ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease
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Abstract
Objective: To assess the prevalence, nature, and associated phenotypes of ATP13A2
gene mutations among patients with juvenile parkinsonism (onset21 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