title: ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease.
abstract: OBJECTIVE
  To assess the prevalence, nature, and associated phenotypes of ATP13A2 gene mutations among patients with juvenile parkinsonism (onset <21 years) or young onset (between 21 and 40 years) Parkinson disease (YOPD).
  
  
  METHODS
  We studied 46 patients, mostly from Italy or Brazil, including 11 with juvenile parkinsonism and 35 with YOPD. Thirty-three cases were sporadic and 13 had positive family history compatible with autosomal recessive inheritance. Forty-two had only parkinsonian signs, while four (all juvenile-onset) had multisystemic involvement. The whole ATP13A2 coding region (29 exons) and exon-intron boundaries were sequenced from genomic DNA.
  
  
  RESULTS
  A novel homozygous missense mutation (Gly504Arg) was identified in one sporadic case from Brazil with juvenile parkinsonism. This patient had symptoms onset at age 12, levodopa-responsive severe akinetic-rigid parkinsonism, levodopa-induced motor fluctuations and dyskinesias, severe visual hallucinations, and supranuclear vertical gaze paresis, but no pyramidal deficit nor dementia. Brain CT scan showed moderate diffuse atrophy. Furthermore, two Italian cases with YOPD without atypical features carried a novel missense mutation (Thr12Met, Gly533Arg) in single heterozygous state.
  
  
  CONCLUSIONS
  We confirm that ATP13A2 homozygous mutations are associated with human parkinsonism, and expand the associated genotypic and clinical spectrum, by describing a homozygous missense mutation in this gene in a patient with a phenotype milder than that initially associated with ATP13A2 mutations (Kufor-Rakeb syndrome). Our data also suggest that ATP13A2 single heterozygous mutations might be etiologically relevant for patients with YOPD and further studies of this gene in Parkinson disease are warranted.
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands. v.bonifati@erasmusmc.nl
authors.forename: A
authors.initials: A
authors.lastname: Di Fonzo
authors.forename: H F
authors.initials: HF
authors.lastname: Chien
authors.forename: M
authors.initials: M
authors.lastname: Socal
authors.forename: S
authors.initials: S
authors.lastname: Giraudo
authors.forename: C
authors.initials: C
authors.lastname: Tassorelli
authors.forename: G
authors.initials: G
authors.lastname: Iliceto
authors.forename: G
authors.initials: G
authors.lastname: Fabbrini
authors.forename: R
authors.initials: R
authors.lastname: Marconi
authors.forename: E
authors.initials: E
authors.lastname: Fincati
authors.forename: G
authors.initials: G
authors.lastname: Abbruzzese
authors.forename: P
authors.initials: P
authors.lastname: Marini
authors.forename: F
authors.initials: F
authors.lastname: Squitieri
authors.forename: M W
authors.initials: MW
authors.lastname: Horstink
authors.forename: P
authors.initials: P
authors.lastname: Montagna
authors.forename: A Dalla
authors.initials: AD
authors.lastname: Libera
authors.forename: F
authors.initials: F
authors.lastname: Stocchi
authors.forename: S
authors.initials: S
authors.lastname: Goldwurm
authors.forename: J J
authors.initials: JJ
authors.lastname: Ferreira
authors.forename: G
authors.initials: G
authors.lastname: Meco
authors.forename: E
authors.initials: E
authors.lastname: Martignoni
authors.forename: L
authors.initials: L
authors.lastname: Lopiano
authors.forename: L B
authors.initials: LB
authors.lastname: Jardim
authors.forename: B A
authors.initials: BA
authors.lastname: Oostra
authors.forename: E R
authors.initials: ER
authors.lastname: Barbosa
authors.forename: V
authors.initials: V
authors.lastname: Bonifati
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D001938:Brazil / Q000453:epidemiology; D002648:Child; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D010300:Parkinson Disease / Q000453:epidemiology / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000453:epidemiology / Q000235:genetics*; D010641:Phenotype; D015995:Prevalence; D006180:Proton-Translocating ATPases / Q000235:genetics*
chemical_list: C514983:ATP13A2 protein, human; D006180:Proton-Translocating ATPases