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Role of a Single Hit?

Katja Hedrich, PhD; Johann Hagenah, MD; Ana Djarmati, PhD; Anja Hiller, MD; Thora Lohnau, BS; Kathrin Lasek, MD; Anne Grünewald, MS; Rüdiger Hilker, MD; Susanne Steinlechner, MD; Heather Boston, BS; Norman Kock, MD; Christiane Schneider-Gold, MD; Wolfram Kress, MD; Hartwig Siebner, MD; Ferdinand Binkofski, MD; Rebekka Lencer, MD; Alexander Münchau, MD; Christine Klein, MD

Arch Neurol. 2006;63:833-838.

Background  Although homozygous mutations in the PTEN-induced putative kinase 1 (PINK1) gene have been unequivocally associated with early-onset Parkinson disease (PD), the role of single heterozygous PINK1 mutations is less clear.

Objective  To investigate the role of homozygous and heterozygous PINK1 mutations in a large German pedigree (family W).

Design  Mutation analysis of PINK1 and results of standardized neurological and motor examination by 3 independent movement disorder specialists, including blinded video rating.

Settings  University of Lübeck.

Participants  Twenty family members.

Main Outcome Measures  The PINK1 genotype and PD status of all family members.

Results  The index patient of family W carried a homozygous nonsense mutation (c.1366C>T; p.Q456X) and presented with a phenotype closely resembling idiopathic PD but with an onset at 39 years of age. The family included a total of 4 affected homozygous members (age, 60-71 years; age at onset, 39-61 years), 6 members with slight or mild signs of PD (affected) and a heterozygous mutation (age, 31-49 years), and 5 unaffected heterozygous mutation carriers (age, 34-44 years). Although none of the heterozygous affected family members was aware of their signs (asymptomatic), the clinical findings were unequivocal and predominantly or exclusively present on their dominant right-hand side, eg, unilaterally reduced or absent arm swing and unilateral rigidity. The heterozygous members were all considerably younger than the affected homozygous mutation carriers.

Conclusions  Heterozygous PINK1 mutations may predispose to PD, as was previously suggested by the presence of dopamine hypometabolism in asymptomatic mutation carriers. Long-term follow-up of our large family W provides an excellent opportunity to further evaluate the role of single heterozygous PINK1 mutations later in life, which will have major implications on genetic counseling.

Author Affiliations: Departments of Neurology (Drs Hedrich, Hagenah, Djarmati, Hiller, Lasek, Kock, Binkofski, and Klein and Mss Lohnau, Grünewald, and Boston), Human Genetics (Drs Hedrich, Djarmati, Kock, and Klein and Mss Lohnau and Boston), and Psychiatry and Psychotherapy (Drs Steinlechner and Lencer), University of Lübeck, Lübeck, Germany; Departments of Neurology, Medical University of Cologne, Cologne, Germany (Dr Hilker), Georg-August University, Göttingen, Germany (Dr Schneider-Gold), Christian-Albrechts University, Kiel, Germany (Dr Siebner), and University Medical Center Hamburg Eppendorf, Hamburg, Germany (Dr Münchau); Department of Human Genetics, Julius-Maximilians University, Würzburg, Germany (Dr Kress); Faculty of Biology, University of Belgrade, Belgrade, Serbia (Dr Djarmati); and NeuroImage Nord, Hamburg-Kiel-Lübeck, Germany (Drs Siebner and Binkofski).

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