How much phenotypic variation can be attributed to parkin genotype?
To establish phenotype-genotype correlations in early-onset parkinsonism, we have compared the phenotype of a large series of 146 patients with and 250 patients without parkin mutations. Although no single sign distinguished the groups, patients with mutations had significantly earlier and more symmetrical onset, dystonia more often at onset and hyperreflexia, slower progression of the disease, and a tendency toward a greater response to levodopa despite lower doses. After forward stepwise multiple logistic regression analysis, dystonia at onset and brisk reflexes were not longer significantly different but were correlated with age at onset rather than the presence of the parkin mutation. Age at onset in carriers of parkin mutations varied as did the rate of progression of the disease: the younger the age at onset the slower the evolution. The genotype influenced the phenotype: carriers of at least one missense mutation had a higher United Parkinson's Disease Rating Scale motor score than those carrying two truncating mutations. The localization of the mutations was also important because missense mutations in functional domains of parkin resulted in earlier onset. Patients with a single heterozygous mutation had significantly later and more asymmetrical onset and more frequent levodopa-induced fluctuations and dystonia than patients with two mutations.
Lohmann
Ebba
E
INSERM U289, Hôpital de la Salpêtrière, Paris, France.
Periquet
Magali
M
Bonifati
Vincenzo
V
Wood
Nick W
NW
De Michele
Giuseppe
G
Bonnet
Anne-Marie
AM
Fraix
Valérie
V
Broussolle
Emmanuel
E
Horstink
Martin W I M
MW
Vidailhet
Marie
M
Verpillat
Patrice
P
Gasser
Thomas
T
Nicholl
David
D
Teive
Hélio
H
Raskin
Salmo
S
Rascol
Olivier
O
Destée
Alain
A
Ruberg
Merle
M
Gasparini
Francesca
F
Meco
Giuseppe
G
Agid
Yves
Y
Durr
Alexandra
A
Brice
Alexis
A
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000978:Antiparkinson Agents / Q000627:therapeutic use; D018450:Disease Progression; D005091:Exons / Q000235:genetics; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007980:Levodopa / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
D000978:Antiparkinson Agents; D007980:Levodopa; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein