View and Standard Neuropathological Analysis of Brain Sections from Affected Pedigree Members
Total Page：16
File Type：pdf, Size：1020Kb
BMC Neurology BioMed Central Research article Open Access Pedigree with frontotemporal lobar degeneration – motor neuron disease and Tar DNA binding protein-43 positive neuropathology: genetic linkage to chromosome 9 Agnes A Luty1,2,3, John BJ Kwok1,2,3, Elizabeth M Thompson4, Peter Blumbergs5, William S Brooks1,2, Clement T Loy1,2,3, Carol Dobson- Stone1,2, Peter K Panegyres6,7, Jane Hecker8, Garth A Nicholson9,10, Glenda M Halliday1,2 and Peter R Schofield*1,2,3 Address: 1Prince of Wales Medical Research Institute, Sydney, NSW, Australia, 2University of New South Wales, Sydney, NSW, Australia, 3Garvan Institute of Medical Research, Sydney, NSW, Australia, 4SA Clinical Genetics Service, Women's and Children's Hospital, Adelaide, SA, Australia, 5Institute of Medical and Veterinary Science, Adelaide, SA, Australia, 6Neurosciences Unit, Department of Health, Perth, WA, Australia, 7Neurodegenerative Disorders Research, Subiaco, WA, Australia, 8College Grove Private Hospital, Adelaide, SA, Australia, 9Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord Hospital, Sydney, NSW, Australia and 10Faculty of Medicine, University of Sydney, Sydney, Australia Email: Agnes A Luty - [email protected]; John BJ Kwok - [email protected]; Elizabeth M Thompson - [email protected]; Peter Blumbergs - [email protected]; William S Brooks - [email protected]; Clement T Loy - [email protected]; Carol Dobson-Stone - [email protected]; Peter K Panegyres - [email protected]; Jane Hecker - [email protected]; Garth A Nicholson - [email protected]; Glenda M Halliday - [email protected]; Peter R Schofield* - [email protected] * Corresponding author Published: 29 August 2008 Received: 20 June 2008 Accepted: 29 August 2008 BMC Neurology 2008, 8:32 doi:10.1186/1471-2377-8-32 This article is available from: http://www.biomedcentral.com/1471-2377/8/32 © 2008 Luty et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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 Page 1 of 11 (page number not for citation purposes) BMC Neurology 2008, 8:32 http://www.biomedcentral.com/1471-2377/8/32 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. Background some 9q21-22 from linkage data from 5 American FTLD- Frontotemporal lobar degeneration (FTLD) is the third MND families. Subsequently, both Vance et al. [16] and most common neurodegenerative cause of dementia after Morita et al. [17] reported linkage to chromosome Alzheimer's disease (AD) and dementia with Lewy bodies 9p13.2-21.3 in large FTLD-MND kindreds from Holland (DLB). [1,2] It stems from the degeneration of neurons in and Scandinavia, respectively. Finally, three other families the superficial frontal cortex and anterior temporal lobes. were identified by Valdmanis et al. [18] with linkage to Typically, this results in several distinct clinical presenta- the chromosome 9p locus. Yan et al. [19] have also pro- tions characterised by changes in personality and behav- vided a preliminary abstract report of significant linkage iour, including a decline in manners and social skills in 15 FTLD-MND families. To date, only one gene, IFT74 representative of frontotemporal dementia, as well as lan- has been postulated to be the causative gene of chromo- guage disorders of expression and comprehension, some 9p-linked FTLD-MND. [20] However, only a single known as progressive aphasia and semantic dementia, family has been identified with a mutation in the IFT74 respectively. [3] Contributing to the spectrum of clinical gene, suggesting genetic heterogeneity in this region. phenotypes seen in FTLD is the co-occurrence of FTLD Here, we report a large FTLD-MND family from Australia with motor neurone disease (MND). [4] MND, also with linkage to chromosome 9p21.1-q21.3 and TDP-43 referred to as amyotrophic lateral sclerosis (ALS) is charac- positive pathology, further supporting the evidence for a terised by degeneration of upper and lower motor neu- novel gene associated with this type of neurodegenerative rons, leading to progressive muscle wasting, weakness and disorder. spasticity which ultimately results in profound global paralysis and death, usually due to respiratory failure. Methods Neuropathology FTLD is also a pathologically heterogeneous disorder and The brains of patients III:2, III:3 and III:12 and the spinal can be categorised into cases without detectable inclu- cord of patient III:12 were obtained at the time of autopsy sions known as dementia lacking distinctive histopathol- with consent. Routine neuropathological assessment, ogy (DLDH), cases with tau-positive pathology known as including immunohistochemical screening, was per- tauopathies, and the most frequently recognised cases formed and reviewed and standardised for the present have ubiquitin-positive, tau-negative inclusions (FTLD- study. For all cases, retrospective review of standardised U). [5] The TAR DNA binding protein (TDP-43) is a immunoperoxidase slides using antibodies for tau nuclear protein implicated in exon splicing and transcrip- (MN1020, PIERCE, USA, diluted 1:10,000/cresyl violet), tion regulation, [6] and was recently identified as a major ubiquitin (Z0458, DAKO, Denmark, diluted1:200/cresyl protein component of the ubiquitin-immunoreactive violet), Aβ (gift from Professor Masters, University of Mel- inclusions characteristic of sporadic and familial FTLD-U, bourne, dilution 1:200/cresyl violet), and a-synuclein with and without MND, as well as in sporadic cases of (610787, Pharmigen, USA, diluted1:200/cresyl violet) MND [7-9]. Recently, mutations in the TDP-43 (TARDBP) were undertaken as previously described. [21] TDP-43 gene have recently been reported in familial and sporadic protein was visualised following microwave antigen forms of MND. [10-14] retrieval (sections were boiled for 3 min in 0.2 M citrate buffer, pH 6.0) using commercially available antibody There is increasing evidence that FTLD and MND may rep- (BC001487, PTG, USA, diluted 1:500), peroxidase visual- resent two phenotypic variants resulting from a common isation and counterstaining with 0.5% cresyl violet. To underlying genetic cause. This is supported by both the determine final diagnoses all cases were screened using presence of ubiquitin/TDP-43 pathology and also by current diagnostic criteria for AD, [22] dementia with genetic loci on chromosome 9 in families with FTLD and Lewy bodies, [23] FTLD, [9] MND, [24] and other neuro- MND. Hosler et al. [15] identified a region on chromo- degenerative syndromes including corticobasal degenera- Page 2 of 11 (page number not for citation purposes) BMC Neurology 2008, 8:32 http://www.biomedcentral.com/1471-2377/8/32 tion, [25] progressive supranuclear palsy [26] and vascular formed with microsatellite markers (ABI Prism Linkage dementia. [27] Mapping Set, version 2.5, MD-10). Parametric pair-wise and multipoint LOD scores were calculated using the Genetic analyses MLINK and LINKMAP computer programs in the LINK- The study was approved by the University of New South AGE 5.2 package. Autosomal dominant inheritance was Wales Human Research Ethics Committee and complies assumed with age dependent penetrance, a phenocopy with the guidelines of the National Health and Medical rate