Journal of Neurology

, Volume 255, Issue 5, pp 643–648 | Cite as

Clinical and molecular characterisation of a Parkinson family with a novel PINK1 mutation

  • J. Prestel
  • K. Gempel
  • T. K. Hauser
  • K. Schweitzer
  • H. Prokisch
  • U. Ahting
  • D. Freudenstein
  • E. Bueltmann
  • T. Naegele
  • D. Berg
  • T. Klopstock
  • T. Gasser
ORIGINAL COMMUNICATION

Abstract

Homozygous mutations in the PINK1 gene have been shown to cause early-onset parkinsonism. Here, we describe a novel homozygous mutation (Q126P), identified in two affected German sisters with a clinical phenotype typical for PINK1-associated parkinsonism.We analysed lactate, pyruvate, carnitine and acylcarnitine blood levels, lactate levels under exercise and in the cerebrospinal fluid, activity of respiratory chain complexes I–IV in muscle biopsies and proteasomal activity in immortalized lymphoblasts, but found no evidence for mitochondrial or proteasomal dysfunction. MR spectroscopy revealed raised myoinositol levels in the basal ganglia of both patients, reflecting possible astroglial proliferation.

Key words

parkinson PINK1 genetics MR spectroscopy 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    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
  2. 2.
    Hatano Y, Li Y, Sato K, et al. (2004) Novel PINK1 mutations in early-onset parkinsonism. Ann Neurol 56:424–427PubMedCrossRefGoogle Scholar
  3. 3.
    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
  4. 4.
    Ibáñez P, Lesage S, Lohmann E, et al. (2006) Mutational analysis of the PINK1 gene in early-onset parkinsonism in Europe and North Africa. Brain 129:686–694PubMedCrossRefGoogle Scholar
  5. 5.
    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
  6. 6.
    Leutenegger AL, Salih MA, Ibáñez P, et al. (2006) Juvenile-onset parkinsonism as a result of the first mutation in the adenosine triphosphate orientation domain of PINK1. Arch Neurol 63:1257–1261PubMedCrossRefGoogle Scholar
  7. 7.
    Valente EM, Salvi S, Ialongo T, et al. (2004) PINK1 mutations are associated with sporadic early-onset parkinsonism. Ann Neurol 56:336–341PubMedCrossRefGoogle Scholar
  8. 8.
    Bonifati V, Rohé CF, Breedveld GJ, et al. (2005) Early-onset parkinsonism associated with PINK1 mutations. Neurology 65:87–95PubMedCrossRefGoogle Scholar
  9. 9.
    Abou-Sleiman PM, Muqit MM, Mc- Donald NQ, et al. (2006) A heterozygous effect for PINK1 mutations in Parkinson’s disease? Ann Neurol 60:414–419PubMedCrossRefGoogle Scholar
  10. 10.
    Silvestri L, Caputo V, Bellacchio E, Atorino L, Dallapiccola B, Valente EM, Casari G (2005) Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism. Hum Mol Genet 14:3477–3492PubMedCrossRefGoogle Scholar
  11. 11.
    Deng H, Jankovic J, Guo Y, Xie W, Le W (2005) Small interfering RNA targeting the PINK1 induces apoptosis in dopaminergic cells SH-SY5Y. Biochem Biophys Res Commun 337:1133–1138PubMedCrossRefGoogle Scholar
  12. 12.
    Petit A, Kawarai T, Paitel E, et al. (2005) Wild-type PINK1 prevents basal and induced neuronal apoptosis, a protective effect abrogated by Parkinson disease- related mutations. J Biol Chem 280:34025–34032PubMedCrossRefGoogle Scholar
  13. 13.
    Park J, Lee SB, Lee S, et al. (2006) Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441:1157–1161PubMedCrossRefGoogle Scholar
  14. 14.
    Clark IE, Dodson MW, Jiang C, et al. (2006) Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441:1162–1166PubMedCrossRefGoogle Scholar
  15. 15.
    Yang Y, Gehrke S, Imai Y, et al. (2006) Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. Proc Natl Acad Sci USA 103:10793–10798PubMedCrossRefGoogle Scholar
  16. 16.
    Wang D, Qian L, Xiong H, et al. (2006) Antioxidants protect PINK1-dependent dopaminergic neurons in Drosophila. Proc Natl Acad Sci USA 103:13269–13270CrossRefGoogle Scholar
  17. 17.
    Valente EM, Brancati F, Ferraris A, et al. (2002) PARK6-linked parkinsonism occurs in several European families. Ann Neurol 51:14–18PubMedCrossRefGoogle Scholar
  18. 18.
    Fischer JC, Ruitenbeek W, Gabreels FJ, et al. (1986) A mitochondrial encephalomyopathy: the first case with an established defect at the level of coenzyme Q Eur J Pediatr 144:441–444PubMedCrossRefGoogle Scholar
  19. 19.
    Barrientos A (2002) In vivo and in organello assessment of OXPHOS activities. Methods 26:307–316PubMedCrossRefGoogle Scholar
  20. 20.
    Heinemeyer W, Fischer M, Krimmer T, Stachon U, Wolf DH (1997) The active sites of the eukaryotic 20 S proteasome and their involvement in subunit precursor processing. J Biol Chem 272:25200–25209PubMedCrossRefGoogle Scholar
  21. 21.
    Seeger U, Klose U, Mader I, Grodd W, Nagele T (2003) Parameterized evaluation of macromolecules and lipids in proton MR spectroscopy of brain diseases. Magn Reson Med 49:19–28PubMedCrossRefGoogle Scholar
  22. 22.
    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
  23. 23.
    Kantarci K, Petersen RC, Boeve BF, et al. (2004) 1H MR spectroscopy in common dementias. Neurology 63:1393–1398PubMedGoogle Scholar
  24. 24.
    O'Neill J, Schuff N, Marks WJ Jr, Feiwell R, Aminoff MJ, Weiner MW (2002) Quantitative 1H magnetic resonance spectroscopy and MRI of Parkinson’s disease. Mov Disord 17:917–927PubMedCrossRefGoogle Scholar
  25. 25.
    Rango M, Arighi A, Biondetti P, et al. (2007) Magnetic resonance spectroscopy in Parkinson’s disease and parkinsonian syndromes. Funct Neurol 22:75–79PubMedGoogle Scholar
  26. 26.
    Firbank MJ, Harrison RM and O’Brien JT (2002) A comprehensive review of proton magnetic resonance spectroscopy studies in dementia and Parkinson’s disease. Dement Geriatr Cogn Disord 14:64–76PubMedCrossRefGoogle Scholar
  27. 27.
    Shen J and Cookson MR (2004) Mitochondria and dopamine: new insights into recessive parkinsonism. Neuron 43:301–304PubMedCrossRefGoogle Scholar
  28. 28.
    Tang B, Xiong H, Sun P, et al. (2006) Association of PINK1 and DJ-1 confers digenic inheritance of early onset Parkinson’s disease. Hum Mol Genet 15:1816–1825PubMedCrossRefGoogle Scholar
  29. 29.
    Albanese A, Valente EM, Romito LM, Bellacchio E, Elia AE and Dallapiccola B (2005) The PINK1 phenotype can be indistinguishable from idiopathic Parkinson disease. Neurology 64:1958–1960PubMedCrossRefGoogle Scholar

Copyright information

© Steinkopff-Verlag 2008

Authors and Affiliations

  • J. Prestel
    • 6
  • K. Gempel
    • 1
  • T. K. Hauser
    • 2
  • K. Schweitzer
    • 6
  • H. Prokisch
    • 3
  • U. Ahting
    • 3
  • D. Freudenstein
    • 4
  • E. Bueltmann
    • 2
  • T. Naegele
    • 2
  • D. Berg
    • 6
  • T. Klopstock
    • 5
  • T. Gasser
    • 6
  1. 1.Metabolic Disease CenterHospital Munich-SchwabingMunichGermany
  2. 2.Dept. of NeuroradiologyRadiological Clinic of the University of TuebingenGermany
  3. 3.Institute of Human GeneticsGSF National Research CenterMunich-NeuherbergGermany
  4. 4.Dept. of NeurosurgeryUniversity of TuebingenGermany
  5. 5.Dept. of Neurology, Klinikum GrosshadernLudwig-Maximilians-UniversityMunichGermany
  6. 6.Hertie-Institute for Clinical Brain ResearchDept. for Neurodegenerative Diseases, University of TuebingenTuebingenGermany

Personalised recommendations