title: Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes.
abstract: OBJECTIVE
  To assess the prevalence, nature, and associated phenotypes of PINK1 gene mutations in a large series of patients with early-onset (<50 years) parkinsonism.
  
  
  METHODS
  The authors studied 134 patients (116 sporadic and 18 familial; 77% Italian) and 90 Italian controls. The whole PINK1 coding region was sequenced from genomic DNA; cDNA was analyzed in selected cases.
  
  
  RESULTS
  Homozygous pathogenic mutations were identified in 4 of 90 Italian sporadic cases, including the novel Gln456Stop mutation; single heterozygous truncating or missense mutations were found in another 4 Italian sporadic cases, including two novel mutations, Pro196Leu and Gln456Stop. Pathogenic mutations were not identified in the familial cases. Novel (Gln115Leu) and known polymorphisms were identified with similar frequency in cases and controls. In cases carrying single heterozygous mutation, cDNA analysis detected no additional mutations, and revealed a major pathogenic effect at mRNA level for the mutant C1366T/Gln456Stop allele. All patients with homozygous mutations had very early disease onset, slow progression, and excellent response to l-dopa, including, in some, symmetric onset, dystonia at onset, and sleep benefit, resembling parkin-related disease. Phenotype in patients with single heterozygous mutation was similar, but onset was later.
  
  
  CONCLUSIONS
  PINK1 homozygous mutations are a relevant cause of disease among Italian sporadic patients with early-onset parkinsonism. The role of mutations found in single heterozygous state is difficult to interpret. Our study suggests that, at least in some patients, these mutations are disease causing, in combination with additional, still unknown factors.
authors: Department of Clinical Genetics, Erasmus MC Rotterdam, The Netherlands. v.bonifati@erasmusmc.nl
authors: V
authors: V
authors: Bonifati
authors: C F
authors: CF
authors: Rohé
authors: G J
authors: GJ
authors: Breedveld
authors: E
authors: E
authors: Fabrizio
authors: M
authors: M
authors: De Mari
authors: C
authors: C
authors: Tassorelli
authors: A
authors: A
authors: Tavella
authors: R
authors: R
authors: Marconi
authors: D J
authors: DJ
authors: Nicholl
authors: H F
authors: HF
authors: Chien
authors: E
authors: E
authors: Fincati
authors: G
authors: G
authors: Abbruzzese
authors: P
authors: P
authors: Marini
authors: A
authors: A
authors: De Gaetano
authors: M W
authors: MW
authors: Horstink
authors: J A
authors: JA
authors: Maat-Kievit
authors: C
authors: C
authors: Sampaio
authors: A
authors: A
authors: Antonini
authors: F
authors: F
authors: Stocchi
authors: P
authors: P
authors: Montagna
authors: V
authors: V
authors: Toni
authors: M
authors: M
authors: Guidi
authors: A
authors: A
authors: Dalla Libera
authors: M
authors: M
authors: Tinazzi
authors: F
authors: F
authors: De Pandis
authors: G
authors: G
authors: Fabbrini
authors: S
authors: S
authors: Goldwurm
authors: A
authors: A
authors: de Klein
authors: E
authors: E
authors: Barbosa
authors: L
authors: L
authors: Lopiano
authors: E
authors: E
authors: Martignoni
authors: P
authors: P
authors: Lamberti
authors: N
authors: N
authors: Vanacore
authors: G
authors: G
authors: Meco
authors: B A
authors: BA
authors: Oostra
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002648:Child; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000032:analysis / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D016678:Genome / Q000235:genetics; D005838:Genotype; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense; D010300:Parkinson Disease / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D000099202:PTEN-Induced Putative Kinase
chemical_list: D018076:DNA, Complementary; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase