Clinical spectrum of homozygous and heterozygous PINK1 mutations in a large German family with Parkinson disease: role of a single hit?
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.
Hedrich
Katja
K
Department of Neurology, University of Lübeck, Germany.
Hagenah
Johann
J
Djarmati
Ana
A
Hiller
Anja
A
Lohnau
Thora
T
Lasek
Kathrin
K
Grünewald
Anne
A
Hilker
Rüdiger
R
Steinlechner
Susanne
S
Boston
Heather
H
Kock
Norman
N
Schneider-Gold
Christiane
C
Kress
Wolfram
W
Siebner
Hartwig
H
Binkofski
Ferdinand
F
Lencer
Rebekka
R
Münchau
Alexander
A
Klein
Christine
C
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
D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase