title: The clinical and genetic heterogeneity of paroxysmal dyskinesias.
abstract: Paroxysmal dyskinesia can be subdivided into three clinical syndromes: paroxysmal kinesigenic dyskinesia or choreoathetosis, paroxysmal exercise-induced dyskinesia, and paroxysmal non-kinesigenic dyskinesia. Each subtype is associated with the known causative genes PRRT2, SLC2A1 and PNKD, respectively. Although separate screening studies have been carried out on each of the paroxysmal dyskinesia genes, to date there has been no large study across all genes in these disorders and little is known about the pathogenic mechanisms. We analysed all three genes (the whole coding regions of SLC2A1 and PRRT2 and exons one and two of PNKD) in a series of 145 families with paroxysmal dyskinesias as well as in a series of 53 patients with familial episodic ataxia and hemiplegic migraine to investigate the mutation frequency and type and the genetic and phenotypic spectrum. We examined the mRNA expression in brain regions to investigate how selective vulnerability could help explain the phenotypes and analysed the effect of mutations on patient-derived mRNA. Mutations in the PRRT2, SLC2A1 and PNKD genes were identified in 72 families in the entire study. In patients with paroxysmal movement disorders 68 families had mutations (47%) out of 145 patients. PRRT2 mutations were identified in 35% of patients, SLC2A1 mutations in 10%, PNKD in 2%. Two PRRT2 mutations were in familial hemiplegic migraine or episodic ataxia, one SLC2A1 family had episodic ataxia and one PNKD family had familial hemiplegic migraine alone. Several previously unreported mutations were identified. The phenotypes associated with PRRT2 mutations included a high frequency of migraine and hemiplegic migraine. SLC2A1 mutations were associated with variable phenotypes including paroxysmal kinesigenic dyskinesia, paroxysmal non-kinesigenic dyskinesia, episodic ataxia and myotonia and we identified a novel PNKD gene deletion in familial hemiplegic migraine. We found that some PRRT2 loss-of-function mutations cause nonsense mediated decay, except when in the last exon, whereas missense mutations do not affect mRNA. In the PNKD family with a novel deletion, mRNA was truncated losing the C-terminus of PNKD-L and still likely loss-of-function, leading to a reduction of the inhibition of exocytosis, and similar to PRRT2, an increase in vesicle release. This study highlights the frequency, novel mutations and clinical and molecular spectrum of PRRT2, SLC2A1 and PNKD mutations as well as the phenotype-genotype overlap among these paroxysmal movement disorders. The investigation of paroxysmal movement disorders should always include the analysis of all three genes, but around half of our paroxysmal series remain genetically undefined implying that additional genes are yet to be identified.
authors.affiliation: 1 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK 2 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Alice R
authors.initials: AR
authors.lastname: Gardiner
authors.affiliation: 1 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK 2 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Fatima
authors.initials: F
authors.lastname: Jaffer
authors.affiliation: 3 Paediatrics and Child Health, Children's Hospital, Westmead, University of Sydney, Australia.
authors.forename: Russell C
authors.initials: RC
authors.lastname: Dale
authors.affiliation: 4 Neurogenetics Laboratory, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Robyn
authors.initials: R
authors.lastname: Labrum
authors.affiliation: 5 Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Roberto
authors.initials: R
authors.lastname: Erro
authors.affiliation: 6 Developmental Neurosciences, UCL Institute of Child Health, London WC1N 3JH, UK.
authors.forename: Esther
authors.initials: E
authors.lastname: Meyer
authors.affiliation: 2 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK 7 Department of Neurology, Papageorgiou Hospital, Thessaloniki University of Athens, Greece.
authors.forename: Georgia
authors.initials: G
authors.lastname: Xiromerisiou
authors.affiliation: 5 Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK 8 Department of Neurology University of Athens, Greece 9 Department of Neurology, Philipps University, Marburg, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Stamelou
authors.affiliation: 10 Department of Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Walker
authors.affiliation: 10 Department of Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Kullmann
authors.affiliation: 2 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Warner
authors.affiliation: 5 Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Jarman
authors.affiliation: 1 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Mike
authors.initials: M
authors.lastname: Hanna
authors.affiliation: 6 Developmental Neurosciences, UCL Institute of Child Health, London WC1N 3JH, UK 11 Department of Neurology, Great Ormond Street Hospital, London WC1N, UK.
authors.forename: Manju A
authors.initials: MA
authors.lastname: Kurian
authors.affiliation: 5 Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Kailash P
authors.initials: KP
authors.lastname: Bhatia
authors.affiliation: 1 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK 2 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK 4 Neurogenetics Laboratory, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK h.houlden@ucl.ac.uk.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002819:Chorea / Q000235:genetics*; D005260:Female; D018740:Genetic Heterogeneity; D051272:Glucose Transporter Type 1 / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020325:Migraine with Aura / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D055815:Young Adult
chemical_list: D051272:Glucose Transporter Type 1; D008565:Membrane Proteins; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; C495444:PNKD protein, human; C569370:PRRT2 protein, human; D012333:RNA, Messenger; C495677:SLC2A1 protein, human
keywords: PNKD; PRRT2; SLC2A1; gene; paroxysmal movement disorder