Parkin deletions in a family with adult-onset, tremor-dominant parkinsonism: expanding the phenotype.
A gene for autosomal recessive parkinsonism, PARK2 (parkin), has recently been identified on chromosome 6q and shown to be mutated in Japanese and European families, mostly with early-onset parkinsonism. Here we present a large pedigree from South Tyrol (a region of northern Italy) with adult-onset, clinically typical tremor-dominant parkinsonism of apparently autosomal dominant inheritance. Haplotype analysis excluded linkage to the chromosome 2p, 4p, and 4q regions that harbor genes associated with autosomal dominant parkinsonism, but implicated the parkin locus on chromosome 6q. Compound heterozygous deletions in the parkin gene (one large and one truncating) were identified in 4 affected male siblings. The patients were clinically indistinguishable from most patients with idiopathic Parkinson's disease. None of them displayed any of the clinical hallmarks described in patients with previously reported parkin mutations, including diurnal fluctuations, benefit from sleep, foot dystonia, hyperreflexia, and early susceptibility to levodopa-induced dyskinesias. Two affected female individuals carried one (truncating) of the two deletions in a heterozygous state with an apparently normal allele. We conclude that the phenotypic spectrum associated with mutations in the parkin gene is broader than previously reported, suggesting that this gene may be important in the etiology of the more frequent late-onset typical Parkinson's disease.
Klein
C
C
Massachusetts General Hospital, and Department of Neurology, Harvard Medical School, Boston, USA.
Pramstaller
P P
PP
Kis
B
B
Page
C C
CC
Kann
M
M
Leung
J
J
Woodward
H
H
Castellan
C C
CC
Scherer
M
M
Vieregge
P
P
Breakefield
X O
XO
Kramer
P L
PL
Ozelius
L J
LJ
D017668:Age of Onset; D000368:Aged; D004247:DNA / Q000032:analysis; D004252:DNA Mutational Analysis; D005260:Female; D017353:Gene Deletion; D008040:Genetic Linkage / Q000235:genetics; D006801:Humans; D007558:Italy; D008025:Ligases; D008297:Male; D008875:Middle Aged; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics*; D014202:Tremor / Q000235:genetics* / Q000503:physiopathology; D044767:Ubiquitin-Protein Ligases
D011506:Proteins; D004247:DNA; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D008025:Ligases