Association of APOE with age at onset of sporadic amyotrophic lateral sclerosis

Zetterberg, Henrik; Jacobsson, Johan; Rosengren, Lars; Blennow, Kaj; Andersen, Peter M.

doi:10.1016/j.jns.2008.06.025

Cited by 35 publications

(32 citation statements)

References 25 publications

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“…22 Associations have been found with the ApoE gene in European, but not in American populations. 23 Genetic factors seem to be specific for defined populations and genetic findings might be restricted to certain populations.…”

Section: Discussionmentioning

confidence: 99%

Homozygous SMN2 deletion is a protective factor in the Swedish ALS population

et al. 2012

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Abnormal survival motor neuron 1 (SMN1)-copy number has been associated with an increased risk of amyotrophic lateral sclerosis (ALS) in French and Dutch population studies. The aim of this study was to determine whether SMN gene copy number increases the risk of ALS or modulates its phenotype in a cohort of Swedish sporadic ALS (SALS) patients. In all, 502 Swedes with SALS and 502 Swedish controls matched for gender and age were enrolled. SMN1 and SMN2 gene copy numbers were studied by a semiquantitative PCR method. A genotype-phenotype comparison was performed in order to determine whether SMN genes modulate the phenotype of ALS. The results were also compared with our previously reported French cohort of ALS patients. There was no difference between Swedish patients and controls in the frequency of SMN1 and SMN2 copy numbers. The frequency of SMN1 gene copies differed significantly between the French and Swedish ALS populations. The duration of the disease was significantly longer in the Swedish cohort with homozygous deletions of SMN2 when compared with the French cohort. Abnormal SMN1 gene copy number cannot be considered as a universal genetic susceptibility factor for SALS and this result underlines the importance of reproducing association gene studies in groups from different origins. We also suggest that SMN2 gene copy number might have different effects on ALS progression in disparate human populations.

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Section: Discussionmentioning

confidence: 99%

Homozygous SMN2 deletion is a protective factor in the Swedish ALS population

et al. 2012

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“…MTHFR C677T variant was selected because linked to an increased level of homocysteine (Hcy) and, in preliminary studies, ALS subjects showed higher median Hcy levels compared to age-and sex-matched controls (Valentino et al 2010); higher Hcy levels were also correlated with a possible marker of disease progression (Zoccolella et al 2010). Finally, alleles E2, E3, and E4 of APOE gene were included in our analysis because of their association with some neurodegenerative disorders, such as ALS (Zetterberg et al 2008). Results of our study did not disclose haplotypes common to G93D mutation carriers or to wild-type subjects.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic Heterogeneity in a SOD1 G93D Italian ALS Family: An Example of Human Model to Study a Complex Disease

et al. 2010

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We report different clinical expression in seven members of a large family with amyotrophic lateral sclerosis (ALS) and the G93D mutation in exon 4 of the Cu/Zn superoxide dismutase (SOD1) gene. The ALS clinical course in the proband showed an unusually fast progression of the disease compared to the paucisymptomatic presentation associated to this mutation in the two previously Italian families described. The remaining mutation carriers did not show the aggressive clinical course displayed by the proband. We selected few genes known to be ALS modifiers searching for genetic variants that could explain the wide phenotypic diversity within the family. Exclusion of causative genes such as TDP43, FUS, PGRN and VAPB was performed too. We believe that this kind of family with contrasting phenotypes of ALS may be considered an excellent human model to study the relationship between a wider genetic profile, including modifier genes, and the clinical expression of the disease. Therefore, the novelty of our approach is also represented by the study of a single family to reproduce a composite structure in which search for possible modifier genes/genetic variants linked to SOD1 mutated.

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“…Age of onset shows heritability in ALS due to SOD1 mutation, and variation in the APOE gene has been associated with the age at which ALS manifests [133]. Variation in the KIFAP3 gene has been associated with survival in a GWAS study [63], but this was not replicated in a subsequent study [110], although association with the primary lateral sclerosis (PLS) phenotype was [86].…”

Section: Modifier Genesmentioning

confidence: 99%

The genetics and neuropathology of amyotrophic lateral sclerosis

et al. 2012

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons leading to death from respiratory failure within about 3 years of symptom onset. A family history of ALS is obtained in about 5 % but the distinction between familial and apparently sporadic ALS is artificial and genetic factors play a role in all types. For several years, only one gene was known to have a role in ALS pathogenesis, SOD1. In the last few years there has been a rapid advance in our genetic knowledge of the causes of ALS, and the relationship of the genetic subtypes with pathological subtypes and clinical phenotype. Mutations in the gene for TDP-43 protein, TARDBP, highlight this, with pathology mimicking closely that found in other types of ALS, and a phenotypic spectrum that includes frontotemporal dementia. Mutations in the FUS gene, closely related to TDP-43, lead to a similar clinical phenotype but distinct pathology, so that the three pathological groups represented by SOD1, TARDBP, and FUS are distinct. In this review, we explore the genetic architecture of ALS, highlight some of the genes implicated in pathogenesis, and describe their phenotypic range and overlap with other diseases.

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Association of APOE with age at onset of sporadic amyotrophic lateral sclerosis

Cited by 35 publications

References 25 publications

Homozygous SMN2 deletion is a protective factor in the Swedish ALS population

Homozygous SMN2 deletion is a protective factor in the Swedish ALS population

Phenotypic Heterogeneity in a SOD1 G93D Italian ALS Family: An Example of Human Model to Study a Complex Disease

The genetics and neuropathology of amyotrophic lateral sclerosis

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