C9orf72 Repeat Expansion In Patients Research Articles

Screening for the C9ORF72 expansion in Greek Huntington Disease phenocopies and controls and meta-analysis of current data.

Background:Several European studies examined the role of C9orf72 repeat expansion in patients with Huntington-disease like phenotypes (HD-L). The scope of our study is to investigate the expansion frequency in a Greek HD-L cohort and the meta-analysis of all published cases. This will be of use in genetic counseling of these cases.Methods:A cohort of 74 patients with HD-L and 67 healthy controls were screened for the C9orf72 expansion status. Case-controls comparison was assessed with the Pearson’s chi-square statistic for a 2 × 2 table.A systematic database search was conducted and seven studies, including the current study, were considered eligible for inclusion in a meta-analysis considering a total of 812 patients with HD phenocopies. Pooled mutation frequency was calculated using a Random Effects model or the Mantel-Haezsel fixed effects model, depending on the observed heterogeneity.Results:In our cohort, one patient was found to have a pathologic expansion of C9orf72, and none from the control group (chi-square: 0.91, p-value: 0.34). Pooled mutation frequency was found at 2% (CI: 1–3%) with low heterogeneity (I2:15%).Discussion:Based on this meta-analysis the recommendation for genetic testing for C9orf72 expansions is further solidified.

C9orf72-associated frontotemporal dementia in the Russian population

To evaluate the frequency of C9orf72-associated frontotemporal dementia (FTD) in the Russian population and to study clinical features of GGGGCC-repeat expansion carriers. Twenty-eight patients with FTD are included in the study: 15 with a behavioral variant of FTD (bvFTD) and 13 with a agrammatic/non-fluent variant of primary progressive aphasia (avPPA). The mean age was 62 years (34-80), the mean disease duration was 4 years (1-10). The positive family history was noted in 46% of cases. DNA diagnosis was performed using repeat-primed polymerase chain reaction. The frequency of the C9orf72 repeat expansion in patients with FTD was 14%, in patients with bvFTD 20%, in patients with avPPA 8%. The mean age of disease onset in the expansion carriers was 63 (55-75) years. The frequency of the C9orf72 repeats expansion in familial FTD cases was 31%, in sporadic cases 7%. bvFTD with parkinsonian syndrome was noted in two out of four cases, bvFTD with amyotrophic lateral sclerosis (ALS) was shown in one case, avPPA with ALS was shown in one case. One female patient with bvFTD with parkinsonian syndrome presented with cognitive fluctuations that required a differential diagnosis with Lewy body disease. This is the first study of the genetic structure of FTD in the Russian population. The prevalence and clinical characteristics of C9orf72-associated FTD were defined, in particular, the spectrum of motor symptoms was shown along with behavioral and aphasic disturbances. DNA diagnosis plays an important role in confirming the diagnosis and selection of patients for potential disease-modifying treatment.

The role of C9orf72 in neurodegenerative disorders: a systematic review, an updated meta-analysis, and the creation of an online database

A pathologic expansion of a noncoding GGGGCC hexanucleotide repeat of the C9orf72 gene has been strongly associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) cases predominantly in Caucasian populations. In the last decade, scientific interest had been drawn to this gene and many studies conducted have shown a possible correlation with other neurodegenerative diseases as well. We performed an extensive literature search for C9orf72 mutation and its frequency in various neurological and psychiatric diseases. In addition, we performed a meta-analysis of the data related to ALS and familial ALS. An online cloud-based database and an interactive map were developed. The overall mutation frequency of C9orf72 is 20% for familial FTD, 16% for familial ALS and around 6%–8% for sporadic ALS and FTD. The updated meta-analysis that we performed showed that the pooled frequency of C9orf72 repeat expansion in patients with familial ALS was 23% (CI: 18%–28%) and in patients with sporadic ALS 3% (CI: 3%–4%). The subgroup analysis regarding the origin of the population revealed significant differences between Caucasian and Asian patients. Our analysis supports the direct causal relation of the C9orf72 expansion in ALS and FTD. On the contrary, the role of C9orf72 in other neurodegenerative disorders remains controversial. The system that we developed—the online database and the interactive map—is hopefully a stepping stone for an ever-growing platform that will aid scientists from all over the world in contributing to the meta-analysis of C9orf72-related publications.

No C9orf72 repeat expansion in patients with primary progressive multiple sclerosis

Pathological repeat expansion (RE) of the C9orf72 hexanucleotide sequence is associated to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia disease continuum, although other heterogeneous clinical phenotypes have been documented. The occurrence of multiple sclerosis (MS) in some C9orf72 carriers with a more severe ALS disease course has suggested a possible modifying role for MS. However, C9orf72 RE seems not to play a role in MS pathogenesis. In this study, we screened C9orf72 in 189 Italian patients with primary progressive MS (PPMS), a rare clinical form characterized by less inflammation over neurodegenerative features. We failed to detect C9orf72 RE, but a significant representation of intermediate alleles (≥ 20 units) was observed in our PPMS cohort (2.1%) compared to healthy controls (0%, p < 0.05). In the normal range, allele distribution showed a trimodal pattern (2,5,8-repeat units) in PPMS and healthy controls with no significant difference. Our findings further demonstrate that C9orf72 RE is not genetically associated to MS spectrum, but suggest that intermediate alleles may represent risk factors as already reported for Parkinson disease.

Identification of C9orf72 repeat expansions in patients with amyotrophic lateral sclerosis and frontotemporal dementia in mainland China

The GGGGCC repeat expansion in the C9orf72 gene was recently identified as a major cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in white populations. To estimate the frequency of hexanucleotide repeats in patients with ALS and FTD from mainland China, we screened for C9orf72 in a cohort of 128 patients and 150 control subjects using the repeat-primed polymerase chain reaction method. We observed pathogenic repeat expansions in a family with ALS-FTD and in a patient with sporadic FTD. In the family with ALS-FTD, the proband and the 2 asymptomatic siblings exhibited C9orf72 repeat expansions, and the clinical feature of the proband was characterized by pure motor syndrome with no cognitive impairment. The patient with sporadic FTD presented primarily with deteriorating behavior and mental status. Genotype analysis revealed that the proband shared the previously reported 20-single nucleotide polymorphism risk haplotype, whereas the patient with sporadic FTD carried all single nucleotide polymorphisms except rs2814707-A. To our knowledge, this study is the first to report 2 C9orf72 mutation patients in mainland China, and they shared the similar risk haplotype identified in white populations, suggesting that ALS and FTD associated with C9orf72 mutation was probably derived from a single founder.