title: Clinical spectrum of homozygous and heterozygous PINK1 mutations in a large German family with Parkinson disease: role of a single hit?
abstract: 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).
  
  
  METHODS
  Mutation analysis of PINK1 and results of standardized neurological and motor examination by 3 independent movement disorder specialists, including blinded video rating.
  
  
  METHODS
  University of Lübeck.
  
  
  METHODS
  Twenty family members.
  
  
  METHODS
  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.
authors.affiliation: Department of Neurology, University of Lübeck, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Hedrich
authors.forename: Johann
authors.initials: J
authors.lastname: Hagenah
authors.forename: Ana
authors.initials: A
authors.lastname: Djarmati
authors.forename: Anja
authors.initials: A
authors.lastname: Hiller
authors.forename: Thora
authors.initials: T
authors.lastname: Lohnau
authors.forename: Kathrin
authors.initials: K
authors.lastname: Lasek
authors.forename: Anne
authors.initials: A
authors.lastname: Grünewald
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Hilker
authors.forename: Susanne
authors.initials: S
authors.lastname: Steinlechner
authors.forename: Heather
authors.initials: H
authors.lastname: Boston
authors.forename: Norman
authors.initials: N
authors.lastname: Kock
authors.forename: Christiane
authors.initials: C
authors.lastname: Schneider-Gold
authors.forename: Wolfram
authors.initials: W
authors.lastname: Kress
authors.forename: Hartwig
authors.initials: H
authors.lastname: Siebner
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Binkofski
authors.forename: Rebekka
authors.initials: R
authors.lastname: Lencer
authors.forename: Alexander
authors.initials: A
authors.lastname: Münchau
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D004252:DNA Mutational Analysis / Q000379:methods; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D005858:Germany / Q000453:epidemiology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics* / Q000503:physiopathology; D011494:Protein Kinases / Q000235:genetics*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase