Neurological Sciences

, Volume 34, Issue 11, pp 1925–1931 | Cite as

Altered intrinsic brain activity in patients with paroxysmal kinesigenic dyskinesia by PRRT2 mutation

Altered brain activity by PRRT2 mutation
  • ChunYan Luo
  • Yongping Chen
  • Wei Song
  • Qin Chen
  • QiYong Gong
  • Hui-Fang Shang
Original Article


The proline-rich transmembrane protein 2 (PRRT2) gene has been recently identified as a causative gene of paroxysmal kinesigenic dyskinesia (PKD), with an insertion mutation c.649_650insC (p.P217fsX7) reported as the most common mutation. However, the pathogenic mechanism of the mutation of PRRT2 remains largely unknown. Resting-state functional magnetic resonance imaging is a promising approach to assess cerebral function and reveals underlying functional changes. Resting-state functional magnetic resonance imaging was performed in 4 Chinese PKD patients with p.P217fsX7 mutation, 6 Chinese PKD patients without the mutation, and 10 healthy control subjects. Voxel-based analysis was used to characterize alterations in the amplitude of low-frequency fluctuation (ALFF). When compared with the healthy control subjects, both groups of PKD patients showed alterations in spontaneous brain activities within cortical–basal ganglia circuitry. Besides, the group of patients with p.P217fsX7 mutation also exhibited increased ALFF in the right postcenral gyrus and right rolandic operculum area, while the alteration of ALFF in group of patients without the mutation additionally involved the middle orbitofrontal cortex. Direct comparative analysis between these two patient groups revealed significantly increased ALFF in the right postcentral gyrus in the group with p.P217fsX7 mutation. Increased spontaneous brain activity in the cortical–basal ganglia circuitry, especially in the motor preparation areas, is a common pathophysiology in PKD. Differences in the spatial patterns of increased ALFF between patients with and those without the mutation might reflect the distinct pathological mechanism resulting from PRRT2 mutation.


Paroxysmal kinesigenic dyskinesia (PKD) Proline-rich transmembrane protein 2 (PRRT2Mutation C.649_650insC Resting-state functional magnetic resonance imaging (rfMRI) Amplitude of low-frequency fluctuation (ALFF) 

Supplementary material

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Supplementary material 1 (DOCX 14291 kb)


  1. 1.
    Goodenough DJ, Fariello RG, Annis BL, Chun RW (1978) Familial and acquired paroxysmal dyskinesias. a proposed classification with delineation of clinical features. Arch Neurol 35:827–831PubMedCrossRefGoogle Scholar
  2. 2.
    Bruno MK, Hallett M, Gwinn-Hardy K, Sorensen B, Considine E, Tucker S, Lynch DR, Mathews KD, Swoboda KJ, Harris J, Soong BW, Ashizawa T, Jankovic J, Renner D, Fu YH, Ptacek LJ (2004) Clinical evaluation of idiopathic paroxysmal kinesigenic dyskinesia: new diagnostic criteria. Neurology 63:2280–2287PubMedCrossRefGoogle Scholar
  3. 3.
    Chen WJ, Lin Y, Xiong ZQ, Wei W, Ni W, Tan GH, Guo SL, He J, Chen YF, Zhang QJ, Li HF, Lin Y, Murong SX, Xu J, Wang N, Wu ZY (2011) Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat Genet 43:1252–1255PubMedCrossRefGoogle Scholar
  4. 4.
    Wang JL, Cao L, Li XH, Hu ZM, Li JD, Zhang JG, Liang Y, San A, Li N, Chen SQ, Guo JF, Jiang H, Shen L, Zheng L, Mao X, Yan WQ, Zhou Y, Shi YT, Ai SX, Dai MZ, Zhang P, Xia K, Chen SD, Tang BS (2011) Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias. Brain 134:3493–3501PubMedCrossRefGoogle Scholar
  5. 5.
    Lee HY, Huang Y, Bruneau N, Roll P, Roberson ED, Hermann M, Quinn E, Maas J, Edwards R, Ashizawa T, Baykan B, Bhatia K, Bressman S, Bruno MK, Brunt ER, Caraballo R, Echenne B, Fejerman N, Frucht S, Gurnett CA, Hirsch E, Houlden H, Jankovic J, Lee WL, Lynch DR, Mohamed S, Muller U, Nespeca MP, Renner D, Rochette J, Rudolf G, Saiki S, Soong BW, Swoboda KJ, Tucker S, Wood N, Hanna M, Bowcock A, Szepetowski P, Fu YH, Ptacek LJ (2012) Mutations in the novel protein PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions. Cell Rep 1:2–12CrossRefGoogle Scholar
  6. 6.
    Heron SE, Grinton BE, Kivity S, Afawi Z, Zuberi SM, Hughes JN, Pridmore C, Hodgson BL, Iona X, Sadleir LG, Pelekanos J, Herlenius E, Goldberg-Stern H, Bassan H, Haan E, Korczyn AD, Gardner AE, Corbett MA, Gecz J, Thomas PQ, Mulley JC, Berkovic SF, Scheffer IE, Dibbens LM (2012) PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome. Am J Hum Genet 90:152–160PubMedCrossRefGoogle Scholar
  7. 7.
    Meneret A, Grabli D, Depienne C, Gaudebout C, Picard F, Durr A, Lagroua I, Bouteiller D, Mignot C, Doummar D, Anheim M, Tranchant C, Burbaud P, Jedynak CP, Gras D, Steschenko D, Devos D, Billette de Villemeur T, Vidailhet M, Brice A, Roze E (2012) PRRT2 mutations: a major cause of paroxysmal kinesigenic dyskinesia in the European population. Neurology 79:170–174PubMedCrossRefGoogle Scholar
  8. 8.
    Schubert J, Paravidino R, Becker F, Berger A, Bebek N, Bianchi A, Brockmann K, Capovilla G, Bernardina BD, Fukuyama Y, Hoffmann GF, Jurkat-Rott K, Anttonen AK, Kurlemann G, Lehesjoki AE, Lehmann-Horn F, Mastrangelo M, Mause U, Muller S, Neubauer B, Pust B, Rating D, Robbiano A, Ruf S, Schroeder C, Seidel A, Specchio N, Stephani U, Striano P, Teichler J, Turkdogan D, Vigevano F, Viri M, Bauer P, Zara F, Lerche H, Weber YG (2012) PRRT2 Mutations are the major cause of benign familial infantile seizures. Hum Mutat 33:1439–1443PubMedCrossRefGoogle Scholar
  9. 9.
    Li J, Zhu X, Wang X, Sun W, Feng B, Du T, Sun B, Niu F, Wei H, Wu X, Dong L, Li L, Cai X, Wang Y, Liu Y (2012) Targeted genomic sequencing identifies PRRT2 mutations as a cause of paroxysmal kinesigenic choreoathetosis. J Med Genet 49:76–78PubMedCrossRefGoogle Scholar
  10. 10.
    Cao L, Huang XJ, Zheng L, Xiao Q, Wang XJ, Chen SD (2012) Identification of a novel PRRT2 mutation in patients with paroxysmal kinesigenic dyskinesias and c.649dupC as a mutation hot-spot. Parkinsonism Relat Disord 18:704–706PubMedCrossRefGoogle Scholar
  11. 11.
    Ono S, Yoshiura K, Kinoshita A, Kikuchi T, Nakane Y, Kato N, Sadamatsu M, Konishi T, Nagamitsu S, Matsuura M, Yasuda A, Komine M, Kanai K, Inoue T, Osamura T, Saito K, Hirose S, Koide H, Tomita H, Ozawa H, Niikawa N, Kurotaki N (2012) Mutations in PRRT2 responsible for paroxysmal kinesigenic dyskinesias also cause benign familial infantile convulsions. J Hum Genet 57:338–341PubMedCrossRefGoogle Scholar
  12. 12.
    van Vliet R, Breedveld G, van de Rijk AJ, Brilstra E, Verbeek N, Verschuuren-Bemelmans C, Boon M, Samijn J, Diderich K, van de Laar I, Oostra B, Bonifati V, Maat-Kievit A (2012) PRRT2 phenotypes and penetrance of paroxysmal kinesigenic dyskinesia and infantile convulsions. Am Acad Neurol 79:777–784Google Scholar
  13. 13.
    Lee Y-C, Lee M-J, Yu HY, Chen C, Hsu CH, Lin KP, Liao KK, Chang MH, Liao YC, Soong BW (2012) PRRT2 mutations in paroxysmal kinesigenic dyskinesia with infantile convulsions in a Taiwanese cohort. PLoS One 7:e38543PubMedCrossRefGoogle Scholar
  14. 14.
    Logothetis NK, Wandell BA (2004) Interpreting the BOLD signal. Annu Rev Physiol 66:735–769PubMedCrossRefGoogle Scholar
  15. 15.
    Cordes D, Haughton VM, Arfanakis K, Carew JD, Turski PA, Moritz CH, Quigley MA, Meyerand ME (2001) Frequencies contributing to functional connectivity in the cerebral cortex in “resting-state” data. Am J Neuroradiol 22:1326–1333PubMedGoogle Scholar
  16. 16.
    Fransson P (2005) Spontaneous low-frequency BOLD signal fluctuations: an fMRI investigation of the resting-state default mode of brain function hypothesis. Hum Brain Mapp 26:15–29PubMedCrossRefGoogle Scholar
  17. 17.
    Biswal B, Yetkin FZ, Haughton VM, Hyde JS (1995) Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn Reson Med 34:537–541PubMedCrossRefGoogle Scholar
  18. 18.
    Zang YF, He Y, Zhu CZ, Cao QJ, Sui MQ, Liang M, Tian LX, Jiang TZ, Wang YF (2007) Altered baseline brain activity in children with ADHD revealed by resting-state functional MRI. Brain Dev 29:83–91PubMedCrossRefGoogle Scholar
  19. 19.
    Huang XQ, Lui S, Deng W, Chan RC, Wu QZ, Jiang LJ, Zhang JR, Jia ZY, Li XL, Li F, Chen L, Li T, Gong QY (2010) Localization of cerebral functional deficits in treatment-naive, first-episode schizophrenia using resting-state fMRI. Neuroimage 49:2901–2906PubMedCrossRefGoogle Scholar
  20. 20.
    Hoptman MJ (2010) Amplitude of low-frequency oscillations in schizophrenia a resting state fMRI study. Schizophr Res 117:13–20PubMedCrossRefGoogle Scholar
  21. 21.
    Yang H, Wu QZ, Guo LT, Li QQ, Long XY, Huang XQ, Chan RC, Gong QY (2011) Abnormal spontaneous brain activity in medication-naive ADHD children: a resting state fMRI study. Neurosci Lett 502:89–93PubMedCrossRefGoogle Scholar
  22. 22.
    Wang Z, Yan C, Zhao C, Qi Z, Zhou W, Lu J, He Y, Li K (2011) Spatial patterns of intrinsic brain activity in mild cognitive impairment and alzheimer’s disease: a resting-state functional MRI study. Hum Brain Mapp 32:1720–1740PubMedCrossRefGoogle Scholar
  23. 23.
    Zhou B, Chen Q, Zhang Q, Chen L, Gong Q, Shang H, Tang H, Zhou D (2010) Hyperactive putamen in patients with paroxysmal kinesigenic choreoathetosis: a resting-state functional magnetic resonance imaging study. Mov Disord 25:1226–1231PubMedCrossRefGoogle Scholar
  24. 24.
    Song XW, Dong ZY, Long XY, Li SF, Zuo XN, Zhu CZ, He Y, Yan CG, Zang YF (2011) REST: a toolkit for resting-state functional magnetic resonance imaging data processing. PLoS One 6:e25031PubMedCrossRefGoogle Scholar
  25. 25.
    Oakes TR, Fox AS, Johnstone T, Chung MK, Kalin N, Davidson RJ (2007) Integrating VBM into the General Linear Model with voxelwise anatomical covariates. Neuroimage 34:500–508PubMedCrossRefGoogle Scholar
  26. 26.
    Casanova R, Srikanth R, Baer A, Laurienti PJ, Burdette JH, Hayasaka S, Flowers L, Wood F, Maldjian JA (2007) Biological parametric mapping: a statistical toolbox for multimodality brain image analysis. Neuroimage 34:137–143PubMedCrossRefGoogle Scholar
  27. 27.
    Halsband U, Ito N, Tanji J, Freund HJ (1993) The role of premotor cortex and the supplementary motor area in the temporal control of movement in man. Brain 116(Pt 1):243–266PubMedCrossRefGoogle Scholar
  28. 28.
    Bush G, Vogt BA, Holmes J, Dale AM, Greve D, Jenike MA, Rosen BR (2002) Dorsal anterior cingulate cortex: a role in reward-based decision making. Proc Natl Acad Sci USA 99:523–528PubMedCrossRefGoogle Scholar
  29. 29.
    Obermann M, Yaldizli O, de Greiff A, Konczak J, Lachenmayer ML, Tumczak F, Buhl AR, Putzki N, Vollmer-Haase J, Gizewski ER, Diener HC, Maschke M (2008) Increased basal-ganglia activation performing a non-dystonia-related task in focal dystonia. Eur J Neurol 15:831–838PubMedCrossRefGoogle Scholar
  30. 30.
    Alexander GE, DeLong MR, Strick PL (1986) Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 9:357–381PubMedCrossRefGoogle Scholar
  31. 31.
    Saint-Cyr JA (2003) Frontal-striatal circuit functions: context, sequence, and consequence. J Int Neuropsychol Soc 9:103–127PubMedGoogle Scholar
  32. 32.
    Kim MO, Im JH, Choi CG, Lee MC (1998) Proton MR spectroscopic findings in paroxysmal kinesigenic dyskinesia. Mov Disord 13:570–575PubMedCrossRefGoogle Scholar
  33. 33.
    Volonte MA, Perani D, Lanzi R, Poggi A, Anchisi D, Balini A, Comi G, Fazio F (2001) Regression of ventral striatum hypometabolism after calcium/calcitriol therapy in paroxysmal kinesigenic choreoathetosis due to idiopathic primary hypoparathyroidism. J Neurol Neurosurg Psychiatry 71:691–695PubMedCrossRefGoogle Scholar
  34. 34.
    Joo EY, Hong SB, Tae WS, Kim JH, Han SJ, Seo DW, Lee KH, Kim MH, Kim S, Lee MH, Kim BT (2005) Perfusion abnormality of the caudate nucleus in patients with paroxysmal kinesigenic choreoathetosis. Eur J Nucl Med Mol Imaging 32:1205–1209PubMedCrossRefGoogle Scholar
  35. 35.
    Franssen H, Fortgens C, Wattendorff AR, van Woerkom TC (1983) Paroxysmal kinesigenic choreoathetosis and abnormal contingent negative variation. a case report. Arch Neurol 40:381–385PubMedCrossRefGoogle Scholar
  36. 36.
    Busard HL, Renier WO, Gabreels FJ, Vos AJ, Declerck AC, Verhey FH (1984) Autosomal dominant paroxysmal kinesigenic choreoathetosis. an electroneurophysiological study. Clin Neurol Neurosurg 86:281–289PubMedCrossRefGoogle Scholar
  37. 37.
    Fattapposta F, My F, Valente D, Quadrini R, D’Alessio C, Amabile G (2003) Preprogramming motor dysfunction in paroxysmal kinesigenic choreoathetosis. Funct Neurol 18:29–34PubMedGoogle Scholar
  38. 38.
    Liu Q, Qi Z, Wan XH, Li JY, Shi L, Lu Q, Zhou XQ, Qiao L, Wu LW, Liu XQ, Yang W, Liu Y, Cui LY, Zhang X (2012) Mutations in PRRT2 result in paroxysmal dyskinesias with marked variability in clinical expression. J Med Genet 49:79–82PubMedCrossRefGoogle Scholar
  39. 39.
    Ji J, Tsuk S, Salapatek AM, Huang X, Chikvashvili D, Pasyk EA, Kang Y, Sheu L, Tsushima R, Diamant N, Trimble WS, Lotan I, Gaisano HY (2002) The 25-kDa synaptosome-associated protein (SNAP-25) binds and inhibits delayed rectifier potassium channels in secretory cells. J Biol Chem 277:20195–20204PubMedCrossRefGoogle Scholar
  40. 40.
    Hu K, Carroll J, Fedorovich S, Rickman C, Sukhodub A, Davletov B (2002) Vesicular restriction of synaptobrevin suggests a role for calcium in membrane fusion. Nature 415:646–650PubMedCrossRefGoogle Scholar
  41. 41.
    Jokeit H, Okujava M, Woermann FG (2001) Carbamazepine reduces memory induced activation of mesial temporal lobe structures: a pharmacological fMRI-study. BMC Neurol 1:6PubMedCrossRefGoogle Scholar
  42. 42.
    Koepp MJ (2011) Gender and drug effects on neuroimaging in epilepsy. Epilepsia 4:35–37CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2013

Authors and Affiliations

  • ChunYan Luo
    • 1
  • Yongping Chen
    • 1
  • Wei Song
    • 1
  • Qin Chen
    • 1
  • QiYong Gong
    • 2
    • 3
  • Hui-Fang Shang
    • 1
  1. 1.Department of NeurologySichuan University, West China HospitalChengduChina
  2. 2.Department of Radiology, Huaxi MR Research CenterSichuan University, West China HospitalChengduChina
  3. 3.Division of Medical Imaging, Faculty of MedicineUniversity of LiverpoolLiverpoolUK

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