Analysis of C9orf72 in patients with frontotemporal dementia and amyotrophic lateral sclerosis from Argentina

Itzcovich, Tatiana; Xi, Zhengrui; Martinetto, Horacio; Chrem-Méndez, Patricio; Russo, María Julieta; Ambrosi, Bruno de; Uchitel, Osvaldo D.; Nogués, Martín; Silva, Emanuel; Rojas, Galeno; Bagnatti, Pablo; Amengual, Alejandra; Campos, Jorge; Rogaeva, Ekaterina; George-Hyslop, Peter St; Allegri, Ricardo; Sevlever, Gustavo; Surace, Ezequiel

doi:10.1016/j.neurobiolaging.2016.02.001

Cited by 18 publications

(18 citation statements)

References 15 publications

(17 reference statements)

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“…Indeed, a lesser proportion of Cubans with sporadic ALS carried the C9orf72 repeat expansion (2.1%) compared with the carrier rate reported in a pooled analysis of European sporadic ALS cases (5.1%) 6. In keeping with the known variations in the frequency of C9orf72 repeat expansions across different populations, the proportion of Cubans with sporadic ALS carrying the C9orf72 repeat expansion was comparable with the rate seen in other Latin-American populations (Brazil 3.6%38; Argentina 2%39) and greater than that seen in a pooled analysis of Asian sporadic ALS cases (0.3%) 6. No known SOD1 , TARDBP or FUS mutations were found in the Cuban ALS cohort studied.…”

Section: Discussionsupporting

confidence: 69%

Comparison of the clinical and genetic features of amyotrophic lateral sclerosis across Cuban, Uruguayan and Irish clinic-based populations

Ryan

Vaillant

McLaughlin

et al. 2019

J Neurol Neurosurg Psychiatry

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ObjectivesThis study compares the clinical characteristics of patients with amyotrophic lateral sclerosis (ALS) within three clinic-based populations from Cuba, Uruguay and Ireland and determines the impact of known ALS-associated genetic variants on phenotypic manifestations within the Cuban population.MethodsDemographic and clinical information was collected on 115 Cuban, 220 Uruguayan and 1038 Irish patients with ALS attending national specialist clinics through 1996–2017. All Cuban patients and 676 Irish patients underwent next-generation DNA sequencing and were screened for the pathogenic C9orf72 repeat expansion.ResultsThe mean age of onset was younger in the Cuban (53.0 years, 95% CI 50.4 to 55.6) and Uruguayan (58.2 years, 95% CI 56.5 to 60.0) populations compared with the Irish population (61.6 years, 95% CI 60.9 to 62.4). No differences in survival between populations were observed. 1.7 % (95% CI 0.6 to 4.1) of Cubans with ALS carried the C9orf72 repeat expansion compared with 9.9% (95% CI 7.8 to 12.0) of Irish patients with ALS (p=0.004). Other known variants identified in the Cuban population included ANG (one patient), CHCHD10 (one patient) and DCTN1 (three patients).Conclusions and relevanceThis study is the first to describe the clinical characteristics of ALS in Cuban and Uruguayan populations and report differences between the Cuban and Irish genetic signature in terms of known ALS-associated genetic variants. These novel clinical and genetic data add to our understanding of ALS across different and understudied populations.

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Section: Discussionsupporting

confidence: 69%

Comparison of the clinical and genetic features of amyotrophic lateral sclerosis across Cuban, Uruguayan and Irish clinic-based populations

Ryan

Vaillant

McLaughlin

et al. 2019

J Neurol Neurosurg Psychiatry

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“…51 In human kidney and neuroblastoma cell lines (HEK293T cells), intermediate repeats (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) have shown significantly decreased C9orf72 promoter activity compared with normal short repeats (2-6 units), 53 with lower transcriptional activity appearing more prominent in the presence of small deletions flanking the GGGGCC unit. Overall, these findings suggest that increasing repeat length can lead to decreased promoter activity via increased methylation of CpG sequences in larger repeats, with transcriptional silencing of the promoter.…”

Section: Intermediate Alleles Affect Normal Transcriptional Activity mentioning

confidence: 99%

“…In the GEO-PD consortium, Asian controls appeared to carry smaller normal repeat lengths (7)(8)(9)(10)(11)(12)(13)(14) compared with Caucasian controls (0-32). 38 Caucasian alleles frequently contain up to 43 repeats, 4 52 but in Chinese samples, >12 repeats are rarely observed.…”

Section: Variation Of Large-normal and Intermediate Repeat Lengths Bymentioning

confidence: 99%

“…Small repeat sizes of 20-22 were reportedly pathogenic in FTD, 8 Eight studies found no significant difference in mean repeat lengths between expansion-negative FTD cases and controls. [10][11][12][13][14][15][16][17] Sporadic FTD cases appear to show similar allele frequency distribution as controls, with the two-unit repeat being the most common, followed by the 5-repeat, 6-repeat, 7-repeat or 8-repeat unit. [12][13][14][15][16][17][18][19] Repeat range was higher in a Dutch study of 363 FTD patients where…”

Section: Introductionmentioning

confidence: 99%

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Intermediate C9orf72 alleles in neurological disorders: does size really matter?

Tan

2017

J Med Genet

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C9orf72 repeat expansions is a major cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) worldwide. Sizes of <20 hexanucleotide repeats are observed in controls, while up to thousands associate with disease. Intermediate C9orf72 repeat lengths, however, remain uncertain. We systematically reviewed the role of intermediate C9orf72 alleles in C9orf72-related neurological disorders. We identified 49 studies with adequate available data on normal or intermediate C9orf72 repeat length, involving subjects with FTD, ALS, Parkinson’s disease (PD), atypical parkinsonism, Alzheimer’s disease (AD) and other aetiologies. We found that, overall, normal or intermediate C9orf72 repeat lengths are not associated with higher disease risk across these disorders, but intermediate allele sizes appear to associate more frequently with neuropsychiatric phenotypes. Intermediate sizes were detected in subjects with personal or family history of FTD and/or psychiatric illness, parkinsonism complicated by psychosis and rarely in psychiatric cohorts. Length of the hexanucleotide repeat may be influenced by ethnicity (with Asian controls displaying shorter normal repeat lengths compared with Caucasians) and underlying haplotype, with more patients and controls carrying the ‘risk’ haplotype rs3849942 displaying intermediate alleles. There is some evidence that intermediate alleles display increased methylation levels and affect normal transcriptional activity of the C9orf72 promoter, but the ‘critical’ repeat size required for initiation of neurodegeneration remains unknown and requires further study. In common neurological diseases, intermediate C9orf72 repeats do not influence disease risk but may associate with higher frequency of neuropsychiatric symptoms. This has important clinical relevance as intermediate carriers pose a challenge for genetic counselling.

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“…Frontotemporal dementia (FTD) affects 15-22/100,000 Americans, 1 and is the second leading cause of early-onset dementia, characterized by severe behavior and language disturbances due to frontal and temporal neuronal death. 2 Amyotrophic lateral sclerosis (ALS), which affects approximately 5/100,000 Americans, 3 lies on a clinicopathologic continuum with FTD, 4 and causes severe motor impairment due to neuronal loss in the spinal cord and motor cortex. 5 These incurable disorders have progressive, short disease courses, spanning approximately 3 years for ALS and 3-10 years for FTD.…”

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confidence: 99%

Sex differences in the prevalence of genetic mutations in FTD and ALS

Curtis¹,

Masellis

Hsiung

et al. 2017

Neurology

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Analysis of C9orf72 in patients with frontotemporal dementia and amyotrophic lateral sclerosis from Argentina

Cited by 18 publications

References 15 publications

Comparison of the clinical and genetic features of amyotrophic lateral sclerosis across Cuban, Uruguayan and Irish clinic-based populations

Comparison of the clinical and genetic features of amyotrophic lateral sclerosis across Cuban, Uruguayan and Irish clinic-based populations

Intermediate C9orf72 alleles in neurological disorders: does size really matter?

Sex differences in the prevalence of genetic mutations in FTD and ALS

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