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Open Access Highly Accessed Research article

Pedigree with frontotemporal lobar degeneration – motor neuron disease and Tar DNA binding protein-43 positive neuropathology: genetic linkage to chromosome 9

Agnes A Luty123, John BJ Kwok123, Elizabeth M Thompson4, Peter Blumbergs5, William S Brooks12, Clement T Loy123, Carol Dobson-Stone12, Peter K Panegyres67, Jane Hecker8, Garth A Nicholson109, Glenda M Halliday12 and Peter R Schofield123*

Author Affiliations

1 Prince of Wales Medical Research Institute, Sydney, NSW, Australia

2 University of New South Wales, Sydney, NSW, Australia

3 Garvan Institute of Medical Research, Sydney, NSW, Australia

4 SA Clinical Genetics Service, Women's and Children's Hospital, Adelaide, SA, Australia

5 Institute of Medical and Veterinary Science, Adelaide, SA, Australia

6 Neurosciences Unit, Department of Health, Perth, WA, Australia

7 Neurodegenerative Disorders Research, Subiaco, WA, Australia

8 College Grove Private Hospital, Adelaide, SA, Australia

9 Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord Hospital, Sydney, NSW, Australia

10 Faculty of Medicine, University of Sydney, Sydney, Australia

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BMC Neurology 2008, 8:32  doi:10.1186/1471-2377-8-32

Published: 29 August 2008

Abstract

Background

Frontotemporal lobar degeneration (FTLD) represents a clinically, pathologically and genetically heterogenous neurodegenerative disorder, often complicated by neurological signs such as motor neuron-related limb weakness, spasticity and paralysis, parkinsonism and gait disturbances. Linkage to chromosome 9p had been reported for pedigrees with the neurodegenerative disorder, frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND). The objective in this study is to identify the genetic locus in a multi-generational Australian family with FTLD-MND.

Methods

Clinical review and standard neuropathological analysis of brain sections from affected pedigree members. Genome-wide scan using microsatellite markers and single nucleotide polymorphism fine mapping. Examination of candidate genes by direct DNA sequencing.

Results

Neuropathological examination revealed cytoplasmic deposition of the TDP-43 protein in three affected individuals. Moreover, we identify a family member with clinical Alzheimer's disease, and FTLD-Ubiquitin neuropathology. Genetic linkage and haplotype analyses, defined a critical region between markers D9S169 and D9S1845 on chromosome 9p21. Screening of all candidate genes within this region did not reveal any novel genetic alterations that co-segregate with disease haplotype, suggesting that one individual carrying a meiotic recombination may represent a phenocopy. Re-analysis of linkage data using the new affection status revealed a maximal two-point LOD score of 3.24 and a multipoint LOD score of 3.41 at marker D9S1817. This provides the highest reported LOD scores from a single FTLD-MND pedigree.

Conclusion

Our reported increase in the minimal disease region should inform other researchers that the chromosome 9 locus may be more telomeric than predicted by published recombination boundaries. Moreover, the existence of a family member with clinical Alzheimer's disease, and who shares the disease haplotype, highlights the possibility that late-onset AD patients in the other linked pedigrees may be mis-classified as sporadic dementia cases.