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NEUROLOGY 2007;68:1557-1562
© 2007 American Academy of Neurology

ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease

A. Di Fonzo, MD, H. F. Chien, MD, M. Socal, MD, S. Giraudo, BS, C. Tassorelli, MD, G. Iliceto, MD, G. Fabbrini, MD, R. Marconi, MD, E. Fincati, MD, G. Abbruzzese, MD, P. Marini, MD, F. Squitieri, MD, M. W. Horstink, MD, PhD, P. Montagna, MD, A. Dalla Libera, MD, F. Stocchi, MD, S. Goldwurm, MD, PhD, J. J. Ferreira, MD, G. Meco, MD, E. Martignoni, MD, L. Lopiano, MD, L. B. Jardim, MD, PhD, B. A. Oostra, PhD, E. R. Barbosa, MD, The Italian Parkinson Genetics Network* and V. Bonifati, MD, PhD

From the Department of Clinical Genetics (A. Di Fonzo, B.A.O., V.B.), Erasmus MC, Rotterdam, The Netherlands; Department of Neurology (H.F.C., E.R.B.), University of São Paulo, Brazil; Hospital de Clínicas de Porto Alegre (M.S., L.B.J.), Brazil; Department of Neuroscience (S. Giraudo, L.L.), University of Turin, Italy; Institute IRCCS Mondino (C.T.), Pavia, Italy; Department of Neurology (G.I.), University of Bari, Italy; Department of Neurological Sciences (G.F., G.M.), La Sapienza University, Rome; Neurology Division (R.M.), Misericordia Hospital, Grosseto, Italy; Department of Neurology (E.F.), University of Verona, Italy; Department of Neurosciences (G.A.), Ophthalmology & Genetics, University of Genova, Italy; Department of Neurology (P. Marini), University of Florence, Italy; Neurogenetics Unit (F. Squitieri), IRCCS Neuromed, Pozzilli, Italy; Department of Neurology (M.W.H.), Radboud University Nijmegen Medical Center, Netherlands; Department of Neurology (P. Montagna), University of Bologna, Italy; Neurology Division (A. Dalla Libera), Boldrini Hospital, Thiene, Italy; IRCCS San Raffaele Pisana (F. Stocchi), Rome, Italy; Parkinson Institute (S. Goldwurm), Istituti Clinici di Perfezionamento, Milan; Neurological Clinical Research Unit (J.J.F.), Institute of Molecular Medicine, Lisbon, Portugal; A. Avogadro University (E.M.), Novara, and Institute IRCCS S. Maugeri, Scientific Institute of Veruno, Italy; and Department of Neurological Sciences, University of Milan, and Foundation Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena (A. Di Fonzo), Milan, Italy.

Address correspondence and reprint requests to Dr. V. Bonifati, Department of Clinical Genetics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands v.bonifati{at}erasmusmc.nl

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.

See also page 1553

Supplemental dataat www.neurology.org

*Members of the Italian Parkinson Genetics Network are listed in the appendix.

The Italian control DNA samples were from the Human Genetic Bank of Patients Affected by PD and Parkinsonisms, Parkinson Institute–Istituti Clinici di Perfezionamento, Milan, supported by the Italian Telethon Foundation (grant GTF04007). Supported by a research grant from the Internationaal Parkinson Fonds (The Netherlands) to V.B.

Disclosure: The authors report no conflicts of interest.

Received November 15, 2006. Accepted in final form February 2, 2007.


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