Abstract
BackgroundFrontotemporal 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.MethodsClinical 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.ResultsNeuropathological 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.ConclusionOur 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.
Highlights
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
[3] Contributing to the spectrum of clinical phenotypes seen in FTLD is the co-occurrence of FTLD with motor neurone disease (MND). [4] motor neuron disease (MND), referred to as amyotrophic lateral sclerosis (ALS) is characterised by degeneration of upper and lower motor neurons, leading to progressive muscle wasting, weakness and spasticity which results in profound global paralysis and death, usually due to respiratory failure
FTLD is a pathologically heterogeneous disorder and can be categorised into cases without detectable inclusions known as dementia lacking distinctive histopathology (DLDH), cases with tau-positive pathology known as tauopathies, and the most frequently recognised cases have ubiquitin-positive, tau-negative inclusions (FTLDU)
Summary
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). There is increasing evidence that FTLD and MND may represent two phenotypic variants resulting from a common underlying genetic cause This is supported by both the presence of ubiquitin/TDP-43 pathology and by genetic loci on chromosome 9 in families with FTLD and MND. We report a large FTLD-MND family from Australia with linkage to chromosome 9p21.1-q21.3 and TDP-43 positive pathology, further supporting the evidence for a novel gene associated with this type of neurodegenerative disorder
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