C9ORF72 hexanucleotide repeat expansion in ALS patients from the Central European Russia population

Abstract

Cohorts of amyotrophic lateral sclerosis (ALS) patients and control individuals of Caucasian origin from the Central European Russia (Moscow city and region) were analyzed for the presence of hexanucleotide repeat GGGGCC expansion within the first intron of the C9ORF72 gene. The presence of a large (>40) repeat expansion was found in 15% of familial ALS cases (3 of 20 unrelated familial cases) and 2.5% of sporadic ALS cases (6 of 238) but in none of control cases. These results suggest that the frequency of C9ORF72 hexanucleotide repeats expansions in the Central European Russian ALS patients is significantly lower than in Western European or Northern American ALS patients of Caucasian origin but higher than in Asian ALS patients.

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

“…9 Both patients in the latter study with 22 repeats exhibited cognitive and behavioural impairment similar to larger expansions and had family history of FTD, while two patients with 20 and 21 repeats had family history of dementia and psychiatric illness. In atypical PD or PD with psychosis, intermediate expansions (20)(21)(22)(23)(24)(25)(26)(27)(28)(29) were detected in three female cases with atypical parkinsonian syndromes (severe rigid akinetic parkinsonism) and neuropsychiatric symptoms including schizoaffective psychosis and an FTD-like dementia. 42 Unfortunately, these cases did not have pathological diagnosis.…”

“…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.…”

“…16 Homozygous 56 57 ► TDP43 formation may be 'age-related' findings; pathological studies found no expansion or intermediate alleles (20)(21)(22)(23)(24)(25)(26)(27)(28)(29) repeats) among LRRK2 G2019S carriers and AD cases with concomitant TDP43-positive inclusions. 16 Variation of large-normal and intermediate C9orf72 repeat lengths by ethnicity needs to be determined ► European haplotype exists in Asian cohorts, 25 27 49 but at a lower frequency (<2% in Chinese controls compared with 9% in European controls).…”

C9ORF72 G4C2-repeat expansion and frontotemporal dementia first reported case in Argentina

“…The paternal branch of the pedigree starts with the grandfather, who as mentioned earlier was born in Russia. Cases of ALS-C9ORF72 have been recently described in Russia, although with low prevalence (Abramycheva et al, 2015).…”

Cross-Sectional Survey of Relevant Literatures as to the Current Proposed Disease Mechanisms and Treatments of Amyotrophic Lateral Sclerosis (ALS)

“…68 In an international cross-sectional study evaluating 4448 ALS patients, 37% of individuals with FALS are in possession of this mutation, having as many as 700-1600 copies of the repeat sequence compared to controls who only have 23 copies. 69 Comparable studies have been conducted in French (46% FALS, 8% SALS), 70 Italian (46% FALS), 71 Greek (50% FALS, 8.2% SALS), 72 Turkish (18.3% FALS, 3.1% SALS), 73 Slavic (5.9% SALS), 74 and Russian (15% FALS, 2.5% SALS) 75 populations testing positive for the GGGGCC repeat. Studies on Chinese SALS populations have yielded results indicating this sequence is not correlated to their patient populations, potentially describing a predilection for the C9orf72 hexanucleotide repeat for Caucasians.…”