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.

Fig. 1

Gwent kindred pedigree. Numbers above individuals indicate case number. Numbers below individuals denote age at onset. Asterisk indicates cases with DNA available

Fig. 2

Neocortex and hippocampus pathology. Case 7: frontal cortex TDP-43 a and ubiquitin positive b NCI. Case 5: internal capsule white matter TDP-43 positive glia c and threads d; dentate gyrus neurons showing more ubiquitin e than TDP-43 f staining NCI. Scale bar 40 μm

Fig. 3

TDP-43 pathology in brain stem and spinal cord. Case 5, 9 a, b: spinal cord, anterior horn cell NCI. Case 9c, d: hypoglossal nucleus, “skein-like” NCI and dendritic staining. Case 5 e: hypoglossal nucleus, NCI and dendritic processes. Case 7 f: substantia nigra, NCI. Scale bar 20 μm

Fig. 4

Case 7, cerebellar pathology: Purkinje neuron with Bielschowsky staining dystrophic granular layer dendritesa and “torpedo” b. Purkinje neurons with ubiquitin staining NCI c, TDP-43 staining NCI d, e and anti-neurofilament antibody staining dystrophic dendrites within the granular layer f. Scale bar 40 μm

Fig. 5

The chromosome 9p21 shared haplotype: a the previous linkage regions for FTD/ALS families on chromosome 9 shown with the Gwent kindred shared haplotype; b the Gwent shared haplotype with the genes contained within the region