Journal of Neurology

, Volume 255, Issue 9, pp 1372–1377 | Cite as

Subclinical sensory abnormalities in unaffected PINK1 heterozygotes

  • M. Fiorio
  • E. M. Valente
  • M. Gambarin
  • A. R. Bentivoglio
  • T. Ialongo
  • A. Albanese
  • P. Barone
  • M. T. Pellecchia
  • F. Brancati
  • G. Moretto
  • A. Fiaschi
  • M. Tinazzi



Mutations in the PINK1 gene, encoding a mitochondrial protein kinase, represent the second cause of autosomal recessive parkinsonism (ARP) after Parkin. While homozygous or compound heterozygous mutations in these genes are unequivocally causative of ARP, the role of single heterozygous mutations is still largely debated. An intriguing hypothesis suggests that these mutations could represent a risk factor to develop parkinsonism, by contributing to nigral cell degeneration. Since the substantia nigra plays an important role in temporal processing of sensory stimuli, as revealed from studies in idiopathic PD, we sought to investigate whether any subclinical sensory abnormalities could be detected in patients with PINK1- related parkinsonism and in unaffected PINK1 heterozygous carriers.


We adopted a psychophysical method, the temporal discrimination paradigm, to assess PINK1 homozygous patients, unaffected relatives who were heterozygous carriers of the same mutations and healthy control subjects. Temporal discrimination threshold (TDT) and temporal order judgement (TOJ) for pairs of tactile, visual or visuo-tactile stimuli were measured according to a standardized protocol.


Higher mean tactile and visuo-tactile TDTs and TOJs were detected in PINK1 mutation carriers, including not only homozygous patients but also healthy heterozygotes, compared to control subjects (for all comparisons, p < 0.001).


In clinically unaffected subjects, the mere presence of a heterozygous PINK1 mutation is sufficient to determine sensory alterations which can be disclosed by a psychophysical task. Deficits in temporal processing might be considered as subclinical signs of alteration at least in PINK1-related parkinsonism.

Key words

PINK1 Parkinson’s disease sensory systems temporal discrimination endophenotype 


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  1. 1.
    Alexander GE, DeLong MR, Strick PL (1986) Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Ann Rev Neurosci 9:357–381PubMedCrossRefGoogle Scholar
  2. 2.
    Farrer MJ (2006) Genetics of Parkinson disease: paradigm shifts and future prospects. Nat Rev Genet 7:306–318PubMedCrossRefGoogle Scholar
  3. 3.
    Kubo S, Hattori N, Mizuno Y (2006) Recessive Parkinson’s disease. Mov Disord 21:885–893PubMedCrossRefGoogle Scholar
  4. 4.
    Klein C, Lohmann-Hedrich K, Rogaeva E, Schlossmacher MG, Lang AE (2007) Deciphering the role of heterozygous mutations in genes associated with parkinsonism. Lancet Neurol 6:652–662PubMedCrossRefGoogle Scholar
  5. 5.
    Valente EM, Ferraris A (2007) Heterozygous mutations in genes causing parkinsonism: monogenic disorders go complex. Lancet Neurol 6:576–578PubMedCrossRefGoogle Scholar
  6. 6.
    Hilker R, Klein C, Ghaemi M, et al. (2001) Positron emission tomographic analysis of the nigrostriatal dopaminergic system in familial parkinsonism associated with mutations in the parkin gene. Ann Neurol 49:367–376PubMedCrossRefGoogle Scholar
  7. 7.
    Khan NL, Valente EM, Bentivoglio AR, et al. (2002) Clinical and subclinical dopaminergic dysfunction in PARK6- linked parkinsonism: an 18F-dopa PET study. Ann Neurol 52:849–853PubMedCrossRefGoogle Scholar
  8. 8.
    Buhmann C, Binkofski F, Klein C, et al. (2005) Motor reorganization in asymptomatic carriers of a single mutant Parkin allele: a human model for presymptomatic parkinsonism. Brain 128:2281–2290PubMedCrossRefGoogle Scholar
  9. 9.
    Khan NL, Scherfler C, Graham E, et al. (2005) Dopaminergic dysfunction in unrelated, asymptomatic carriers of a single parkin mutation. Neurology 64:134–136PubMedGoogle Scholar
  10. 10.
    Pastor MA, Day BL, Macaluso E, Friston KJ, Frackowiak RSJ (2004) The functional neuroanatomy of temporal discrimination. J Neuroscience 24:2585–2591CrossRefGoogle Scholar
  11. 11.
    Pastor MA, Macaluso E, Day BL, Frackowiak RS (2006) The neural basis of temporal auditory discrimination. Neuroimage 30:512–520PubMedCrossRefGoogle Scholar
  12. 12.
    Jahanshahi M, Jones CR, Dirnberger G, Frith CD (2006) The substantia nigra pars compacta and temporal processing. J Neurosci 26:12266–12273PubMedCrossRefGoogle Scholar
  13. 13.
    Artieda J, Pastor MA, Lacruz F, Obeso JA (1992) Temporal discrimination is abnormal in Parkinson’s disease. Brain 115:199–210PubMedCrossRefGoogle Scholar
  14. 14.
    Tinazzi M, Frasson E, Bertolasi L, Fiaschi A, Aglioti S (1999) Temporal discrimination of somesthetic stimuli is impaired in dystonic patients. Neuroreport 10:1547–1550PubMedCrossRefGoogle Scholar
  15. 15.
    Tinazzi M, Fiorio M, Bertolasi L, Aglioti SM (2004) Timing of tactile and visuotactile events is impaired in patients with cervical dystonia. J Neurol 251:85–90PubMedCrossRefGoogle Scholar
  16. 16.
    Fiorio M, Tinazzi M, Bertolasi L, Aglioti SM (2003) Temporal processing of visuotactile and tactile stimuli in writer’s cramp. Ann Neurol 53:630–635PubMedCrossRefGoogle Scholar
  17. 17.
    Aglioti SM, Fiorio M, Forster B, Tinazzi M (2003) Temporal discrimination of cross-modal and unimodal stimuli in generalized dystonia. Neurology 60:782–785PubMedCrossRefGoogle Scholar
  18. 18.
    Pastor MA, Artieda J, Jahanshahi M, Obeso JA (1992) Time estimation and reproduction is abnormal in Parkinson’s disease. Brain 115:211–225PubMedCrossRefGoogle Scholar
  19. 19.
    Harrington DL, Haaland KY, Hermanowicz N (1998) Temporal processing in the basal ganglia. Neuropsychology 12:3–12PubMedCrossRefGoogle Scholar
  20. 20.
    Fiorio M, Gambarin M, Valente EM, et al. (2007) Defective temporal processing of sensory stimuli in DYT1 mutation carriers: a new endophenotype of dystonia? Brain 130:134–142PubMedCrossRefGoogle Scholar
  21. 21.
    Bentivoglio AR, Cortelli P, Valente EM, et al. (2001) Phenotypic characterisation of autosomal recessive PARK6-linked parkinsonism in three unrelated Italian families. Mov Disord 16:999–1006PubMedCrossRefGoogle Scholar
  22. 22.
    Valente EM, Abou-Sleiman PM, Caputo V, et al. (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304:1158–1160PubMedCrossRefGoogle Scholar
  23. 23.
    Albanese A, Valente EM, Romito LM, Bellacchio E, Elia AE, Dallapiccola B (2005) The PINK1 phenotype can be indistinguishable from idiopathic Parkinson disease. Neurology 64:1958–1960PubMedCrossRefGoogle Scholar
  24. 24.
    Bares M, Rektor I (2001) Basal ganglia involvement in sensory and cognitive processing. A depth electrode CNV study in human subjects. Clin Neurophysiol 112:2022–2030PubMedCrossRefGoogle Scholar
  25. 25.
    Jahanshahi M, Rowe J, Saleem T, et al. (2002) Striatal contribution to cognition: working memory and executive function in Parkinson’s disease before and after unilateral posteroventral pallidotomy. J Cogn Neurosci 14:298–310PubMedCrossRefGoogle Scholar
  26. 26.
    Ivry RB (1996) The representation of temporal information in perception and motor control. Curr Opin Neurobiol 6:851–857PubMedCrossRefGoogle Scholar
  27. 27.
    Rao SM, Mayer AR, Harrington DL (2001) The evolution of brain activation during temporal processing. Nat Neurosci 4:317–323PubMedCrossRefGoogle Scholar
  28. 28.
    Graziano MS, Gross CG (1993) A bimodal map of space: somatosensory receptive fields in the macaque putamen with corresponding visual receptive fields. Exp Brain Res 97:96–109PubMedCrossRefGoogle Scholar
  29. 29.
    Hedrich K, Hagenah J, Djarmati A, et al. (2006) Clinical spectrum of homozygous and heterozygous PINK1 mutations in a large German family with Parkinson disease: role of a single hit? Arch Neurol 63:833–838PubMedCrossRefGoogle Scholar
  30. 30.
    Valente EM, Salvi S, Ialongo T, et al. (2004) PINK1 mutations are associated with sporadic early-onset parkinsonism. Ann Neurol 56:336–341PubMedCrossRefGoogle Scholar
  31. 31.
    Rogaeva E, Johnson J, Lang AE, et al. (2004) Analysis of the PINK1 gene in a large cohort of cases with Parkinson disease. Arch Neurol 61:1898–1904PubMedCrossRefGoogle Scholar
  32. 32.
    Abou-Sleiman PM, Muqit MM, McDonald NQ, et al. (2006) A heterozygous effect for PINK1 mutations in Parkinson’s disease? Ann Neurol 60:414–419PubMedCrossRefGoogle Scholar
  33. 33.
    Kay DM, Moran D, Moses L, et al. (2007) Heterozygous parkin point mutations are as common in control subjects as in Parkinson’s patients. Ann Neurol 61:47–54PubMedCrossRefGoogle Scholar
  34. 34.
    Valente EM, Ferraris A (2007) Heterozygous mutations in genes causing parkinsonism: monogenic disorders go complex. Lancet Neurol 6:576–578PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • M. Fiorio
    • 1
  • E. M. Valente
    • 2
    • 3
  • M. Gambarin
    • 1
  • A. R. Bentivoglio
    • 4
  • T. Ialongo
    • 4
  • A. Albanese
    • 5
  • P. Barone
    • 6
  • M. T. Pellecchia
    • 6
  • F. Brancati
    • 2
    • 7
  • G. Moretto
    • 8
  • A. Fiaschi
    • 1
  • M. Tinazzi
    • 1
    • 8
  1. 1.Dept. of Neurological and Vision SciencesSection of Rehabilitative Neurology, University of VeronaVeronaItaly
  2. 2.IRCCS CSSMendel InstituteRomeItaly
  3. 3.Operative Unit of Pediatric Genetics and ImmunologyDept. of Medical and Surgical Pediatric Sciences, University of MessinaMessinaItaly
  4. 4.Institute of NeurologyCatholic UniversityRomeItaly
  5. 5.IRCCS National Neurological InstituteCarlo BestaMilanItaly
  6. 6.Dept. of Neurological SciencesUniversity Federico IINaplesItaly
  7. 7.CeSI, Aging Research Centre and Dept. of Biomedical SciencesG. d’Annunzio University FoundationChietiItaly
  8. 8.Neurology UnitBorgo Trento HospitalVeronaItaly

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