title: How much phenotypic variation can be attributed to parkin genotype?
abstract: 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.
authors.affiliation: INSERM U289, Hôpital de la Salpêtrière, Paris, France.
authors.forename: Ebba
authors.initials: E
authors.lastname: Lohmann
authors.forename: Magali
authors.initials: M
authors.lastname: Periquet
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bonifati
authors.forename: Nick W
authors.initials: NW
authors.lastname: Wood
authors.forename: Giuseppe
authors.initials: G
authors.lastname: De Michele
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Bonnet
authors.forename: Valérie
authors.initials: V
authors.lastname: Fraix
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Broussolle
authors.forename: Martin W I M
authors.initials: MW
authors.lastname: Horstink
authors.forename: Marie
authors.initials: M
authors.lastname: Vidailhet
authors.forename: Patrice
authors.initials: P
authors.lastname: Verpillat
authors.forename: Thomas
authors.initials: T
authors.lastname: Gasser
authors.forename: David
authors.initials: D
authors.lastname: Nicholl
authors.forename: Hélio
authors.initials: H
authors.lastname: Teive
authors.forename: Salmo
authors.initials: S
authors.lastname: Raskin
authors.forename: Olivier
authors.initials: O
authors.lastname: Rascol
authors.forename: Alain
authors.initials: A
authors.lastname: Destée
authors.forename: Merle
authors.initials: M
authors.lastname: Ruberg
authors.forename: Francesca
authors.initials: F
authors.lastname: Gasparini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Meco
authors.forename: Yves
authors.initials: Y
authors.lastname: Agid
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
mesh_terms: 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*
chemical_list: D000978:Antiparkinson Agents; D007980:Levodopa; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein