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ABSTRACT: The pathogenesis of amyotrophic lateral sclerosis (ALS) is considered to be multifactorial. Several epidemiological studies showed a lower incidence of ALS in women than in men. This suggests a possible protective effect of female reproductive hormones. The aim of this study was to investigate the association between female reproductive hormones and ALS. We performed a population-based, case-control study in the Netherlands between 1st January 2006 and 1st December 2009. Only women with a natural menopause were included in the analysis. A total of 209 (85 %) of 246 female patients and 672 (93 %) of 719 controls returned a questionnaire on reproductive history to calculate the reproductive time-span and lifetime endogenous estrogen exposure (calculated by subtracting the duration of pregnancies and of oral contraceptive use, and the number of post-ovulatory weeks from the reproductive time-span). 131 (63 %) patients and 430 (64 %) age-matched, population-based controls had experienced a natural menopause. Multivariate analysis showed that increasing the reproductive time-span by a year decreases the risk of ALS with an OR of 0.95 (p = 0.005). Each year longer reproductive time-span [HR 0.90 (p = 0.01)] and lifetime endogenous estrogen exposure [HR 0.96 (p = 0.025)] were associated with a longer survival of ALS patients. The positive association of a longer reproductive time-span and susceptibility and survival of ALS might imply that longer exposure to female reproductive hormones has a neuroprotective effect on motor neurons.
Journal of Neurology 09/2012; · 3.47 Impact Factor
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Michael Van Es,
Paul Van Vught,
Jan Veldink,
Peter Andersen,
Anna Birve,
Robin Lemmens,
Simon Cronin, Anneke van der Kooi,
Marianne de Visser,
Helenius Schelhaas,
Orla Hardiman,
Ioannis Ragoussis,
Diether Lambrechts,
Wim Robberecht,
John Wokke,
Roel Ophoff,
Leonard van den Berg
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ABSTRACT: A genome-wide association study (GWAS) using pooled DNA samples from 386 sporadic ALS patients and 542 controls from the USA, identified genetic variation in FGGY (FLJ10986) as a risk factor, as well as 66 additional candidate SNPs. Considering the large number of hypotheses that are tested in GWAS, independent replication of associations is crucial for identifying true-positive genetic risk factors for disease. The primary aim of this study was to study the association between FGGY and sporadic ALS in large, homogeneous populations from northern Europe. Genotyping experiments were performed using Illumina Beadchips, Sequenom iPLEX assays and Taqman technology on large case-control series from The Netherlands, Belgium, Sweden and Ireland (total: 1883 sporadic ALS patients and 2063 controls). No significant association between sporadic ALS and the six previously reported associated SNPs in FGGY was observed: rs6700125 (p=0.56), rs6690993 (p=0.30), rs10493256 (p=0.68), rs6587852 (p=0.64), rs1470407 (p=0.28) and rs333662 (p=0.44). Screening of the additional candidate loci did not yield significant associations either, with the lowest p-value in joint analysis for rs7772593 (p=0.14). We concluded that common genetic variation in FGGY is not associated with susceptibility to sporadic ALS in genetically homogeneous populations from northern Europe.
Amyotrophic Lateral Sclerosis 02/2009; · 3.40 Impact Factor
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Nicole Monnier,
Isabelle Marty,
Julien Faure,
Claudia Castiglioni,
Claude Desnuelle,
Sabrina Sacconi,
Brigitte Estournet,
Ana Ferreiro,
Norma Romero,
Annie Laquerriere,
Leila Lazaro,
Jean-Jacques Martin,
Eva Morava,
Annick Rossi, Anneke Van der Kooi,
Marianne de Visser,
Corien Verschuuren,
Joël Lunardi
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ABSTRACT: Mutations of the ryanodine receptor cause dominant and recessive forms of congenital myopathies with cores. Quantitative defects of RYR1 have been reported in families presenting with recessive forms of the disease and epigenic regulation has been recently proposed to explain potential maternal monoallelic silencing of the RYR1 gene. We investigated nine families presenting with a recessive form of the disease and showing a quantitative defect of RYR1 expression. Genetic analysis allowed the identification of a mutation on both alleles of the RYR1 gene for all patients, 15 being novel variants. We evidenced for all patients an alteration of the expression of the RYR1 gene caused by amorphic mutations responsible either for mRNA or protein instability. In seven families the variant present on the second allele was a missense mutation. In the remaining two families the second variant led to a hypomorphic expression of the RYR1 gene and was associated with a severe neonatal phenotype, pointing out the minimal amount of RYR1 needed for skeletal muscle function. Noticeably, a novel additional exon 3b was characterized in the most severely affected cases. This study showed that all cases presenting with a quantitative defect of RYR1 expression in our panel of patients affected by recessive core myopathies were caused by the presence of one recessive null allele and that variability of the phenotype depended on the nature of the mutation present on the second allele. Our study also indicated that presence of a second mutation must be investigated in sporadic cases or in dominant cases presenting with a familial clinical variability.
Human Mutation 06/2008; 29(5):670-8. · 5.69 Impact Factor
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Guglielmina Pepe,
Enrico Bertini,
Paolo Bonaldo,
Kate Bushby,
Betti Giusti,
Marianne de Visser,
Pascale Guicheney,
Giovanna Lattanzi,
Luciano Merlini,
Francesco Muntoni,
Ichizo Nishino,
Ikuya Nonaka,
Rabah Ben Yaou,
Patrizia Sabatelli,
Caroline Sewry,
Haluk Topaloglu, Anneke van der Kooi
Neuromuscular Disorders 01/2003; 12(10):984-93. · 2.80 Impact Factor
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Gisèle Bonne,
Jaqueline Capeau,
Marianne De Visser,
Denis Duboc,
Luciano Merlini,
Glenn E Morris,
Francesco Muntoni,
Dominique Recan,
Caroline Sewry,
Stefano Squarzoni,
Colin Stewart,
Beril Talim, Anneke van der Kooi,
Howard Worman,
Ketty Schwartz
Neuromuscular Disorders 03/2002; 12(2):187-94. · 2.80 Impact Factor
