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Clinical spectrum of homozygous and heterozygous PINK1 mutations in a large German family with Parkinson disease: role of a single hit?
Hedrich, Katja; Hagenah, Johann; Djarmati, Ana et al.
2006In Archives of neurology, 63 (6), p. 833-8
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Keywords :
Adult; Age of Onset; Aged; DNA Mutational Analysis/methods; Family Health; Female; Genetic Predisposition to Disease; Germany/epidemiology; Heterozygote; Homozygote; Humans; Male; Middle Aged; Mutation; Parkinson Disease/genetics/physiopathology; Protein Kinases/genetics
Abstract :
[en] 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 Lubeck. 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.
Disciplines :
Genetics & genetic processes
Author, co-author :
Hedrich, Katja
Hagenah, Johann
Djarmati, Ana
Hiller, Anja
Lohnau, Thora
Lasek, Kathrin
GRÜNEWALD, Anne  
Hilker, Rudiger
Steinlechner, Susanne
Boston, Heather
Kock, Norman
Schneider-Gold, Christiane
Kress, Wolfram
Siebner, Hartwig
Binkofski, Ferdinand
Lencer, Rebekka
Munchau, Alexander
More authors (8 more) Less
External co-authors :
yes
Language :
English
Title :
Clinical spectrum of homozygous and heterozygous PINK1 mutations in a large German family with Parkinson disease: role of a single hit?
Publication date :
2006
Journal title :
Archives of neurology
ISSN :
0003-9942
Volume :
63
Issue :
6
Pages :
833-8
Peer reviewed :
Peer reviewed
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