Cerebellum Dysfunction in Patients With PRRT2 -Related Paroxysmal Dyskinesia

Abstract

Background and Objectives:The main culprit gene for paroxysmal kinesigenic dyskinesia, characterized by brief and recurrent attacks of involuntary movements, is PRRT2. The location of the primary dysfunction associated with paroxysmal dyskinesia remains a matter of debate and may vary depending on the etiology. While striatal dysfunction has often been implicated in these patients, evidence from preclinical models indicate that the cerebellum could also play a role. We aimed to investigate the role of the cerebellum in the pathogenesis of PRRT2-related dyskinesia in humans.Methods:We enrolled 22 consecutive right-handed patients with paroxysmal kinesigenic dyskinesia with a pathogenic variant of PRRT2, and their matched controls. Participants underwent a multi-modal neuroimaging protocol. We recorded anatomic and diffusion-weighted MRI, as well as resting-state functional MRI during which we tested the after-effects of sham and repetitive transcranial magnetic stimulation applied to the cerebellum on endogenous brain activity. We quantified: (i) the structural integrity of gray matter using voxel-based morphometry; (ii) the structural integrity of white matter using fixel-based analysis; (iii) the strength and direction of functional cerebellar connections using spectral dynamic causal modeling.Results:PRRT2 patients had: (i) decreased gray matter volume in the cerebellar lobule VI and in the medial prefrontal cortex; (ii) microstructural alterations of white matter in the cerebellum and along the tracts connecting the cerebellum to the striatum and the cortical motor areas; (iii) dysfunction of cerebellar motor pathways to the striatum and the cortical motor areas, as well as abnormal communication between the associative cerebellum (Crus I) and the medial prefrontal cortex. Cerebellar stimulation modulated communication within the motor and associative cerebellar networks, and tended to restore this communication to the level observed in healthy controls.Discussion:Patients with PRRT2-related dyskinesia have converging structural alterations of the motor cerebellum and related pathways with a dysfunction of cerebellar output towards the cerebello-thalamo-striato-cortical network. We hypothesize that abnormal cerebellar output is the primary dysfunction in patients with a PRRT2 pathogenic variant, resulting in striatal dysregulation and paroxysmal dyskinesia. More broadly, striatal dysfunction in paroxysmal dyskinesia might be secondary to aberrant cerebellar output transmitted by thalamic relays in certain disorders.Clinical trial number:NCT03481491 (https://ichgcp.net/clinical-trials-registry/NCT03481491)

Altered brain connectivity in hyperkinetic movement disorders: A review of resting-state fMRI

“…( Huang et al, 2017 ) In paroxysmal kinesigenic dyskinesia patients with a PRRT2 gene mutation, decreased FC within a DMN was found. ( Ekmen et al, 2022 ) Overall, it can be noted that there are inconsistent results with regards to resting-state networks in patients with dystonia.…”

“…For dystonia, 46 articles were included, ( Zhang et al, 2020 , Pan et al, 2019 , Jochim et al, 2018 , Putzel et al, 2018 , Mantel et al, 2018 , Ni et al, 2017 , Huang et al, 2017 , Li et al, 2017 , Long et al, 2017 , Haslinger et al, 2017 , Kiyuna et al, 2017 , Battistella et al, 2016 , Sarasso et al, 2020 , Liu et al, 2016 , Ren et al, 2015 , Bharath et al, 2015 , Dresel et al, 2014 , Delnooz et al, 2015 , Hinkley et al, 2013 , Delnooz et al, 2013 , Delnooz et al, 2012 , Mohammadi et al, 2012 , Wei et al, 2021 , Jiang et al, 2019 , Pan et al, 2021 , Feng e al., 2021 , de Faria et al, 2020 , Norris et al, 2020 , Glickman et al, 2020 , Mantel et al, 2020 , Ma et al, 2021 , Corp et al, 2019 , Fang et al, 2021 , Giannì et al, 2022 , Qin et al, 2019 , Zito et al, 2022 , Kim et al, 2022 , Hou et al, 2022 , Ekmen et al, 2022 , Nieuwhof et al, 2022 , Filip et al, 2022 , Battistella and Simonyan, 2019 , Bianchi et al, 2019 , Kita et al, 2018 , Fuertinger and Simonyan, 2018 , Qin et al, 2018 ) concerning cervical dystonia (CD; n = 14), writer’s cramp (n = 10), laryngeal dystonia (n = 8), musician's dystonia (n = 5), paroxysmal kinesigenic dyskinesia (n = 6), blepharospasm (n = 6), oromandibular dystonia (n = 2), dyskinetic cerebral palsy (n = 2), spastic cerebral palsy (n = 1), dystonic tremor (n = 1), and generalized dystonia (n = 1). Most studies matched patients and healthy participants for age and gender.…”

A multi-layer mean-field model for the cerebellar cortex: design, validation, and prediction

“…In future applications, this will allow to tune the MF toward specific functional or dysfunctional states that affect the cerebellum. Among these it is worth mentioning ataxias (Pedroso et al, 2019; Rosenthal, 2022), paroxysmal dyskinesia (Mendonça and Alves da Silva, 2021; Ekmen et al, 2022), dystonia (Mahajan et al, 2021; Morigaki et al, 2021), autistic spectrum disorders (Bruchhage et al, 2018; Kelly et al, 2020) as well as other pathologies like and multiple sclerosis (Tornes et al, 2014; Schreck et al, 2018), dementia (Monteverdi et al, 2022) and Parkinson disease (Wu and Hallett, 2013; Shen et al, 2020), in which a cerebellum involvement has been reported. The cerebellar MF could be applied to whole-brain simulators using TVB and DCM, as much as it has been done before for the isocortical MF in TVB (Pinotsis et al, 2012; Goldman et al, 2019; Sadeghi et al, 2020; Ruffini and Deco, 2021).…”

No Neuron Operates in Isolation

“…The findings and interpretations of Ekmen et al 1 arise from a solid platform of animal studies. In fact, a critical role for the cerebellum in the pathophysiology of dystonia emerged from rodent studies decades ago.…”

“…Longitudinal studies of gray matter volume in PRRT2 mutation carriers would help to establish the relative contributions of developmental aberrations and neurodegeneration to the reductions in cerebellar lobule V and medial prefrontal cortex gray matter volumes reported by Ekmen e al. 1 In addition, postmortem stereologic studies could pinpoint those neurons specifically affected, directly or indirectly, by PRRT2 haploinsufficiency.…”