkinson and Movement disorders Society, European Academy of Neurology, International Association of Parkinsonism and Related Disorders. C Delorme received travel grant from Merz-pharma, Boston Scientific and Medtronic. Dr. Méneret received travel funding from the Movement Disorders Society, Abbvie and Merz. A Mariani received research support grants from INSERM, JNLF, The L’Oreal Foundation; speech honoraria from CSL, Sanofi-Genzyme, Lundbeck, Teva; consultant for Alzprotect, Biophytis, Bionure-Accure Therapeutics, Digitsole and received travel funding from the Movement Disorders Society, ANAINF, Merck, Merz, Medtronic, Teva and AbbVie, outside the submitted work. D Bendetowicz received research support grants from Fondation Recherche Medicale. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.