Reference : Clinical spectrum of homozygous and heterozygous PINK1 mutations in a large German fa...
Scientific journals : Article
Life sciences : Genetics & genetic processes
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 [> >]
Hiller, Anja [> >]
Lohnau, Thora [> >]
Lasek, Kathrin [> >]
Grünewald, Anne mailto [> >]
Hilker, Rudiger [> >]
Steinlechner, Susanne [> >]
Boston, Heather [> >]
Kock, Norman [> >]
Schneider-Gold, Christiane [> >]
Kress, Wolfram [> >]
Siebner, Hartwig [> >]
Binkofski, Ferdinand [> >]
Lencer, Rebekka [> >]
Munchau, Alexander [> >]
Klein, Christine [> >]
Archives of neurology
Yes (verified by ORBilu)
United States
[en] 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
[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.
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