The Spectrum of PRRT2-Associated Disorders: Update on Clinical Features and Pathophysiology

Landolfi, Annamaria; Barone, Paolo; Erro, Roberto

doi:10.3389/fneur.2021.629747

Cited by 26 publications

(35 citation statements)

References 59 publications

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“…Similar to previous literature, infants in our cohort presented with focal seizures, typically occurring in clusters, characterized by behavioral arrest, eye deviation, cyanosis and clonic jerking, with a posterior onset ictal rhythm, on a background of prior normal development, and often a positive family history of SeLIE, PKD or HM 1,3,4,6 …”

Section: Discussionsupporting

confidence: 82%

Peri‐ictal EEG in infants with PRRT2‐related self‐limited infantile epilepsy

Fearn,

Macdonald‐Laurs,

Moylan

et al. 2023

Epileptic Disorders

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ObjectivePathogenic PRRT2 variants cause self‐limited (familial) infantile epilepsy (SeLIE), which is responsive to sodium channel blocking antiseizure medications. The interictal EEG is typically normal. We describe a cohort of infants with PRRT2‐related SeLIE with striking peri‐ictal EEG abnormalities.MethodsWe included all infants diagnosed with PRRT2‐related SeLIE during July 2020 to November 2021 at the Royal Children's Hospital, Melbourne. Clinical features and results of aetiologic investigations were collected from electronic medical records. All EEGs were reviewed independently by two epileptologists.ResultsTen infants presented with focal seizures at a median age of 5 months (range: 3–6 months). Eight had a family history of epilepsy, paroxysmal kinesigenic dyskinesia (PKD) or hemiplegic migraine. Seven of the eight infants with an EEG performed within 24 h of the most recent seizure had epileptiform discharges. Their EEGs showed focal sharp waves, spikes, polyspikes or fast activity independently over the left and right temporo‐occipital regions. Conversely, the two infants with last known seizure greater than 24 h prior to their EEG had no epileptiform discharges. Oxcarbazepine was commenced in two infants and was effective. Eight infants were initially treated with levetiracetam, and all were subsequently switched to oxcarbazepine due to ongoing seizures or side effects.SignificancePosterior polymorphic focal epileptiform discharges on a peri‐ictal EEG recording are a feature of PRRT2‐related SeLIE. This finding, particularly in the presence of a family history of infantile epilepsy, PKD or hemiplegic migraine, suggests a diagnosis of PRRT2‐related SeLIE and has important treatment implications.

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Section: Discussionsupporting

confidence: 82%

Peri‐ictal EEG in infants with PRRT2‐related self‐limited infantile epilepsy

Fearn,

Macdonald‐Laurs,

Moylan

et al. 2023

Epileptic Disorders

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“…Nevertheless, it is thought that all the variants of this gene linked to PKD result in similar gene haploinsufficiency with a subsequent protein loss of function. 33 It is thus likely that the effect of the variation is representative of the PRRT2 -PKD patient population and that this aspect does not interfere with the generalizability of our findings. Another potential limitation is that we did not randomize the order of the sham and active TMS sessions.…”

Section: Discussionmentioning

confidence: 83%

Cerebellum Dysfunction in Patients With PRRT2 -Related Paroxysmal Dyskinesia

et al. 2022

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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)

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“…Indeed, the two auto-immune epilepsy cases in our cohort (EPBL-0135, -0148) are homozygous for this allele. The presence of risk or protective alleles in epilepsy patients may provide an explanation of the phenotypic variability of some well-known genetic epilepsies, such as SCN1A (Guerrini et al, 2010), PRRT2 (Landol et al, 2021) and BTD (BTD Database, n.d.) epilepsies.…”

Section: Discussionmentioning

confidence: 99%

The complex etiology of Epilepsy: Genetic analysis and HLA association in patients in the Middle East

Fadda

Alsabbagh

Vasudeva

et al. 2022

Preprint

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Epilepsy is one of the most common neurological disorders. The cost to the health system and the impact on quality of life for patients with intractable epilepsies and associated comorbidities is significant. Disease etiology and pathogenesis are still not well understood. Genetic mutations have been shown to be associated with 70% of epilepsies, with the majority being non-monogenic, and the remaining 30% enigmatic. This knowledge gap necessitates further research. The goal of this study is to partially bridge this gap through the genetic analysis of a cohort of patients with epilepsy from an understudied and highly consanguineous population, primarily of ethnicities from the Middle East and North Africa region. Whole exome sequencing was carried out in 81 patients with epilepsy and their family members at a tertiary center in Qatar. We used the data to identify pathogenic variants and type HLA alleles for 13 class I & II genes. We associated the resulting alleles with disease status, using controls of a closely related ethnicity. The genetic yield was approximately 22% for known epilepsy genes. We also suggest a list of 20 genes that could be culprits. Analysis of the biological pathways in which these genes are involved show that focal and generalized epilepsy genes are highly interwound. HLA analysis revealed that class II HLA genes are associated with disease status, particularly DRB4*03:01N, which plays a strong protective role. Our findings suggest that an immune etiology may contribute to the disease together with a genetic culprit, emphasizing the complexity of the etiology of the disease.

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The Spectrum of PRRT2-Associated Disorders: Update on Clinical Features and Pathophysiology

Cited by 26 publications

References 59 publications

Peri‐ictal EEG in infants with PRRT2‐related self‐limited infantile epilepsy

Peri‐ictal EEG in infants with PRRT2‐related self‐limited infantile epilepsy

Cerebellum Dysfunction in Patients With PRRT2 -Related Paroxysmal Dyskinesia

The complex etiology of Epilepsy: Genetic analysis and HLA association in patients in the Middle East

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