Genetic and phenotypic heterogeneity in sporadic and familial forms of paroxysmal dyskinesia

Groffen, Alexander J.; Klapwijk, Thom; Rootselaar, Anne-Fleur van; Groen, Justus L.; Tijssen, Marina A. J.

doi:10.1007/s00415-012-6592-5

Cited by 49 publications

(44 citation statements)

References 33 publications

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“…Age at onset ranged from 6 to 14 years (median age 9 years) in the patients with mutations, and from 9.5 to 19 years in mutation-negative patients (median age 15 years; P < 0.01), which was consistent with the previous findings in Chinese patients. Further studies in other populations confirmed the predominance of PRRT2 mutations in patients with PKD [8,11,[15][16][17][18]. However, a small number of patients with typical PKD do not harbor point mutations or micro-rearrangements in PRRT2 (personal data) suggesting, along with previous reports, the existence of at least another gene implicated in this disorder, located in locus EKD3 (the family previously linked to EKD2 on chromosome 16 was found to have a PRRT2 mutation) [11,[19][20][21].…”

Section: Pkdsupporting

confidence: 60%

PRRT2 mutations and paroxysmal disorders

Méneret

Gaudebout

Riant

et al. 2013

Euro J of Neurology

101

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In the past year, mutations in the PRRT2 gene have been identified in patients with paroxysmal kinesigenic dyskinesia and other paroxysmal disorders. We conducted a review of the literature on PRRT2 mutation-associated disorders. Our objectives were to describe the wide clinical spectrum associated with PRRT2 mutations, and to present the current hypotheses on the underlying pathophysiology. PRRT2 mutations are associated with a wide range of clinical syndromes: the various paroxysmal dyskinesias, infantile seizures, paroxysmal torticollis, migraine, hemiplegic migraine, episodic ataxia and even intellectual disability in the homozygous state. The PRRT2 protein, through its interaction with SNAP-25, could play a role in synaptic regulation in the cortex and the basal ganglia. The pathogenesis may be caused by PRRT2 loss of function, which may induce synaptic deregulation and neuronal hyperexcitability. However, this does not explain the phenotypic variability, which is likely modulated by environmental factors, modifier genes or age-dependent expression. The clinical spectrum of PRRT2 mutations has expanded among paroxysmal disorders and beyond. Unraveling the molecular pathways linking the genetic defect to its clinical expression will be crucial for the diagnosis and treatment of these disorders.

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Section: Pkdsupporting

confidence: 60%

PRRT2 mutations and paroxysmal disorders

Méneret

Gaudebout

Riant

et al. 2013

Euro J of Neurology

101

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“…Thus, it seems possible that hypomorphic mutations of human PIGN could also cause PxD or other disease phenotypes that are less severe than those of MCAHS1. Similar variability in phenotype is seen in SLC2A1 variants associated with PxD in humans [14, 15, 56]. …”

Section: Discussionmentioning

confidence: 59%

A homozygous PIGN missense mutation in Soft-Coated Wheaten Terriers with a canine paroxysmal dyskinesia

et al. 2016

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Hereditary paroxysmal dyskinesias (PxD) are a heterogeneous group of movement disorders classified by frequency, duration, and triggers of the episodes. A young-adult onset canine PxD has segregated as an autosomal recessive trait in Soft-Coated Wheaten Terriers. The medical records and videos of episodes from 25 affected dogs were reviewed. The episodes of hyperkinesia and dystonia lasted from several minutes to several hours and could occur as often as >10/day. They were not associated with strenuous exercise or fasting but were sometimes triggered by excitement. The canine PxD phenotype most closely resembled paroxysmal non-kinesigenic dyskinesia (PNKD) of humans. Whole genome sequences were generated with DNA from 2 affected dogs and analyzed in comparison to 100 control canid whole genome sequences. The two whole genome sequences from dogs with PxD had a rare homozygous PIGN:c.398C > T transition, which predicted the substitution of an isoleucine for a highly conserved threonine in the encoded enzyme. All 25 PxD-affected dogs were PIGN:c.398T allele homozygotes, whereas there were no c.398T homozygotes among 1185 genotyped dogs without known histories of PxD. PIGN encodes an enzyme involved in the biosynthesis of glycosylphosphatidylinositol (GPI), which anchors a variety of proteins including CD59 to the cell surface. Flow cytometry of PIGN-knockout HEK239 cells expressing recombinant human PIGN with the c.398T variant showed reduced CD59 expression. Mutations in human PIGN have been associated with multiple congenital anomalies-hypotonia-seizures syndrome-1 (MCAHS1). Movement disorders can be a part of MCAHS1, but this is the first PxD associated with altered GPI anchor function.Electronic supplementary materialThe online version of this article (doi:10.1007/s10048-016-0502-4) contains supplementary material, which is available to authorized users.

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“…22 Few citations of paroxysmal kinesigenic dyskinesia and paroxysmal nonkinesigenic dyskinesia associated with GLUT1 deficiency syndrome were reported. 2,22,23 In paroxysmal kinesigenic dyskinesia, dyskinesias are precipitated by voluntary movements and it usually lasts less than 5 minutes. Typically, an attack is induced by a sudden voluntary movement, an example of which is getting up quickly to answer the doorbell or the telephone.…”

Section: Uncommon Manifestationsmentioning

confidence: 98%

Atypical Manifestations in Glut1 Deficiency Syndrome

et al. 2016

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Glucose transporter type 1 deficiency syndrome is a genetically determined, treatable, neurologic disorder that is caused by an insufficient transport of glucose into the brain. It is caused by a mutation in the SCL2A1 gene, which is so far the only known to be associated with this condition. Glucose transporter type 1 deficiency syndrome consists of a wide clinical spectrum that usually presents with cognitive impairment, epilepsy, paroxysmal exercise-induced dyskinesia, acquired microcephaly, hemolytic anemia, gait disturbance, and dyspraxia in different combinations. However, there are other clinical manifestations that we consider equally peculiar but that have so far been poorly described in literature. In this review, supported by a video contribution, we will accurately describe this type of clinical manifestation such as oculogyric crises, weakness, paroxysmal kinesigenic and nonkinesigenic dyskinesia in order to provide an additional instrument for a correct, rapid diagnosis.

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Genetic and phenotypic heterogeneity in sporadic and familial forms of paroxysmal dyskinesia

Cited by 49 publications

References 33 publications

PRRT2 mutations and paroxysmal disorders

PRRT2 mutations and paroxysmal disorders

A homozygous PIGN missense mutation in Soft-Coated Wheaten Terriers with a canine paroxysmal dyskinesia

Atypical Manifestations in Glut1 Deficiency Syndrome

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