Monday, May 28, 2007


Is there a paternal age effect in Parkinson Disease is this a question that anyone is studying? Has it ever been studied? Would there be any funding to find out? Could there be de novo germ line mutations in the sporadic cases?

Genetic predisposition - Why do some patients with Parkinson’s disease develop symptoms at age 30 and others at age 60? Why do some patients do well on medications for many years while others have dose fluctuations early in the disease? Could a genetic predisposition be the determining factor? A major step towards the answer was the recent discovery of a specific gene in an Italian family with many members affected by the disease. A specific protein called a-synuclein was found to be abnormal in these patients. This exciting discovery will certainly contribute towards our understanding of Parkinson’s disease. There are nine genetic abnormalities that have been found to cause Parkinson's disease as of early 2002. However, most often a definite family history is NOT present for most patients. In these sporadic cases, a genetic predisposition may still play a role by increasing the change of getting the disease when patients are exposed to environmental insults.

Neurology. 2006 Feb 14;66(3):415-7. Links
Glucocerebrosidase gene mutations and Parkinson disease in the Norwegian population.Toft M, Pielsticker L, Ross OA, Aasly JO, Farrer MJ.
Department of Neuroscience, Norwegian University of Science and Technology, N-7489 Trondheim, Norway.

An association between mutations in the glucocerebrosidase (GBA) gene and Parkinson disease (PD) was recently reported in Ashkenazi Jews. The authors screened a series of 311 Norwegian patients with PD and 474 controls for 2 common functional mutations of the GBA protein, N370S and L444P. Seven patients (2.3%) and 8 controls (1.7%) carried a mutant GBA allele (p = 0.58). This study does not indicate increased susceptibility to PD in GBA mutations carriers in Norway.

Genetic Testing in Parkinson's Disease
Genetic testing has recently become available for the parkin and PINK1 genes. Parkin is a large gene and testing is difficult. At the current stage of understanding, testing is likely to give a meaningful result only for people who develop the condition before the age of 30 years. Pink1 appears to be a rare cause of inherited Parkinson’s disease. A small percentage (~2 percent) of those developing the condition at an early age appear to carry mutations in the PINK1 gene.

Mol Genet Metab. 2007 Jun;91(2):195-200. Epub 2007 Apr 25. Links
Glucocerebrosidase mutations in Chinese subjects from Taiwan with sporadic Parkinson disease.Ziegler SG, Eblan MJ, Gutti U, Hruska KS, Stubblefield BK, Goker-Alpan O, Lamarca ME, Sidransky E.
Section on Molecular Neurogenetics, Medical Genetics Branch, NHGRI, NIH, Building 35, Room 1A213, Bethesda, MD, USA.

BACKGROUND: An association between glucocerebrosidase, the enzyme deficient in Gaucher disease, and the synucleinopathies has been suggested both by the development of parkinsonism in Gaucher probands and carriers, as well as by the presence of mutations in the gene for glucocerebrosidase (GBA) in different series of subjects with synucleinopathies. In this study, an open access Parkinson repository was used to establish the incidence of GBA alterations in a different ethnic cohort with sporadic Parkinson disease (PD). METHODS: The glucocerebrosidase gene was sequenced in samples collected from 92 Chinese Parkinson disease patients from Taiwan along with 92 clinically screened controls, matched for age and ethnicity. FINDINGS: The frequency of GBA mutations among the Chinese PD probands was 4.3%, in contrast to 1.1% in Chinese controls. Mutant alleles identified included two known mutations, L444P and D409H, and two novel mutations, L174P and Q497R. INTERPRETATION: These results, ascertained in subjects from Taiwan collected in a standardized and clinically rigorous open access Parkinson disease repository and screened by direct sequencing of GBA, demonstrate that GBA mutations are also encountered in Chinese subjects with sporadic PD at a higher frequency than many other known PD genes. The study demonstrates that the association of GBA mutations with the development of parkinsonian pathology is not related to ethnic origin.

1: Arch Neurol. 2007 Mar;64(3):425-30. Links
LRRK2 exon 41 mutations in sporadic Parkinson disease in Europeans.Lesage S, Janin S, Lohmann E, Leutenegger AL, Leclere L, Viallet F, Pollak P, Durif F, Thobois S, Layet V, Vidailhet M, Agid Y, Durr A, Brice A; French Parkinson's Disease Genetics Study Group; Bonnet AM, Borg M, Broussolle E, Damier P, Destee A, Martinez M, Penet C, Rasco O, Tison F, Tranchan C, Verin M.
Institut National de la Sante et de la Recherche Medicale Unite 679, Neurology and Experimental Therapeutics, and Faculte de Medecine, Universite Pierre et Marie Curie, 75651 Paris CEDEX 13, France.

BACKGROUND: Mutations in leucine-rich repeat kinase 2 gene (LRRK2), particularly the G2019S mutation in exon 41, have been detected in familial and sporadic Parkinson disease (PD) cases. OBJECTIVES: To assess the frequency of LRRK2 exon 41 mutations in a series of sporadic PD cases from Europe and to determine the clinical features of LRRK2 mutation carriers. DESIGN: We analyzed European cases of sporadic PD for the presence of LRRK2 exon 41 mutations. These mutations were screened by denaturing high-performance liquid chromatography, and abnormal chromatograph traces were investigated by direct sequencing to determine the exact nature of the variants. Early-onset sporadic PD cases were also screened for parkin mutations. The haplotypes associated with the G2019S mutation were determined. The clinical characteristics of patients carrying LRRK2 mutations were detailed. SETTING: French Network for the Study of Parkinson Disease Genetics. Patients Three hundred twenty patients with apparently sporadic PD from Europe. MAIN OUTCOME MEASURES: Results of genetic analyses. RESULTS: We found the G2019S mutation in 6 patients and identified 2 new variants (Y2006H and T2031S) in 1 patient each. Their clinical features were similar to those of typical PD. All G2019S mutation carriers shared a common haplotype. CONCLUSIONS: The G2019S mutation is almost as frequent in sporadic cases (1.9%) as in previously reported familial cases (2.9%) in Europe and occurs in the same common founder. We identified 2 novel variants. Although the phenotype of LRRK2 mutation carriers closely resembles that of typical PD, the age at onset was younger (29 years in 1 patient) than previously described, and 3 patients were improved by deep brain stimulation.

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.

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

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