caa a22 4500 445364416 CHVBK 20180317142925.0 cr unu---uuuuu 170323e20110201xx s 000 0 eng 10.1007/s10048-010-0259-0 doi (NATIONALLICENCE)springer-10.1007/s10048-010-0259-0 Novel ATP13A2 ( PARK9 ) homozygous mutation in a family with marked phenotype variability [Elektronische Daten] [Lucio Santoro, Guido Breedveld, Fiore Manganelli, Rosa Iodice, Chiara Pisciotta, Maria Nolano, Francesca Punzo, Mario Quarantelli, Sabina Pappatà, Alessio Di Fonzo, Ben Oostra, Vincenzo Bonifati] Mutations in the ATP13A2 (PARK9) and FBXO7 (PARK15) genes are linked to different forms of autosomal recessive juvenile-onset neurodegenerative diseases with overlapping phenotypes, including levodopa-responsive parkinsonism, pyramidal disturbances, cognitive decline, and supranuclear gaze disturbance. However, the associated genotypes and phenotypes are poorly characterized due to the small number of patients described. Here, we report clinical, instrumental, and genetic findings in an Italian family with novel PARK9 and PARK15 mutations. The proband developed a severe progressive phenotype including juvenile-onset parkinsonism, pyramidal disturbances, cognitive decline, and oculomotor abnormalities. On the contrary, his brother only shows mild abnormalities (pyramidal, cognitive, and oculomotor) on the neurological examination at the age of 31years. These two brothers both carry a novel homozygous PARK9 missense (p.G877R) and a novel heterozygous PARK15 mutation (p.R481C). The PARK9 mutation replaces a crucial residue for the ATPase activity, and is therefore most likely a loss-of-function mutation and disease-causing in homozygous state. The pathogenic significance of the PARK15 single heterozygous mutation remains unclear. In both sibs, DaTSCAN single photon emission computed tomography showed marked nigrostriatal dopaminergic defects, and transcranial magnetic stimulation detected prolonged central motor conduction time. MRI, including T2*-weighted imaging, detected no evidence of brain iron accumulation. This family, the third reported with homozygous PARK9 mutations and the first with mutations in two genes for atypical juvenile parkinsonism, illustrates that PARK9-linked disease might display wide intra-familial clinical variability and milder phenotypes, suggesting the existence of strong, still unknown, modifiers. The Author(s), 2010 Parkinsonism nationallicence Movement disorders nationallicence PARK9 nationallicence PARK15 nationallicence ATP13A2 nationallicence FBXO7 nationallicence Santoro Lucio Department of Neurological Sciences, University of Naples "Federico II”, Naples, Italy aut Breedveld Guido Department of Clinical Genetics, Erasmus MC, P.O. Box2040, 3000 CA, Rotterdam, The Netherlands aut Manganelli Fiore Department of Neurological Sciences, University of Naples "Federico II”, Naples, Italy aut Iodice Rosa Department of Neurological Sciences, University of Naples "Federico II”, Naples, Italy aut Pisciotta Chiara Department of Neurological Sciences, University of Naples "Federico II”, Naples, Italy aut Nolano Maria "Salvatore Maugeri” Foundation, IRCCS-Medical Center of Telese Terme, Telese Terme, Italy aut Punzo Francesca Department of Clinical Genetics, Erasmus MC, P.O. Box2040, 3000 CA, Rotterdam, The Netherlands aut Quarantelli Mario Biostructure and Bioimaging Institute, National Research Council, Naples, Italy aut Pappatà Sabina Biostructure and Bioimaging Institute, National Research Council, Naples, Italy aut Di Fonzo Alessio Department of Neurological Sciences, University of Milan, Milan, Italy aut Oostra Ben Department of Clinical Genetics, Erasmus MC, P.O. Box2040, 3000 CA, Rotterdam, The Netherlands aut Bonifati Vincenzo Department of Clinical Genetics, Erasmus MC, P.O. Box2040, 3000 CA, Rotterdam, The Netherlands aut neurogenetics Springer-Verlag 12/1(2011-02-01), 33-39 1364-6745 12:1<33 2011 12 10048 https://doi.org/10.1007/s10048-010-0259-0 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10048-010-0259-0 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Santoro Lucio Department of Neurological Sciences, University of Naples "Federico II”, Naples, Italy aut NATIONALLICENCE 700 1- Breedveld Guido Department of Clinical Genetics, Erasmus MC, P.O. Box2040, 3000 CA, Rotterdam, The Netherlands aut NATIONALLICENCE 700 1- Manganelli Fiore Department of Neurological Sciences, University of Naples "Federico II”, Naples, Italy aut NATIONALLICENCE 700 1- Iodice Rosa Department of Neurological Sciences, University of Naples "Federico II”, Naples, Italy aut NATIONALLICENCE 700 1- Pisciotta Chiara Department of Neurological Sciences, University of Naples "Federico II”, Naples, Italy aut NATIONALLICENCE 700 1- Nolano Maria "Salvatore Maugeri” Foundation, IRCCS-Medical Center of Telese Terme, Telese Terme, Italy aut NATIONALLICENCE 700 1- Punzo Francesca Department of Clinical Genetics, Erasmus MC, P.O. Box2040, 3000 CA, Rotterdam, The Netherlands aut NATIONALLICENCE 700 1- Quarantelli Mario Biostructure and Bioimaging Institute, National Research Council, Naples, Italy aut NATIONALLICENCE 700 1- Pappatà Sabina Biostructure and Bioimaging Institute, National Research Council, Naples, Italy aut NATIONALLICENCE 700 1- Di Fonzo Alessio Department of Neurological Sciences, University of Milan, Milan, Italy aut NATIONALLICENCE 700 1- Oostra Ben Department of Clinical Genetics, Erasmus MC, P.O. Box2040, 3000 CA, Rotterdam, The Netherlands aut NATIONALLICENCE 700 1- Bonifati Vincenzo Department of Clinical Genetics, Erasmus MC, P.O. Box2040, 3000 CA, Rotterdam, The Netherlands aut NATIONALLICENCE 773 0- neurogenetics Springer-Verlag 12/1(2011-02-01), 33-39 1364-6745 12:1<33 2011 12 10048 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer