2 research outputs found
<i>C9orf72 </i>Repeat Expansion Discordance in 6 Multigenerational Kindreds
Background and Objectives:A hexanucleotide repeat expansion in the noncoding region of the C9orf72 gene is the most common genetically identifiable cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in populations of European ancestry. Pedigrees associated with this expansion exhibit phenotypic heterogeneity and incomplete disease penetrance, the basis of which is poorly understood. Relatives of those carrying the C9orf72 repeat expansion exhibit a characteristic cognitive endophenotype independent of carrier status. To examine whether additional shared genetic or environmental risks within kindreds could compel this observation, we have conducted a detailed cross-sectional study of the inheritance within multigenerational Irish kindreds carrying the C9orf72 repeat expansion.Methods:One hundred thirty-one familial ALS pedigrees, 59 of which carried the C9orf72 repeat expansion (45.0% [95% CI 36.7–53.5]), were identified through the Irish population-based ALS register. C9orf72 genotyping was performed using repeat-primed PCR with amplicon fragment length analysis. Pedigrees were further investigated using SNP, targeted sequencing data, whole-exome sequencing, and whole-genome sequencing.Results:We identified 21 kindreds where at least 1 family member with ALS carried the C9orf72 repeat expansion and from whom DNA was available from multiple affected family members. Of these, 6 kindreds (28.6% [95% CI 11.8–48.3]) exhibited discordant segregation. The C9orf72 haplotype was studied in 2 families and was found to segregate with the C9orf72-positive affected relative but not the C9orf72-negative affected relative. No other ALS pathogenic variants were identified within these discordant kindreds.Discussion:Family members of kindreds associated with the C9orf72 repeat expansion may carry an increased risk of developing ALS independent of their observed carrier status. This has implications for assessment and counseling of asymptomatic individuals regarding their genetic risk
Genotype-associated cerebellar profiles in ALS: focal cerebellar pathology and cerebro-cerebellar connectivity alterations
Objective Cerebellar disease burden and cerebro-cerebellar connectivity
alterations are poorly characterised in amyotrophic lateral sclerosis
(ALS) despite the likely contribution of cerebellar pathology to the
clinical heterogeneity of the condition. Methods A prospective imaging
study has been undertaken with 271 participants to systematically
evaluate cerebellar grey and white matter alterations, cerebellar
peduncle integrity and cerebro-cerebellar connectivity in ALS.
Participants were stratified into four groups: (1) patients testing
positive for GGGGCC repeat expansions in C9orf72, (2) patients carrying
an intermediate-length repeat expansion in ATXN2, (3) patients without
established ALS-associated mutations and (4) healthy controls.
Additionally, the cerebellar profile of a single patient with ALS who
had an ATXN2 allele length of 62 was evaluated. Cortical thickness, grey
matter and white matter volumes were calculated in each cerebellar
lobule complemented by morphometric analyses to characterise
genotype-associated atrophy patterns. A Bayesian segmentation algorithm
was used for superior cerebellar peduncle volumetry. White matter
diffusivity parameters were appraised both within the cerebellum and in
the cerebellar peduncles. Cerebro-cerebellar connectivity was assessed
using deterministic tractography. Results Cerebellar pathology was
confined to lobules I-V of the anterior lobe in patients with sporadic
ALS in contrast to the considerable posterior lobe and vermis disease
burden identified in C9orf72 mutation carriers. Patients with
intermediate ATXN2 expansions did not exhibit significant cerebellar
pathology. Conclusions Focal rather than global cerebellar degeneration
characterises ALS. Pathognomonic ALS symptoms which are typically
attributed to other anatomical regions, such as dysarthria, dysphagia,
pseudobulbar affect, eye movement abnormalities and cognitive deficits,
may be modulated, exacerbated or partially driven by cerebellar changes
in ALS