Mutaciones y EP en Uruguay primeros datos

Recientemente se han publicado los primeros estudios moleculares en pacientes uruguayos con EP. Los primeros resultados muestran que casi un 5% de los pacientes urguayos de EP tienen una de las dos mutaciones frecuentes en el gene LRRK2 (PARK8).


Parkinsonism Relat Disord. 2008 Nov 1.

LRRK2 mutations in patients with Parkinson's disease from Peru and Uruguay.

Mata IF, Cosentino C, Marca V, Torres L, Mazzetti P, Ortega O, Raggio V, Aljanati R, Buzó R, Yearout D, Dieguez E, Zabetian CP.

Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA; Department of Neurology, University of Washington, Seattle, WA, USA.

Variation in the leucine-rich repeat kinase 2 (LRRK2) gene represents the most common genetic determinant of Parkinson's disease (PD) identified to date. While the frequency and distribution of LRRK2 mutations have been well-studied in Europe and North America, few data are available from South America. To address this gap in knowledge, we screened two cohorts of patients with PD from Peru (n=240) and Uruguay (n=125) for the three most common LRRK2 mutations (R1441C, R1441G, G2019S). We identified at total of seven patients with mutations, one with R1441G, and six with G2019S. The carrier frequency was significantly greater in the Uruguayan cohort (4.8%) than in the Peruvian cohort (0.4%; p=0.007). This likely resulted from a greater admixture proportion in the Peruvian sample. Haplotype analyses suggested that G2019S was probably brought to Peru and Uruguay by European settlers. In contrast, the origin of R1441G in our cohort was not clear, as the patient with this mutation had a background haplotype that was clearly distinct from that reported in carriers from Europe and North America. Our data add to a growing body of evidence indicating that LRRK2 mutations are widely distributed across South America but might differ by region in prevalence.

Nuevos factores de riesgo genéticos para la enfermedad de Parkinson

A larga lista de variantes genéticas que reportábamos días atrás, y la aun mas larga lista en exploración, debemos agregar la confirmación de estas dos variantes que actúan como significativos factores de riesgo de EP multifactorial, es decir, aquellas formas que, en general, aparecen esporádicamente y con un inicio tardío (que constituyen la mayoría de los casos de EP).

Así como en los últimos anos se han delineado bien las formas de EP causadas por genes de efecto mayor (monogénicas o cuasi-monogénicas) parece irse conformando un “perfil genómico de riesgo” de EP, de forma similar a como se ha ido conformando para otras afecciones (fundamentalmente la enfermedad cardiovascular arteriosclerótica).


J Neural Transm. 2008 Aug;115(8):1141-8. Epub 2008 Apr 30.
A comprehensive genetic study of the proteasomal subunit S6 ATPase in German Parkinson's disease patients.
Wahl C, Kautzmann S, Krebiehl G, Strauss K, Woitalla D, Müller T, Bauer P, Riess O, Krüger R.
Laboratory of Functional Neurogenomics, Center of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tubingen, Germany.
Dysfunction of proteasomal protein degradation is involved in neurodegeneration in Parkinson's disease (PD). Recently we identified the regulatory proteasomal subunit S6 ATPase as a novel interactor of synphilin-1, which is a substrate of the ubiquitin-ligase Parkin (PARK2) and an interacting protein of alpha-synuclein (PARK1). To further investigate a potential role in the pathogenesis of PD, we performed a detailed mutation analysis of the S6 ATPase gene in a large sample of 486 German sporadic and familial PD patients. Direct sequencing revealed two novel intronic variants. An insertion/deletion variant in intron 5 of the S6 ATPase gene was more frequent in patients compared to controls. Moreover, this variant was significantly more frequent in early-onset compared to late-onset PD patients. The identification of a genetic link between a regulatory proteasomal subunit and PD further underscores the relevance of disturbed protein degradation in PD.


Hum Genet. 2008 Oct;124(3):287-8. Epub 2008 Sep 10.
LRRK2 R1628P increases risk of Parkinson's disease: replication evidence.
Tan EK, Tan LC, Lim HQ, Li R, Tang M, Yih Y, Pavanni R, Prakash KM, Fook-Chong S, Zhao Y.
Department of Neurology, Singapore General Hospital, National Neuroscience Institute, Outram Road, Singapore, 169608, Singapore. gnrtek@sgh.com.sg
We showed that the frequency of a LRRK2 variant (c.4883G > C, R1628P) was higher in Parkinson's disease (PD) compared to controls (8.4 vs. 3.4%, P = 0.046, OR 2.5, 95% CI 1.1-5.6). In the multivariate logistic regression (with adjustments made for the effect of age, age of onset, and gender), the heterozygous R1628P genotype was associated with an increased risk of PD compared to controls (OR 3.3, 95% CI 1.4- 7.9, P = 0.007). We provided an independent confirmation that the R1628P variant increases the risk of PD among Chinese.

Ensayos de Terapia Génica en Enfermedad de Parkinson

Estos son los ensayos publicados recientemente sobre Terapia Génica en EP.
Han sido realizados en modelos animales, células en cultivo y en seres humanos (Fase I).


Neurology. 2008 May 20;70(21):1980-3. Epub 2008 Apr 9.
Results from a phase I safety trial of hAADC gene therapy for Parkinson disease.
Eberling JL, Jagust WJ, Christine CW, Starr P, Larson P, Bankiewicz KS, Aminoff MJ.
Department of Molecular Imaging and Neuroscience, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. jleberling@lbl.gov
BACKGROUND: In a primate model of Parkinson disease (PD), intrastriatal infusion of an adeno-associated viral (AAV) vector containing the human aromatic l-amino acid decarboxylase (hAADC) gene results in robust gene expression. After gene transfer, low doses of systemically administered l-dopa are converted to dopamine in the transduced striatal neurons, resulting in behavioral improvement without the side effects typically associated with higher doses of l-dopa. These studies led to the initiation of a phase I safety trial. Here we report the findings for the first cohort of five patients. METHODS: Patients with moderate to advanced PD received bilateral infusion of a low dose of the AAV-hAADC vector into the putamen. PET scans using the AADC tracer, 6-[18F]fluoro-l-m-tyrosine (FMT), were performed at baseline and at 1 and 6 months after infusion as an in vivo measure of gene expression. RESULTS: PET results showed an average 30% increase in FMT uptake (K(i)(c)) in the putamen after gene transfer. Preliminary analysis of clinical data indicates a modest improvement, but absence of a control and the nonblinded analyses make interpretation difficult. CONCLUSIONS: Thus far, this gene therapy approach has been well tolerated and shows PET evidence of sustained gene expression. These initial findings demonstrate the safety of the therapy; higher doses of adeno-associated viral vector containing the human aromatic l-amino acid decarboxylase gene in the next cohort of patients may further increase dopamine production in the putamen and provide more profound clinical benefit.

Lancet. 2007 Jun 23;369(9579):2097-105.
Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson's disease: an open label, phase I trial.
Kaplitt MG, Feigin A, Tang C, Fitzsimons HL, Mattis P, Lawlor PA, Bland RJ, Young D, Strybing K, Eidelberg D, During MJ.
Department of Neurological Surgery, Weill Medical College of Cornell University, New York, NY, USA.
BACKGROUND: Dopaminergic neuronal loss in Parkinson's disease leads to changes in the circuitry of the basal ganglia, such as decreased inhibitory GABAergic input to the subthalamic nucleus. We aimed to measure the safety, tolerability, and potential efficacy of transfer of glutamic acid decarboxylase (GAD) gene with adeno-associated virus (AAV) into the subthalamic nucleus of patients with Parkinson's disease. METHODS: We did an open label, safety and tolerability trial of unilateral subthalamic viral vector (AAV-GAD) injection in 11 men and 1 woman with Parkinson's disease (mean age 58.2, SD=5.7 years). Four patients received low-dose, four medium-dose, and four high-dose AAV-GAD at New York Presbyterian Hospital. Inclusion criteria consisted of Hoehn and Yahr stage 3 or greater, motor fluctuations with substantial off time, and age 70 years or less. Patients were assessed clinically both off and on medication at baseline and after 1, 3, 6, and 12 months at North Shore Hospital. Efficacy measures included the Unified Parkinson's Disease Rating Scale (UPDRS), scales of activities of daily living (ADL), neuropsychological testing, and PET imaging with 18F-fluorodeoxyglucose. The trial is registered with the ClinicalTrials.gov registry, number NCT00195143. FINDINGS: All patients who enrolled had surgery, and there were no dropouts or patients lost to follow-up. There were no adverse events related to gene therapy. Significant improvements in motor UPDRS scores (p=0.0015), predominantly on the side of the body that was contralateral to surgery, were seen 3 months after gene therapy and persisted up to 12 months. PET scans revealed a substantial reduction in thalamic metabolism that was restricted to the treated hemisphere, and a correlation between clinical motor scores and brain metabolism in the supplementary motor area. INTERPRETATION: AAV-GAD gene therapy of the subthalamic nucleus is safe and well tolerated by patients with advanced Parkinson's disease, suggesting that in-vivo gene therapy in the adult brain might be safe for various neurodegenerative diseases.

J Gene Med. 2007 Jul;9(7):605-12.
Comparison of cDNA and genomic forms of tyrosine hydroxylase gene therapy of the brain with Trojan horse liposomes.
Xia CF, Chu C, Li J, Wang Y, Zhang Y, Boado RJ, Pardridge WM.
Department of Medicine, UCLA, Los Angeles, CA 90024, USA.
BACKGROUND: The present study examines whether chromosomal derived forms of therapeutic genes can be delivered to brain following intravenous administration. The brain expression of a rat tyrosine hydroxylase (TH) cDNA is compared to the brain expression of a plasmid DNA encoding the 18 kb rat TH gene. METHODS: TH gene expression is measured in cell culture and in vivo in brain in experimental Parkinson's disease (PD). A total of four eukaryotic expression plasmids encoding rat TH were engineered wherein the size of the TH expression cassette ranged from 1.5 kb, in the case of the cDNA form of the gene, to 17.5 kb, in the case of the largest size genomic construct. The TH expression plasmids were delivered to either cultured cells or to rat brain in vivo with Trojan horse liposomes (THLs), which target the non-viral plasmid DNA to cells via cell membrane receptors. RESULTS: The pattern of TH gene expression in cell culture and in vivo was similar: the cDNA form of the TH gene was fast-acting with short duration of action, and the genomic form of the TH gene was slow-acting with longer duration of action. The most sustained replacement of striatal TH enzyme activity in experimental PD was produced by combination gene therapy where both the cDNA and the genomic forms of the TH gene were administered simultaneously. CONCLUSIONS: Eukaryotic expression plasmids encoding genomic forms of therapeutic genes, as large as 18 kb, can be successfully incorporated in THLs and delivered to brain following intravenous administration.

Gene Ther. 2006 Dec;13(23):1639-44.
Koike H, Ishida A, Shimamura M, Mizuno S, Nakamura T, Ogihara T et al, Prevention of onset of Parkinson's disease by in vivo gene transfer of human hepatocyte growth factor in rodent model: a model of gene therapy for Parkinson's disease.
Division of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SNi). As neurotrophic factors support the survival and enhance the function of dopaminergic neurons, gene therapy using neurotrophic factors has become the center of interest. Thus, we focused on hepatocyte growth factor (HGF) as a neurotrophic and angiogenic growth factor. At 7 days before injection of 6-hydroxydopamine into the SNi, stereotaxic transfection of human HGF or lacZ plasmid was performed into the unilateral striatum of rats. Expression of human HGF in the injected sites could be detected in rats transfected with HGF plasmid DNA, using immunohistochemical staining. Consistently, human immunoreactive HGF protein could be detected at least up to 12 days after transfection. Interestingly, PD rats transfected with lacZ demonstrated amphetamine-induced rotational asymmetry. However, transfection of HGF plasmid DNA resulted in significant inhibition of abnormal rotation up to 24 weeks in a dose-dependent manner. Over 90% of dopaminergic neurons were lost in PD rats transfected with lacZ, whereas over 70% survived in rats transfected with HGF, as assessed by immunohistochemical staining. Overall, the present study demonstrated that overexpression of HGF prevented neuronal death in a PD rat model, providing a potential novel therapy for PD.

Riesgos familiares en Enfermedad de Parkinson

Mov Disord. 2008 Jun 15;23(8):1174-83.
Familial aggregation of Parkinson's disease: a meta-analysis.
Thacker EL, Ascherio A.
Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA. ethacker@post.harvard.edu

We sought to determine the relative risk (RR) of Parkinson's disease (PD) for having a first-degree relative with PD versus having no first-degree relative with PD. Studies of familial aggregation of PD were identified by searching Medline and other sources. From each study, RRs were extracted or calculated based on the published data. Studies were categorized according to methodological characteristics, as well as by first-degree relationship type and age at PD onset restrictions. Meta-analyses and meta-regressions were based on random effect models. Twenty-nine studies of familial aggregation of PD were identified with results for first-degree relatives. The best estimate of the RR of PD for having a first-degree relative with PD was 2.9 (95% CI: 2.2, 3.8; P = 2.2 E-14), based on the studies with the most rigorous methods. The RR for sibling pairs was 4.4 (95% CI: 3.1, 6.1; P < 1.0 E-30), while for child-parent pairs it was 2.7 (95% CI: 2.0, 3.7; P = 3.6 E-10). The RR for early onset PD was 4.7 (95% CI: 3.2, 6.8; P = 6.7 E-16), while for late onset PD it was 2.7 (95% CI: 1.9, 3.9; P = 1.8 E-8). Inclusion of methodologically less rigorous investigations tended to increase the RR estimates. Summary RRs were clearly elevated above one for all study methods, all first-degree relationship types, and all age at onset categories. Familial aggregation of PD is strong and unlikely to be due to chance or to deficiencies in study methodology.

(c) 2008 Movement Disorder Society

Asesoramiento Genético en Enfermedad de Parkinson

La Enfermedad de Parkinson (EP) es una patología neurodegenerativa compleja y multifactorial en su etiopatogenia. Si bien se consideró en un principio como improbable una base genética en la misma, trabajos de la última década han implicado a varios genes en su patogénesis, han identificado varias formas monogénicas de EP y han evidenciado un significativo componente hereditario, al menos en un subgrupo de pacientes (y familias).

Si bien la mayoría de los casos de Enfermedad de Parkinson (EP) son de presentación esporádica (no hay otros afectados en la familia) y empiezan luego de los 60 años, en algunos casos (o algunas familias) aparecen varios individuos afectados y/o la EP se inicia en la juventud. En los casos de inicio en la juventud y/o con antecedentes familiares el rol de los genes es probablemente más significativo. Estos casos son aproximadamente un 10% de los casos de EP. De todos modos, los genes influencian la aparición de EP aún en los casos sin antecedentes familiares y de inicio más tardío.

Como los genes influencian el riesgo de EP y los genes se transmiten de padres a hijos y se comparten entre hermanos, entonces los familiares de pacientes con EP tienen un riesgo aumentado de padecer la EP. Los familiares de primer grado (hijos, padres y hermanos) de pacientes con EP tienen al menos el triple de riesgo (a lo largo de su vida) de sufrir EP que otras personas. Este riesgo de recurrencia depende sobre todo de la edad de inicio de la enfermedad, aproximadamente:

–Antes de los 45 años: el riesgo para familiares de primer grado es 1/12

–Entre los 45 y 55 años: el riesgo para familiares de primer grado es 1/20

–Luego de los 65 años: el riesgo para familiares de primer grado es 1/50

Estos riesgos son promedios, por lo que en algunas famlias este riesgo puede ser tan alto como un 50% (herencia autosómica dominante) o tan bajos como 2-3% (formas multifactoriales). En la mayoría de los casos el riesgo es intermedio a estos valores y menor al 10%.

El asesoramiento genético permite analizar a cada familia en particular y calcular (al menos aproximadamente) estos riesgo para cada familia (o individuo) y discutirlos con los interesados. Los datos de presentación clínica de la afección, los datos obtenidos de la realización sistematizada de la historia familiar y los datos empíricos sore recurrencia de la afección, permiten una estimación aproximada de estos riesgos (que son, en general, significativos, solamente para los familaires de primer grado, fundamentalmente hijos y hermanos).

Adicionalmente, y en casos seleccionados, se puede recurrir a análisis de genética molecular, sobre genes (o mutaciones) específicos, que aportan datos más precisos de riesgo, pero muchas veces difíciles de interpretar. Este tipo de estudios se denominan de “Genética predictiva”, en el sentido de que conociendo el genotipo del individuo (para determinadas variantes genéticas) se puede predecir (al menos parcialmente) el fenotipo (en este caso, el riesgo de determinada enfermedad) para afecciones de inicio tardía y con un extenso período presintomático (como la EP). En estos casos las implicancias del test, las cuestiones psicoemocionales que lo acompañan, y la dificil interpretación de los resultados, obligan a un cuidadoso proceso de asesoramiento genético pre y postest.

El asesoramiento genético tradicional era esencialmente reproductivo y no tenía como objetivo primario la prevención de patologías genéticas, sino mejorar la calidad de vida de las personas o parejas que sufrían por la posibilidad de aparición de estas afecciones en su descendencia, brindándoles la posibilidad de tomar decisiones reproductivas basándose en una información fidedigna. En los últimos años, ha surgido un moderno asesoramiento genético orientado específicamente a la prevención primaria o secundaria de diversas afecciones como el cáncer u otras afecciones frecuentes vinculadas al envejecimiento. En las últimas dos décadas, al impulso del Proyecto Genoma Humano y desarrollos asociados, ha ocurrido un cambio de modelo en la Genética Médica que ha pasado de ocuparse exclusivamente de las “enfermedades genéticas” a la “genética de las enfermedades”. La moderna medicina genómica se ocupa de la interacción entre el genoma de los individuos y su ambiente en la determinación de las enfermedades, generando herramientas aplicables al diagnóstico, tratamiento, pronóstico y diseño de estrategias y programas preventivos. El amplio espectro de la medicina genómica incluye un gran número de enfermedades; entre ellas, las enfermedades cardiovasculares, la diabetes, la hipertensión, las dislipemias, la osteoporosis, la obesidad, el asma, el cáncer, las enfermedades neurodegenerativas y las enfermedades gastrointestinales, que incluyen buena parte de las patologías crónicas frecuentes y prevenibles. Entonces, el objetivo central de la medicina genómica es el asesoramiento genético individualizado para prevenir la enfermedad o la mortalidad prematura en individuos genéticamente susceptibles. En este marco, los datos fundamentales se derivan del análisis de la historia familiar y del uso de diagnósticos moleculares específicos, y éstos aportan datos relevantes para identificar individuos susceptibles, para ayudar en el diagnóstico, para seleccionar el tratamiento más adecuado y para elaborar pronósticos.

La Genética Médica (como especialidad de la Medicina) aporta una serie de herramientas que pueden ser útiles en la atención de los pacientes y familias con EP. Es altamente probable que en el futuro inmediato estas herramientas de diagnóstico, tratamiento y prevención, aumenten y se desarrollen nuevas, ya que se realiza un intensa investigación en temas vinculados a la genética de la EP.

Genética en la Enfermedad de Parkinson en Revista "Diga 33"

Revista Diga 33, Número 13

Asociaciones de polimorfismos geneticos y EP (actualizado set 08)

Desde la publicacion del libro han aparecido nuevos datos que completan la Tabla 3 (p. 23)

Aqui algunas de ellas:

DeStefano AL et al, Replication of association between ELAVL4 and Parkinson disease: the GenePD study, Hum Genet. 2008; 124(1):95-9.


Hum Genet. 2008 Aug;124(1):89-94. Epub 2008 Jun 22.
Calbindin 1, fibroblast growth factor 20, and alpha-synuclein in sporadic Parkinson's disease.
Mizuta I, Tsunoda T, Satake W, Nakabayashi Y, Watanabe M, Takeda A, Hasegawa K, Nakashima K, Yamamoto M, Hattori N, Murata M, Toda T.
Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Parkinson's disease (PD), one of the most common human neurodegenerative disorders, is characterized by the loss of dopaminergic neurons in the substantia nigra of the midbrain. Our recent case-control association study of 268 SNPs in 121 candidate genes identified alpha-synuclein (SNCA) as a susceptibility gene for sporadic PD (P = 1.7 x 10(-11)). We also replicated the association of fibroblast growth factor 20 (FGF20) with PD (P = 0.0089). To find other susceptibility genes, we added 34 SNPs to the previous screen. Of 302 SNPs in a total 137 genes, but excluding SNCA, SNPs in NDUFV2, FGF2, CALB1 and B2M showed significant association (P < p =" 7.1">


Neurology. 2008 Jul 1;71(1):28-34. Epub 2008 May 28
Haplotypes and gene expression implicate the MAPT region for Parkinson disease: the GenePD Study.
Tobin JE, Latourelle JC, Lew MF, Klein C, Suchowersky O, Shill HA, Golbe LI, Mark MH, Growdon JH, Wooten GF, Racette BA, Perlmutter JS, Watts R, Guttman M, Baker KB, Goldwurm S, Pezzoli G, Singer C, Saint-Hilaire MH, Hendricks AE, Williamson S, Nagle MW, Wilk JB, Massood T, Laramie JM, DeStefano AL, Litvan I, Nicholson G, Corbett A, Isaacson S, Burn DJ, Chinnery PF, Pramstaller PP, Sherman S, Al-hinti J, Drasby E, Nance M, Moller AT, Ostergaard K, Roxburgh R, Snow B, Slevin JT, Cambi F, Gusella JF, Myers RH.
Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA. jetobinphd@gmail.com
BACKGROUND: Microtubule-associated protein tau (MAPT) has been associated with several neurodegenerative disorders including forms of parkinsonism and Parkinson disease (PD). We evaluated the association of the MAPT region with PD in a large cohort of familial PD cases recruited by the GenePD Study. In addition, postmortem brain samples from patients with PD and neurologically normal controls were used to evaluate whether the expression of the 3-repeat and 4-repeat isoforms of MAPT, and neighboring genes Saitohin (STH) and KIAA1267, are altered in PD cerebellum. METHODS: Twenty-one single-nucleotide polymorphisms (SNPs) in the region of MAPT on chromosome 17q21 were genotyped in the GenePD Study. Single SNPs and haplotypes, including the H1 haplotype, were evaluated for association to PD. Relative quantification of gene expression was performed using real-time RT-PCR. RESULTS: After adjusting for multiple comparisons, SNP rs1800547 was significantly associated with PD affection. While the H1 haplotype was associated with a significantly increased risk for PD, a novel H1 subhaplotype was identified that predicted a greater increased risk for PD. The expression of 4-repeat MAPT, STH, and KIAA1267 was significantly increased in PD brains relative to controls. No difference in expression was observed for 3-repeat MAPT. CONCLUSIONS: This study supports a role for MAPT in the pathogenesis of familial and idiopathic Parkinson disease (PD). Interestingly, the results of the gene expression studies suggest that other genes in the vicinity of MAPT, specifically STH and KIAA1267, may also have a role in PD and suggest complex effects for the genes in this region on PD risk.


Am J Hum Genet. 2008 Feb;82(2):283-9. Epub 2008 Jan 31.
Variation in the miRNA-433 binding site of FGF20 confers risk for Parkinson disease by overexpression of alpha-synuclein.
Wang G, van der Walt JM, Mayhew G, Li YJ, Züchner S, Scott WK, Martin ER, Vance JM.
Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA.
Parkinson disease (PD) is a common neurodegenerative disorder caused by environmental and genetic factors. We have previously shown linkage of PD to chromosome 8p. Subsequently, fibroblast growth factor 20 (FGF20) at 8p21.3-22 was identified as a risk factor in several association studies. To identify the risk-conferring polymorphism in FGF20, we performed genetic and functional analysis of single-nucleotide polymorphisms within the gene. In a sample of 729 nuclear families with 1089 affected and 1165 unaffected individuals, the strongest evidence of association came from rs12720208 in the 3' untranslated region of FGF20. We show in several functional assays that the risk allele for rs12720208 disrupts a binding site for microRNA-433, increasing translation of FGF20 in vitro and in vivo. In a cell-based system and in PD brains, this increase in translation of FGF20 is correlated with increased alpha-synuclein expression, which has previously been shown to cause PD through both overexpression and point mutations. We suggest a novel mechanism of action for PD risk in which the modulation of the susceptibility gene's translation by common variations interfere with the regulation mechanisms of microRNA. We propose this is likely to be a common mechanism of genetic modulation of individual susceptibility to complex disease.


Clin Genet. 2007 Nov;72(5):387-93. Epub 2007 Sep 14.
The role of common genetic risk variants in Parkinson disease.
Tan EK.
Department of Neurology, Singapore General Hospital, National Neuroscience Institute, Singapore. gnrtek@sgh.com.sg
Despite the discovery of at least five pathogenic genes in Parkinson disease (PD), the genetic etiology in the vast majority of PD remains to be clarified. Common genetic variants could act as susceptibility risk factors. Our previous meta-analysis of PD genetic association studies, over a 30-year period yielded four genes (N-acetylcysteine 2, monoamine oxidase B, glutathione transferase, and mitochondrial tRNA), as their common variants were found to be associated with PD. More recently, international collaborative studies and meta-analysis have identified the S18Y variant of ubiquitin carboxy-terminal hydrolase L1, Rep 1 variant of alpha-synuclein and tau H1 haplotype to be genetic susceptibility risk/protective factors. However, the most significant, common genetic risk factor in PD has been its association with the leucine-rich repeat kinase-2 (LRRK2) G2385R variant. We conducted an analysis of independent studies involving 2205 PD and 1817 controls and found the average carrier rate of G2385R variant to be about 9% in PD and 4% in controls (p <>


Vilar R, Coelho H, Rodrigues E, Gama MJ, Rivera I, Taioli E, Lechner MC. Association of A313 G polymorphism (GSTP1*B) in the glutathione-S-transferase P1 gene with sporadic Parkinson's disease. Eur J Neurol. 2007 Feb;14(2):156-61
Genetic predisposition, environmental toxins and aging contribute to Parkinson's disease (PD) multifactorial etiology. Weak environmental neurotoxic factors may accumulate over time increasing the disease risk in genetically predisposed subjects. Polymorphic genes encoding drug-metabolizing-enzymes (DMEs) are considered to account for PD susceptibility by determining individual toxic response variability. In this work, the allelic distributions and genotype associations of three major brain-expressed DMEs were characterized, in sporadic PD cases and controls. No significant association was found between CYP2D6 genotype and PD, but subjects with extensive metabolizer (EM) CYP2D6 phenotype, and the variant GSTP1*B genotype were at significantly higher PD risk than the corresponding poor or intermediary metabolizers (CYP2D6 poor metabolizer phenotype+intermediary metabolizers). A significant association was observed between the GSTP1*B allele and zygosity with PD (GSTP1*A/*B- 51.58%/34.37%, odds ratio (OR) = 2.29; 95% confidence interval (95% CI) = 1.25-4.18; *B/*B- 6.32%/1.05%, OR = 10.67; 95% CI = 1.19-94.79). This association was particularly strong in the elder patients group (> or =69 year) who showed double PD risk for GSTP1*B heterozygous, whilst GSTP1*B/*B homozygous were exclusively found amongst patients. An interaction between GSTM1 and GSTP1 was observed in this late onset PD group. The present results suggest that native GSTP1 encoding the fully active transferase variant should play a relevant role in dopaminergic neuroprotection.


Am J Med Genet B Neuropsychiatr Genet. 2007 Apr 5;144(3):300-4.
Tumor necrosis factor-alpha promoter polymorphism is associated with the risk of Parkinson's disease.
Wu YR, Feng IH, Lyu RK, Chang KH, Lin YY, Chan H, Hu FJ, Lee-Chen GJ, Chen CM.
Department of Neurology, Chang Gung Memorial Hospital, Chang-Gung University College of Medicine, Taipei, Taiwan.
Inflammatory events may contribute to the pathogenesis of Parkinson's disease (PD). We conducted a case-control study in a cohort of 369 PD cases and another cohort of 326 ethnically matched controls to investigate the association of tumor necrosis factor-alpha (TNF-alpha) promoter single nucleotide polymorphisms (SNPs) with the risk of PD. The overall genotype distribution at T-1031C and C-857T sites showed significant difference between PD cases and controls (P = 0.0062 and 0.0035, respectively). However, only the more frequent -1031 CC genotype was evidently associated with PD (P = 0.0085, odds ratio: 2.96; 95% CI: 1.38-7.09). Pairwise SNP linkage disequilibrium showed -1031 and -863 sites are in strong linkage disequilibrium (D' = 0.93, Delta(2) = 0.80). Pairwise haplotype analysis among the four sites showed that -1031C-863A may act as a risk haplotype among PD cases (P = 0.0028, odds ratio: 2.18; 95% CI: 1.33-3.69). (c) 2006 Wiley-Liss, Inc.


J Neurosci Res. 2007 Apr;85(5):919-34.
Oxidative damage in nucleic acids and Parkinson's disease.
Nakabeppu Y, Tsuchimoto D, Yamaguchi H, Sakumi K.
Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan. yasuka@bioreg.kyushu-u.ac.jp
Oxidative DNA lesions, such as 8-oxoguanine (8-oxoG), accumulate in nuclear and mitochondrial genomes during aging, and such accumulation can increase dramatically in patients with Parkinson's disease (PD). To counteract oxidative damage to nucleic acids, human and rodents are equipped with three distinct enzymes. One of these, MTH1, hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-2'-deoxyguanosine triphosphate and 2-hydroxy-2'-deoxyadenosine triphosphate, to their monophosphate forms. The other two enzymes are 8-oxoG DNA glycosylase encoded by the OGG1 gene and adenine/2-hydroxyadenine DNA glycosylase encoded by the MUTYH gene. We have shown a significant increase in 8-oxoG in mitochondrial DNA as well as an elevated expression of MTH1, OGG1, and MUTYH in nigrostriatal dopaminergic neurons of PD patients, suggesting that the buildup of these lesions may cause dopamine neuron loss. We established MTH1-null mice and found that MTH1-null fibroblasts were highly susceptible to cell death caused by H(2)O(2) characterized by pyknosis and electron-dense deposits in the mitochondria, and that this was accompanied by an ongoing accumulation of 8-oxoG in nuclear and mitochondrial DNA. We also showed that MTH1-null mice exhibited an increased accumulation of 8-oxoG in striatal mitochondrial DNA, followed by more extreme neuronal dysfunction after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration than that of wild-type mice. In conclusion, oxidative damage in nucleic acids is likely to be a major risk factor for Parkinson's disease, indicating that a solid understanding of the defense mechanisms involved will enable us to develop new strategies for protecting the brain against oxidative stress. (c) 2007 Wiley-Liss, Inc.


Occup Environ Med. 2007 Oct;64(10):673-80. Epub 2007 Apr 20.
Gene-environment interactions in parkinsonism and Parkinson's disease: the Geoparkinson study.
Dick FD, De Palma G, Ahmadi A, Osborne A, Scott NW, Prescott GJ, Bennett J, Semple S, Dick S, Mozzoni P, Haites N, Wettinger SB, Mutti A, Otelea M, Seaton A, Soderkvist P, Felice A; Geoparkinson Study Group.
Department of Environmental and Occupational Medicine, University of Aberdeen, UK. f.dick@abdn.ac.uk
OBJECTIVES: To investigate associations of Parkinson's disease (PD) and parkinsonian syndromes with polymorphic genes that influence metabolism of either foreign chemical substances or dopamine and to seek evidence of gene-environment interaction effects that modify risk. METHODS: A case-control study of 959 prevalent cases of parkinsonism (767 with PD) and 1989 controls across five European centres. Occupational hygienists estimated the average annual intensity of exposure to solvents, pesticides and metals, (iron, copper, manganese), blind to disease status. CYP2D6, PON1, GSTM1, GSTT1, GSTM3, GSTP1, NQO1, CYP1B1, MAO-A, MAO-B, SOD 2, EPHX, DAT1, DRD2 and NAT2 were genotyped. Results were analysed using multiple logistic regression adjusting for key confounders. RESULTS: There was a modest but significant association between MAO-A polymorphism in males and disease risk (G vs T, OR 1.30, 95% CI 1.02 to 1.66, adjusted). The majority of gene-environment analyses did not show significant interaction effects. There were possible interaction effects between GSTM1 null genotype and solvent exposure (which were stronger when limited to PD cases only). CONCLUSIONS: Many small studies have reported associations between genetic polymorphisms and PD. Fewer have examined gene-environment interactions. This large study was sufficiently powered to examine these aspects. GSTM1 null subjects heavily exposed to solvents appear to be at increased risk of PD. There was insufficient evidence that the other gene-environment combinations investigated modified disease risk, suggesting they contribute little to the burden of PD.


Neurotoxicology. 2007 May;28(3):698-701. Epub 2007 Jan 20
Parkin polymorphisms and environmental exposure: decrease in age at onset of Parkinson's disease.
Ghione I, Di Fonzo A, Saladino F, Del Bo R, Bresolin N, Comi GP, Rango M.
Centro per il Morbo di Parkinson, Centro Dino Ferrari, Department of Neurological Sciences, University of Milan, Fondazione I.R.C.C.S., Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy.
We tested the hypothesis that parkin polymorphisms (SNPs) and environmental exposure (EE) interact to reduce the age of onset of idiopathic Parkinson disease (PD). We prospectively and consecutively enrolled a total of 81 Italian PD patients. The diagnosis of PD was based on the UK Parkinson's Disease Society's brain bank criteria. Twenty-one patients with a positive family history for PD or tremor were excluded from the study. We collected information about medical history and EE. PARK1, PARK2 genes and PARK8 (exon 41) were screened. We detected one parkin mutation in a single patient and three parkin polymorphisms in a total of 25 patients; no alpha synuclein mutations, no common mutations of LRKK2 gene were found. The mutation-positive patient has been excluded from the study. The cohort of the remaining 59 patients has been divided into four subgroups, according to the presence/absence of parkin polymorphisms and the presence/absence of environmental factors-exposure. The age of onset of PD was significantly lower in patients with both SNPs and EE as compared to patients without (62.18+/-9.5 years versus 71.62+/-8 years, p=0.024; -13%). Patients with either SNPs or EE had an intermediate age of onset. The association of parkin polymorphisms and environmental exposure has a strong effect in lowering the age of onset of PD; the effect of environmental exposure or parkin polymorphisms alone seems to influence modestly the age of onset of PD. Individuals with environmental/occupational exposure should be screened for the presence of parkin SNPs.


Acta Neurol Taiwan. 2007 Sep;16(3):150-7.
5,10-methylenetetrahydrofolate reductase C677T gene polymorphism can influence age at onset of Parkinson's disease.
Lin JJ, Yueh KC, Liu CS, Liu JT, Lin SZ.
Department of Neurology, Chushang Show-Chwan Hospital, Nantou, Taiwan. jjlinn@tcts.seed.net.tw
A case-control study was designed to investigate a possible genetic susceptibility of the MTHFR C677T polymorphism and assess whether the genetic polymorphism could be a predictor of levodopa-induced adverse effects in patients with Parkinson's disease (PD) of Chinese descent living in Taiwan. There were 94 sporadic PD patients with levodopa therapy at least for five years and 146 control subjects, matched by sex and gender, in this study. Results revealed that there were no differences of the allelic and genotypic frequencies of the MTHFR C677T polymorphism between PD patients and the controls. Analysis of age at onset stratified by MTHFR C677T polymorphism showed a trend of early age at onset in the PD patients carrying with T allele. The genetic influence was particularly significant in late-onset PD (onset age at or older than 60 years) with an early age at onset for 3.4 years. However, the MTHFR C677T polymorphism was not associated with the risk to develop dyskinesia, motor fluctuation and psychosis induced by levodopa in PD patients. In conclusion, results of the study revealed that the MTHFR C677T polymorphism could significantly influence age at onset of PD in Chinese population, but neither as a genetic susceptibility nor as a predictor of levodopa-induced adverse effects in PD.


J Gerontol A Biol Sci Med Sci. 2008 Feb;63(2):127-34.
Association of NRH:quinone oxidoreductase 2 gene promoter polymorphism with higher gene expression and increased susceptibility to Parkinson's disease.
Wang W, Le WD, Pan T, Stringer JL, Jaiswal AK.
Department of Pharmacology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
The N-ribosyldihydronicotinamide (NRH):quinone oxidoreductase 2 (NQO2) gene encodes an enzyme that catalyzes activation of quinones. Blood DNA from 80 control individuals and 118 age-matched Parkinson's disease patients were analyzed for NQO2 gene promoter polymorphisms. The results revealed three allelic variants, designated I-29, I-16, and D. These results were confirmed in fibroblast cell lines. In patients with Parkinson's disease, there was a significant increase in the frequency of the D allele, but there was no difference in the frequency of the alleles in familial compared to sporadic Parkinson's disease. The D and I-16 promoters direct higher NQO2 gene expression that results in higher enzyme activity. Overexpression of NQO2 in the catecholaminergic neuroblastoma SH-SY5Y cells resulted in increased production of reactive oxygen species when exposed to exogenous dopamine. The results suggest that the association of the D promoter with Parkinson's disease may be due to an increase in expression of the NQO2 gene.


Arch Neurol. 2008 Mar;65(3):379-82
Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders.
Mata IF, Samii A, Schneer SH, Roberts JW, Griffith A, Leis BC, Schellenberg GD, Sidransky E, Bird TD, Leverenz JB, Tsuang D, Zabetian CP.
Department of Neurology, University of Washington School of Medicine, Seattle, USA.
BACKGROUND: Mutations in the glucocerebrosidase (GBA) gene have been reported to modify risk for Parkinson disease (PD) and dementia with Lewy bodies (DLB). However, these findings have not been consistently replicated, and most studies have had substantial methodological shortcomings. OBJECTIVE: To better assess the role of GBA variants in altering risk for Lewy body disorders. DESIGN: Case-control study. SETTING: Four movement disorder clinics in the Seattle, Washington, area. PARTICIPANTS: Seven hundred twenty-one patients with PD, 554 healthy control subjects, and 57 patients with DLB. MAIN OUTCOME MEASURES: Disease status and presence or absence of the 2 most common GBA mutations (N370S and L444P). RESULTS: We observed a significantly higher heterozygote frequency for the 2 mutations in patients with PD (2.9%; P <.001) and those with DLB (3.5%; P = .045) compared with control subjects (0.4%). CONCLUSION: Our findings suggest that GBA mutations exert a large effect on susceptibility for Lewy body disorders at the individual level but are associated with a modest (approximately 3%) population-attributable risk in individuals of European ancestry.


Mov Disord. 2008 Jan 30;23(2):302-5
Telomere length and risk of Parkinson's disease.
Wang H, Chen H, Gao X, McGrath M, Deer D, De Vivo I, Schwarzschild MA, Ascherio A.
Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA. hwangi@hsph.harvard.edu
We investigated whether telomere length was associated with the risk of Parkinson's disease (PD) in a case-control study (96 cases and 172 age-matched controls) nested within the Health Professionals Follow-up Study. Relative ratio of telomere repeat copy number to single-gene copy number in peripheral blood leukocytes was determined by quantitative real time PCR. Men with shorter telomeres had a lower PD risk (multivariate adjusted relative risk for the lowest vs. the highest quartile 0.33; 95% confidence interval: 0.12-0.90). Our results suggest that, contrary to telomere attrition observed in several aging-related diseases, shorter telomeres are not associated with an increased risk of PD.


Am J Med Genet B Neuropsychiatr Genet. 2008 Mar 5;147(2):216-22
The functional polymorphism of the hemoglobin-binding protein haptoglobin influences susceptibility to idiopathic Parkinson's disease.
Costa-Mallen P, Checkoway H, Zabeti A, Edenfield MJ, Swanson PD, Longstreth WT Jr, Franklin GM, Smith-Weller T, Sadrzadeh SM.
Department of Laboratory Medicine, University of Washington, Seattle, Washington 98104, USA. cstpla@u.washington.edu
Oxidative stress and iron have been widely implicated in the etiology of Parkinson's disease (PD). Hemoglobin is the richest source of iron in the body. The human Haptoglobin (Hp) protein is a plasma alpha-2 glycoprotein that removes free Hemoglobin from the circulation and tissues and is important in protection from oxidative stress, in immune system regulation, and angiogenesis. A common genetic polymorphism of Hp exists in the population, where the Hp 1-1, Hp 2-1, and Hp 2-2 forms exhibit profound functional differences. In this study, the Hp genotype corresponding to phenotypes Hp 1-1, 2-1 and 2-2 was determined in 312 idiopathic PD patients and 420 normal control subjects. A significant increase in the number of subjects carrying the Hp 2-1 genotype was present among PD patients. The distribution of Hp genotypes among PD patients (16.0% Hp 1-1, 56.4% Hp 2-1, 27.6% Hp 2-2) was significantly different from the distribution in controls (15.2% Hp 1-1, 48.1% Hp 2-1, 36.7% Hp 2-2) (chi(2) = 6.99, P = 0.030). The odds ratios for PD risk for Hp 2-1 and Hp 1-1 versus Hp 2-2 genotype were 1.51 (1.07-2.12) and 1.36 (0.86-2.15), respectively. Overall, the association of Hp-1 allele with PD resulted stronger among subjects who were never-smokers as compared to ever-smokers. Also, among ever-smokers, Hp genotypes were significantly associated with PD only among women, but not men, indicating the presence of a gene x gender x smoking interaction. To our knowledge, this is the first study that investigates the association of Hp genotypes with the risk of PD. (c) 2007 Wiley-Liss, Inc.


Ann Hum Genet. 2008 Mar;72(Pt 2):157-62.
Gene-gene interaction between FGF20 and MAOB in Parkinson disease.
Gao X, Scott WK, Wang G, Mayhew G, Li YJ, Vance JM, Martin ER.
Center for Genetic Epidemiology and Statistical Genetics, and Miami Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
The fibroblast growth factor 20 (FGF20) and monoamine oxidase B (MAOB) genes are associated with Parkinson Disease (PD) risk and both are in the dopamine bio-pathway. Therefore, we investigated the joint effect between polymorphisms in the FGF20 and MAOB genes for evidence of interaction contributing to PD risk. Fourteen polymorphisms (eight for FGF20, six for MAOB) were genotyped in 736 families and analyzed using conditional logistic regression (CLR). Significant two-locus interactions were found in females between the polymorphisms rs1721100 of FGF20 and rs1799836 of MAOB, and between the polymorphisms rs1721082 of FGF20 and rs1799836 of MAOB. The risk alleles for each SNP identified from CLR, rs1721100 C, rs1721082 T and rs1799836 A, are consistent with previous reports. Using indicator variables for the SNP genotypes, rs1721100 GC with rs1799836 AA showed significant interaction (P = 0.021), compared with the reference group rs1721100 GG with rs1799836 GG. Using an allele-dose model for the risk alleles, rs1721100 and rs1799836 showed significant interaction (P = 0.019). We found similar interaction results between rs1721082 and rs1799836. In conclusion, variants in FGF20 and MAOB show evidence of statistical interactions, which emphasizes the importance of considering them jointly in genetic analysis of PD and illustrates potential patterns of biological interaction contributing to PD risk.

Publicados

Finalmente ve la luz este librito sobre la Genética de la Enfermedad de Parkinson. Como era de esperar, en el tiempo que llevó la corrección y la impresión del mismo han aparecido nuevos datos a tener en cuenta y se han publicado decenas de nuevos trabajos. Por este motivo trataremos por este medio, el único posible, de mantener actualizado el libro e ir reuniendo la información que se debe agregar al mismo. Especialmente en los siguientes aspectos:

Decubrimientos de nuevos genes causales o como factores de susceptibilidad.
Nuevas aplicaciones diagnósticas del análisis molecular de estos genes.
Uso de herramientas de la Genética en prevención y manejo de la Enfermedad de Parkinson (EP).
Mecanismos fisiopatológicos que llevan a la EP.
Terapia Génica en EP y en modelos animales.

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