Familial frontotemporal dementia with amyotrophic lateral sclerosis and a shared haplotype on chromosome 9p

Abstract

Families with autosomal dominant frontotemporal dementia and amyotrophic lateral sclerosis (FTD/ALS) have previously been linked to a locus on chromosome 9p21. We describe the clinical phenotype and pathology of a large family with autosomal dominant FTD/ALS with nine affected members originating from Gwent in South Wales, UK. We also further refine the locus on chromosome 9p21 using a haplotype sharing approach and assess heterogeneity in 9p21 linked families. Within this family, affected individuals present with either FTD or ALS or both diseases simultaneously. In addition there was marked phenotypic variation including ataxia, Parkinsonism, psychosis and visuo-spatial cognitive deficits. The pathological features of the three cases described were consistent with type 2 FTD pathology, as previously reported in similar families. However, we also report distinctive cerebellar and glial pathology and a significant proportion of TDP-43 negative inclusions. No mutations in known genes for FTD or ALS were found. We identified a large 4.8-megabase haplotype on chromosome 9p21, which was shared by all affected family members. This haplotype overlaps and limits the previously reported FTD/ALS linkage region on chromosome 9p21. Sequencing of this region did not identify any evidence of a pathogenic exonic mutation. This suggests that the pathogenic change affects non-coding DNA and that the disease is caused by variation in gene or protein expression.

O1‐05‐01: Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: Clinical, neuroanatomical and neuropathological features

“…The most common presenting syndrome was behavioural variant FTD, though around half of cases had an alternative syndrome at presentation, and over the course of follow-up $60% of cases manifested at least some clinical features of MND. This substantial clinical heterogeneity is in line with previous reports describing chromosome 9-linked FTLD (Momeni et al, 2006;Morita et al, 2006;Vance et al, 2006;Valdmanis et al, 2007;Luty et al, 2008;Le Ber et al, 2009;Gijselinck et al, 2010;Boxer et al, 2011;Pearson et al, 2011), and was reflected in a range of profiles of atrophy distribution and severity on neuroimaging of individual patients here. However, group-wise analyses comparing the C9ORF72 mutation cases with healthy controls and with other mutation groups suggested certain common features that may constitute a core phenotype of this mutation.…”

“…Dominant parietal lobe deficits (acalculia, apraxia) were frequent in the present C9ORF72 mutation cohort; it is of interest that clinical parietal lobe involvement was previously also found to be a common feature of GRN mutations (Rohrer et al, 2008). Previous clinical series of chromosome 9-associated FTLD and FTD-MND have reported similar findings, with initial neuropsychiatric contact in a number of cases and clinical diagnoses including Alzheimer's disease and corticobasal degeneration (Morita et al, 2006;Luty et al, 2008;Lillo et al, 2010;Boxer et al, 2011;Murray et al, 2011;Pearson et al, 2011).…”

“…Involvement of thalamus and cerebellar connections could underpin the prominent neuropsychiatric features shown by these cases (Andreasen et al, 1996;Schmahmann, 2005;Goossens et al, 2007;Straube et al, 2007;Schmahmann and Pandya, 2008;Tedesco et al, 2011), as well as episodic memory deficits ( Van der Werf et al, 2003;de Jong et al, 2008) somatic complaints, hallucinations and delusions (Kessler et al, 2009;Tedesco et al, 2011). Although none of our cases had frank cerebellar ataxia, this has been described in previous cases of chromosome 9 linked FTLD (Pearson et al, 2011).…”

“…FTLD is clinically and pathologically heterogeneous (Lillo et al, 2010;Seelaar et al, 2011) and genetic factors play a significant role, with a genetic basis implicated in up to 40% of cases in series from specialist centres (Rohrer et al, 2009;Rohrer and Warren, 2011). Discovery of disease-causing mutations in the progranulin (GRN) and microtubulin-associated protein tau (MAPT) genes left a substantial minority of cases of autosomal dominant FTLD without an identified genetic substrate; however, linkage to chromosome 9p21 has been described in a number of families with phenotypes of frontotemporal dementia (FTD), motor neuron disease (MND) or overlap syndrome (Morita et al, 2006;Vance et al, 2006;Valdmanis et al, 2007;Luty et al, 2008;Le Ber et al, 2009;Gijselinck et al, 2010;Boxer et al, 2011;Pearson et al, 2011). This elusive chromosome 9 gene has recently been identified as an expanded hexanucleotide (GGGGCC) repeat insertion in a non-coding promoter region of open reading frame 72 (C9ORF72) and is likely to account for a substantial proportion of the remaining genetic susceptibility to FTLD and MND) (Dejesus-Hernandez et al, 2011;Gijselinck et al, 2011;Renton et al, 2011).…”

A Major Genetic Factor at Chromosome 9p Implicated in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD)

“…However, most convincing evidence for the genetic overlap comes from the observation that both ALS and FTLD can occur within the same family or within a single patient of a family. More than 15 autosomal dominant families with ALS and FTLD worldwide are causally linked with a major disease locus at chromosome 9p13-p21 (ALSFTD2 locus) (Boxer et al, 2010;Gijselinck et al, 2010;Le Ber et al, 2009;Luty et al, 2008;Momeni et al, 2006;Morita et al, 2006;Pearson et al, 2011;Valdmanis et al, 2007;Vance et al, 2006). The minimally linked region in all these families is about 3.6 Mb in size containing five known protein-coding genes.…”