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Review
. 2015 Dec;138(Pt 12):3567-80.
doi: 10.1093/brain/awv310. Epub 2015 Nov 23.

The Clinical and Genetic Heterogeneity of Paroxysmal Dyskinesias

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Free PMC article
Review

The Clinical and Genetic Heterogeneity of Paroxysmal Dyskinesias

Alice R Gardiner et al. Brain. .
Free PMC article

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.

Keywords: PNKD; PRRT2; SLC2A1; gene; paroxysmal movement disorder.

Figures

None
The contributions of different genes to inherited paroxysmal movement disorders are incompletely understood. Gardiner et al. identify mutations in 47% of 145 individuals with paroxysmal dyskinesias, with PRRT2 mutations in 35%, SLC2A1 in 10% and PNKD in 2%. New mutations expand the associated phenotypes and implicate overlapping mechanisms.
Figure 1
Figure 1
Genetic structure and mutations in PRRT2, SLC2A1 and PNKD. Schematic diagrams of the PRRT2 (A), SLC2A1 (B) and PNKD (C) genes. In each case mutations that have been previously reported to cause a paroxysmal movement disorder are shown above the gene, and mutations found in this paper are shown below (blue have previously been reported, red are novel).
Figure 2
Figure 2
Family tree and mutation chromatograms. Filled symbols indicate family members that are affected, unfilled symbols are unaffected. The proband is indicated with a black arrow. +/− denotes an individual that is heterozygous for the mutation shown, −/− does not carry the mutation.
Figure 3
Figure 3
The predicted protein consequence of mutations in the PRRT2 gene. Red cross = nonsense-mediated decay; burgundy outline = mutated exon; grey outline = reduced expression. Chromatograms show the presence of a mutation in mRNA, excluding the possibility of nonsense-mediated decay.
Figure 4
Figure 4
Mutation effect in PRRT2 and PNKD frameshift mutations. (A) Schematic diagram of PRRT2 showing the elongation of the protein caused by p.*341Lext27, and the chromatogram identifying the mutation in the patient DNA with no NMD in mRNA from this family. (B) Schematic diagram of the wild-type and truncated PNKD-L, the result of the p.P341Pfs*2 mutation. The cDNA sequencing (B) shows the mutation was present at the mRNA level (top = forward sequencing, bottom = reverse sequencing in the lower figure) and so excludes the possibility of nonsense-mediated decay.
Figure 5
Figure 5
Likely mechanism of action of paroxysmal dyskinesia genes. A suggested mechanism for the paroxysmal dyskinesia genes, where mutations in PRRT2, PNKD and SLC2A1 result in disruption of neurotransmitter release regulation and thus impaired synaptic release. Circles indicate presynaptic vesicles containing neurotransmitter (dots). Yellow vesicles are affected by SLC2A1 mutations, green by PNKD mutations and blue by PRRT2 mutations.

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