OUT OF 46 PATIENTS 21-41 YEARS OLD WITH JUVENILE OR YOUNG ONSET PARKINSONISM 33 WERE SPORADIC

1: Neurology. 2007 May 8;68(19):1557-62. Links
ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease.Di Fonzo A, Chien HF, Socal M, Giraudo S, Tassorelli C, Iliceto G, Fabbrini G, Marconi R, Fincati E, Abbruzzese G, Marini P, Squitieri F, Horstink MW, Montagna P, Libera AD, Stocchi F, Goldwurm S, Ferreira JJ, Meco G, Martignoni E, Lopiano L, Jardim LB, Oostra BA, Barbosa ER; The Italian Parkinson Genetics Network; Bonifati V.
Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands. v.bonifati@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.

PMID: 17485642 [PubMed - in process]


---------------------------------------------------------------------------------

Science. 2003 Jan 10;299(5604):256-9. Epub 2002 Nov 21. Links
Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism.Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P.
Genetic-Epidemiologic Unit, Department of Clinical Genetics, Department of Epidemiology and Biostatistics, Erasmus Medical Center Rotterdam, Post Office Box 1738, 3000 DR Rotterdam, Netherlands. bonifati@kgen.fgg.eur.nl

The DJ-1 gene encodes a ubiquitous, highly conserved protein. Here, we show that DJ-1 mutations are associated with PARK7, a monogenic form of human parkinsonism. The function of the DJ-1 protein remains unknown, but evidence suggests its involvement in the oxidative stress response. Our findings indicate that loss of DJ-1 function leads to neurodegeneration. Elucidating the physiological role of DJ-1 protein may promote understanding of the mechanisms of brain neuronal maintenance and pathogenesis of Parkinson's disease.

------------------------------------------------------------------------------------



--------------------------------------------------------------------------------

NEUROLOGY 2005;65:87-95
© 2005 American Academy of Neurology

c
Frequency, genotypes, and phenotypes
V. Bonifati, MD, PhD, C. F. Rohé, G. J. Breedveld, E. Fabrizio, MD, M. De Mari, MD, C. Tassorelli, MD, A. Tavella, MD, R. Marconi, MD, D. J. Nicholl, MD, PhD, H. F. Chien, MD, E. Fincati, MD, G. Abbruzzese, MD, P. Marini, MD, A. De Gaetano, MD, M. W. Horstink, MD, PhD, J. A. Maat-Kievit, MD, PhD, C. Sampaio, MD, A. Antonini, MD, F. Stocchi, MD, P. Montagna, MD, V. Toni, MD, M. Guidi, MD, A. Dalla Libera, MD, M. Tinazzi, MD, F. De Pandis, MD, G. Fabbrini, MD, S. Goldwurm, MD, A. de Klein, PhD, E. Barbosa, MD, L. Lopiano, MD, E. Martignoni, MD, P. Lamberti, MD, N. Vanacore, MD, G. Meco, MD, B. A. Oostra, PhD and The Italian Parkinson Genetics Network*
From the Department of Clinical Genetics (Drs. Bonifati, Maat-Kievit, de Klein, and Oostra, and C.F. Rohé and G.J. Breedveld), Erasmus MC Rotterdam, The Netherlands; Department of Neurological Sciences "La Sapienza" University (Drs. Bonifati, Fabrizio, Fabbrini, and Meco), Rome, Italy; Department of Neurology (Drs. De Mari, Lamberti), University of Bari, Italy; Institute IRCCS "Mondino" (Drs. Tassorelli, Martignoni), Pavia, Italy; Department of Neuroscience (Drs. Tavella, Lopiano), University of Turin, Italy; Neurology Division (Dr. Marconi), "Misericordia" Hospital, Grosseto, Italy; Department of Neurology (Dr. Nicholl), Queen Elizabeth Hospital, Birmingham, UK; Department of Neurology (Drs. Chien and Barbosa), University of São Paulo, Brazil; Department of Neurology (Dr. Fincati), University of Verona, Italy; Department of Neurosciences, Ophthalmology & Genetics (Dr. Abbruzzese), University of Genova, Italy; Department of Neurology (Dr. Marini), University of Florence, Italy; Neurology Division (Dr. De Gaetano), Hospital of Castrovillari, Italy; Department of Neurology (Dr. Horstink), Nijmegen Academic Hospital, The Netherlands; Neurological Clinical Research Unit (Dr. Sampaio), Institute of Molecular Medicine, Lisbon, Portugal; Parkinson Institute (Drs. Antonini and Goldwurm), Istituti Clinici di Perfezionamento, Milan, Italy; IRCCS Neuromed (Dr. Stocchi), Pozzilli, Italy; Department of Neurology (Dr. Montagna), University of Bologna, Italy; Neurology Division (Dr. Toni), Hospital of Casarano, Italy; Neurology Division (Dr. Guidi), INRCA Institute, Ancona, Italy; Neurology Division (Dr. Dalla Libera), "Boldrini" Hospital, Thiene, Italy; Neurology Division (Dr. Tinazzi), "Borgo Trento" Hospital, Verona, Italy; Neurology Division (Dr. De Pandis), Hospital "Villa Margherita," Benevento, Italy; A. Avogadro University (Dr. Martignoni), Novara, Italy; and National Centre of Epidemiology (Dr. Vanacore), National Institute for Health, Rome, Italy.

Address correspondence and reprint requests to Dr. V. Bonifati, Dept. Clinical Genetics, Erasmus MC Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands; e-mail: v.bonifati@erasmusmc.nl

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.