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.
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Acknowledgments
We are grateful to members of this family for participating in this research. We are grateful for the opportunity to review clinical notes made by Prof. P. Harper, Prof. A. Compston and Dr. T. Pickersgill and to Dr A. Liu (Consultant Neuroradiologist, University Hospital of Wales) for reviewing the radiology. This work was supported by the Motor Neuron Disease Assocaition (UK), the Medical Research Council (UK) Grant G0700943 and the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project Z01 AG000951-06.
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Online Resource 1: Radiological features, coronal and axial T2 MRI showing parieto-occipital atrophy in case 6 (A–D), frontotemporal atrophy in case 8 (E–H) and normal imaging in case 9 (I–L). (PDF 148 kb)
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Pearson, J.P., Williams, N.M., Majounie, E. et al. Familial frontotemporal dementia with amyotrophic lateral sclerosis and a shared haplotype on chromosome 9p. J Neurol 258, 647–655 (2011). https://doi.org/10.1007/s00415-010-5815-x
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DOI: https://doi.org/10.1007/s00415-010-5815-x