Paroxysmal Dyskinesias

McGuire, Sara; Chanchani, Swati; Khurana, Divya S.

doi:10.1016/j.spen.2017.12.007

Cited by 22 publications

(29 citation statements)

References 86 publications

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“…In general, patients with PNKD experience a few attacks daily, which typically last from 10 minutes to several hours, and are characteristically triggered not by exertion or movement as in other paroxysmal dyskinesias, but by alcohol, caffeine, emotion, and sleep deprivation [27]. Notably, KCNMA1 patients had PNKD episodes that were generally shorter and more frequent than those described in the traditional diagnostic criteria [9,11,[24][25][26], sometimes occurring up to hundreds per day [28][29][30], supporting the distinction for PNKD3.…”

Section: Clinical Evaluationmentioning

confidence: 99%

An emerging spectrum of variants and clinical features in KCNMA1-linked channelopathy

et al. 2021

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KCNMA1-linked channelopathy is an emerging neurological disorder characterized by heterogeneous and overlapping combinations of movement disorder, seizure, developmental delay, and intellectual disability. KCNMA1 encodes the BK K + channel, which contributes to both excitatory and inhibitory neuronal and muscle activity. Understanding the basis of the disorder is an important area of active investigation; however, the rare prevalence has hampered the development of large patient cohorts necessary to establish genotype-phenotype correlations. In this review, we summarize 37 KCNMA1 alleles from 69 patients currently defining the channelopathy and assess key diagnostic and clinical hallmarks. At present, 3 variants are classified as gain-offunction with respect to BK channel activity, 14 loss-of-function, 15 variants of uncertain significance, and putative benign/VUS. Symptoms associated with these variants were curated from patient-provided information and prior publications to define the spectrum of clinical phenotypes. In this newly expanded cohort, seizures showed no differential distribution between patients harboring GOF and LOF variants, while movement disorders segregated by mutation type. Paroxysmal non-kinesigenic dyskinesia was predominantly observed among patients with GOF alleles of the BK channel, although not exclusively so, while additional movement disorders were observed in patients with LOF variants. Neurodevelopmental and structural brain abnormalities were prevalent in patients with LOF mutations. In contrast to mutations, disease-associated KCNMA1 single nucleotide polymorphisms were not predominantly related to neurological phenotypes but covered a wider set of peripheral physiological functions. Together, this review provides additional evidence exploring the genetic and biochemical basis for KCNMA1-linked channelopathy and summarizes the clinical repository of patient symptoms across multiple types of KCNMA1 gene variants.

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Section: Clinical Evaluationmentioning

confidence: 99%

An emerging spectrum of variants and clinical features in KCNMA1-linked channelopathy

et al. 2021

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“…Paroxysmal dyskinesias (PD) are a heterogeneous group of rare hyperkinetic movement disorders characterized by recurrent and sudden attacks of dystonic and/or choreic involuntary movements [ 1 – 3 ]. Several genes have been associated with different types of PD with normal interictal examination: PRRT2 is the main gene for paroxysmal kinesigenic dyskinesia (PKD) sometimes with epilepsy [ 4 ]; paroxysmal exercise-induced dyskinesia (PED) is mainly related to some SLC2A1 variants [ 5 ]; paroxysmal non-kinesigenic dyskinesia (PNKD) is related to alterations in MR1 [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Biallelic PDE2A variants: a new cause of syndromic paroxysmal dyskinesia

Doummar

Dentel²,

Lyautey

et al. 2020

Eur J Hum Genet

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Cause of complex dyskinesia remains elusive in some patients. A homozygous missense variant leading to drastic decrease of PDE2A enzymatic activity was reported in one patient with childhood-onset choreodystonia preceded by paroxysmal dyskinesia and associated with cognitive impairment and interictal EEG abnormalities. Here, we report three new cases with biallelic PDE2A variants identified by trio whole-exome sequencing. Mitochondria network was analyzed after Mitotracker™ Red staining in control and mutated primary fibroblasts. Analysis of retrospective video of patients’ movement disorder and refinement of phenotype was carried out. We identified a homozygous gain of stop codon variant c.1180C>T; p.(Gln394*) in PDE2A in siblings and compound heterozygous variants in young adult: a missense c.446C>T; p.(Pro149Leu) and splice-site variant c.1922+5G>A predicted and shown to produce an out of frame transcript lacking exon 22. All three patients had cognitive impairment or developmental delay. The phenotype of the two oldest patients, aged 9 and 26, was characterized by childhood-onset refractory paroxysmal dyskinesia initially misdiagnosed as epilepsy due to interictal EEG abnormalities. The youngest patient showed a proven epilepsy at the age of 4 months and no paroxysmal dyskinesia at 15 months. Interestingly, analysis of the fibroblasts with the biallelic variants in PDE2A variants revealed mitochondria network morphology changes. Together with previously reported case, our three patients confirm that biallelic PDE2A variants are a cause of childhood-onset refractory paroxysmal dyskinesia with cognitive impairment, sometimes associated with choreodystonia and interictal baseline EEG abnormalities or epilepsy.

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“…Reports on individuals with Proline-rich Transmembrane Protein 2 ( PRRT2 ) mutations have varied greatly in the clinical expressions, but most involve benign epilepsies and/or dyskinetic paroxysms [1–7] which may present in association [8] or within the same family [9]. At an early age, the PRRT2 mutations have been associated to benign familial infantile epilepsy, benign infantile epilepsy, and benign myoclonus of early infancy [2, 4, 5].…”

Section: Introductionmentioning

confidence: 99%

“…The PRRT2 mutations have also been linked to paroxysmal dyskinesia, a group of disorders in which the affected children show episodic, sudden abnormal movements that are not associated with loss of consciousness. These disorders include paroxysmal kinesigenic dyskinesia (PKD), triggered by voluntary or involuntary movements; paroxysmal non-kinesigenic dyskinesia, which is not triggered by voluntary movements; and paroxysmal exercise-induced dyskinesia, triggered by repetitive motions and physical exercise [2, 3, 6, 7]. The PRRT2 mutations have also been reported in familial cases of hemiplegic migraine, in children with benign paroxysmal torticollis, and in individuals with progressive and stable ataxia [1, 2, 11, 12].…”

Section: Introductionmentioning

confidence: 99%

PRRT2 gene variant in a child with dysmorphic features, congenital microcephaly, and severe epileptic seizures: genotype-phenotype correlation?

et al. 2019

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BackgroundMutations in Proline-rich Transmembrane Protein 2 (PRRT2) have been primarily associated with individuals presenting with infantile epilepsy, including benign familial infantile epilepsy, benign infantile epilepsy, and benign myoclonus of early infancy, and/or with dyskinetic paroxysms such as paroxysmal kinesigenic dyskinesia, paroxysmal non-kinesigenic dyskinesia, and exercise-induced dyskinesia. However, the clinical manifestations of this disorder vary widely. PRRT2 encodes a protein expressed in the central nervous system that is mainly localized in the pre-synaptic neurons and is involved in the modulation of synaptic neurotransmitter release. The anomalous function of this gene has been proposed to cause dysregulation of neuronal excitability and cerebral disorders.Case presentationWe hereby report on a young child followed-up for three years who presents with a spectrum of clinical manifestations such as congenital microcephaly, dysmorphic features, severe intellectual disability, and drug-resistant epileptic encephalopathy in association with a synonymous variant in PRRT2 gene (c.501C > T; p.Thr167Ile) of unknown clinical significance variant (VUS) revealed by diagnostic exome sequencing.ConclusionSeveral hypotheses have been advanced on the specific role that PRRT2 gene mutations play to cause the clinical features of affected patients. To our knowledge, the severe phenotype seen in this case has never been reported in association with any clinically actionable variant, as the missense substitution detected in PRRT2 gene. Intriguingly, the same mutation was reported in the healthy father: the action of modifying factors in the affected child may be hypothesized. The report of similar observations could extend the spectrum of clinical manifestations linked to this mutation.

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Paroxysmal Dyskinesias

Cited by 22 publications

References 86 publications

An emerging spectrum of variants and clinical features in KCNMA1-linked channelopathy

An emerging spectrum of variants and clinical features in KCNMA1-linked channelopathy

Biallelic PDE2A variants: a new cause of syndromic paroxysmal dyskinesia

PRRT2 gene variant in a child with dysmorphic features, congenital microcephaly, and severe epileptic seizures: genotype-phenotype correlation?

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