Association between centromeric deletions of the <i>SMN</i> gene and sporadic adult‐onset lower motor neuron disease

Moulard, Bruno; Salachas, François; Chassande, B.; Briolotti, Valérie; Meininger, Vincent; Malafosse, Alain; Camu, William

doi:10.1002/ana.410430513

Cited by 71 publications

(48 citation statements)

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“…[9][10][11] Although non-significant, the frequency of homozygous SMN2 deletion was lower in the Swedish than in the French ALS patients (5.8 vs 9.0%, P¼0.15, Table 1). Genotype-Phenotype correlation analysis showed that survival was longer in Swedish patients (n¼27) than French patients (n¼50) with homozygous SMN2 deletion (37.6 (27.0-46.4) months vs 27.0 (19.1-32.1) months, P¼0.039, Table 3, Figure 1).…”

Section: Resultsmentioning

confidence: 84%

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: Resultsmentioning

confidence: 84%

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

et al. 2012

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“…Few genetic factors that modify ALS survival are reported (19,20,47); none were identified in the previous ALS genome analyses (21)(22)(23)(24)46). The identification of KIFAP3 as a determinant of progression rate of sporadic ALS is therefore promising; insights into this pathway may provide new targets for therapies to slow this devastating disease, for example, by reducing levels of KIFAP3 expression or modifying its interactions with 1 or more protein binding partners.…”

Section: Discussionmentioning

confidence: 99%

“…The cause of sporadic ALS is thought to be multifactorial, with environmental, infectious and genetic etiologies. Reported associations with variants in diverse genes (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) have proven difficult to replicate. Advances in the technology for large-scale genotyping of single nucleotide polymorphisms (SNPs) have facilitated unbiased, genome-wide association studies.…”

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confidence: 99%

Reduced expression of the Kinesin-Associated Protein 3 ( KIFAP3 ) gene increases survival in sporadic amyotrophic lateral sclerosis

Landers

Melki

Meininger

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Amyotrophic lateral sclerosis is a degenerative disorder of motor neurons that typically develops in the 6th decade and is uniformly fatal, usually within 5 years. To identify genetic variants associated with susceptibility and phenotypes in sporadic ALS, we performed a genome-wide SNP analysis in sporadic ALS cases and controls. A total of 288,357 SNPs were screened in a set of 1,821 sporadic ALS cases and 2,258 controls from the U.S. and Europe. Survival analysis was performed using 1,014 deceased sporadic cases. Top results for susceptibility were further screened in an independent sample set of 538 ALS cases and 556 controls. SNP rs1541160 within the KIFAP3 gene (encoding a kinesin-associated protein) yielded a genomewide significant result (P ‫؍‬ 1.84 ؋ 10 ؊8 ) that withstood Bonferroni correction for association with survival. Homozygosity for the favorable allele (CC) conferred a 14.0 months survival advantage. Sequence, genotypic and functional analyses revealed that there is linkage disequilibrium between rs1541160 and SNP rs522444 within the KIFAP3 promoter and that the favorable alleles of rs1541160 and rs522444 correlate with reduced KIFAP3 expression. No SNPs were associated with risk of sporadic ALS, site of onset, or age of onset. We have identified a variant within the KIFAP3 gene that is associated with decreased KIFAP3 expression and increased survival in sporadic ALS. These findings support the view that genetic factors modify phenotypes in this disease and that cellular motor proteins are determinants of motor neuron viability.genome-wide association study ͉ single nucleotide polymorphism A myotrophic lateral sclerosis (ALS) is an age-dependent, degenerative disorder of motor neurons (1) that typically develops in the 6th decade and is uniformly fatal, usually within 5 years (2). Approximately 10% of ALS cases are dominantly inherited (3); 20% of these are caused by mutations in the gene encoding copper/zinc superoxide dismutase 1 (SOD1) (4); mutations in the TARDBP gene (5, 6) account for Ϸ5% of cases. Rare familial cases arise from mutations in genes encoding the vesicle-associated membrane associated protein B (7), alsin (a RAB5-guanine nucleotide exchange factor) (8, 9), senataxin (10) or dynactin (11). Recently, we reported that Ϸ5% of familial ALS cases are due to mutations in the FUS/TLS gene (12, 13) whose product binds DNA and RNA, as does TARDBP. The cause of sporadic ALS is thought to be multifactorial, with environmental, infectious and genetic etiologies. Reported associations with variants in diverse genes (14-25) have proven difficult to replicate. Advances in the technology for large-scale genotyping of single nucleotide polymorphisms (SNPs) have facilitated unbiased, genome-wide association studies. Examples include the identification of IL2RA and IL7RA variants as risk factors for multiple sclerosis (26-28) and the recent reports of 6 new gene regions associated with type 2 diabetes (29)(30)(31)(32)(33)(34)(35). To test the hypothesis that commonly occurring genetic

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“…Também estes pacientes não foram avaliados quanto a alteração do gene SOD1. Moulard et al 20 encontraram, em um grupo de 14 pacientes com diagnóstico de AMP dois casos com deleção no gene SMNt (configurando o diagnóstico de AEP de início tardio) e 36% com deleção do gene SMNc, uma porcentagem muito acima daquela observada na população normal (até 5%). Nos casos de ELA (177 pacientes) e ELP (66 pacientes) os autores encontraram deleção do gene SMNc em apenas 6,2% e 1,5% respectivamente, uma percentagem próxima ao esperado, comparando-se com a população normal.…”

Section: Discussionunclassified

“…Os casos de ELA e ELP com deleção do gene SMNc não apresentaram diferenças estatísticas comparando-se com os casos sem deleção considerando a época do início, a sobrevida média, e o sexo. Em contrapartida, os casos de AMP com deleção do gene SMNc apresentaram início mais precoce da doença e quadro clínico mais grave com relação aos casos de AMP sem a deleção sugerindo que, de alguma forma, a ausência do gene SMNc interfira na patogênese da doença, ou mesmo funcionaria como um fator de predisposição genética 20 .…”

Section: Discussionunclassified

Atrofia muscular progressiva: estudo clínico e laboratorial em onze pacientes

Ferraz

Zanoteli

Oliveira

et al. 2004

Arq. Neuro-Psiquiatr.

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RESUMO -A atrofia muscular progressiva (AMP) é um tipo raro de doença do neurônio motor (DNM) com acometimento exclusivo do neurônio motor inferior (NMI) e com características clínicas bem definidas. A eletroneuromiografia é o principal exame subsidiário para a realização do diagnóstico, com demonstração de alterações neurogênicas generalizadas, agudas e crônicas. Outras doenças que mimetizam comprometimento do NMI devem ser excluídas através de investigação laboratorial ampla. Neste estudo são apresentados 11 casos de AMP (5,9% de todos os nossos casos de DNM), sendo 9 homens e 2 mulheres. O início dos sintomas ocorreu preferencialmente abaixo dos 50 anos, com média de idade de 45,5 anos. A cãibra foi o sintoma que mais comumente precedeu a fraqueza muscular. Outras queixas preliminares foram dor, fadiga muscular e fasciculações. O padrão mais freqüente de inauguração dos sintomas foi fraqueza muscular assimétrica, preferencialmente nos membros superiores. Com a evolução da doença, todos os pacientes apresentaram comprometimento bulbar. Não foi identificado nenhum fator predisponente para a doença, nem tampouco as evoluções foram distintas entre os casos. Oftalmoparesia e acometimento dos esfíncteres, sinais pouco comuns nas DNMs, foram observados em dois pacientes que se mantiveram por longo tempo em respiração artificial. As terapêuticas imunossupressoras / imunomodulatórias utilizadas (ciclofosfamida, gamaglobulina hiperimune, plasmaferese) não tiveram resultado favorável. A doença teve caráter progressivo em todos os casos. Todos os pacientes faleceram, com tempo médio de sobrevida de 44 meses. PALAVRAS-CHAVE: atrofia muscular progressiva, esclerose lateral amiotrófica, doenças do neurônio motor, doenças neuromusculares. Progressive muscular atrophy: clinical and laboratory study in eleven patientsABSTRACT -Progressive muscular atrophy (PMA), an infrequent type of motor neuron disease (MND), is a predominantly lower motor neuron degeneration, causing muscle wasting and weakness with loss of weight and fasciculations. The diagnosis is based on rigid criteria, considering clinical aspects and eletroneuromyography findings. Blood tests and radiological investigation are necessary to look for other diagnosis mimicking PMA. We herein present 11 patients with PMA (5.9% of all our MND patients), 9 men and 2 women, which onset of symptoms occurred mainly under de age of 50, with a mean of 45.5 years. Cramp was the most frequent symptom preceding muscular weakness. Muscle pain, fatigue and fasciculations were also cited as starting symptoms. Asymmetric weakness of the arms was the most frequent pattern of onset of the disease. Bulbar muscular weakness developed in all patients during the course of the disease. Predisposing factors and distinctive clinical outcome was not observed in any of the patients. Ophthalmoparesis and esfincter dysfunction were seen in two patients who had a prolonged time in artificial respiratory assistance. Imunnossupressive therapy was ineffective in all patients. Progressive course was se...

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Association between centromeric deletions of the SMN gene and sporadic adult‐onset lower motor neuron disease

Cited by 71 publications

References 24 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

Reduced expression of the Kinesin-Associated Protein 3 ( KIFAP3 ) gene increases survival in sporadic amyotrophic lateral sclerosis

Atrofia muscular progressiva: estudo clínico e laboratorial em onze pacientes

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