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

Luty AA, Kwok JB, Thompson EM, Blumbergs P, Brooks WS, Loy CT, Dobson-Stone C, Panegyres PK, Hecker J, Nicholson GA, Halliday GM, Schofield PR - BMC Neurol (2008)

Bottom Line: 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.This provides the highest reported LOD scores from a single FTLD-MND pedigree.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Prince of Wales Medical Research Institute, Sydney, NSW, Australia. a.luty@powmri.edu.au

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.

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The neuropathology of case III:12. (A) C7 cervical cord showing symmetrical Wallerian degeneration of lateral corticospinal tracts and anterior corticospinal tract. Note atrophy of anterior nerve roots in comparison to dorsal nerve roots. TDP-43 immunopositive skein-like (B) and punctate (C) cytoplasmic inclusions within anterior horn cells of the spinal cord. (D) Normal TDP-43 positive nuclear staining of the anterior horn cell. (E) Anterior horn cell showing Bunina bodies. (F) Spongiosis in layers 2 and 3 of parasagittal motor cortex. (G) Residual Betz cell in motor cortex. Bar = 10 μm in B, C, D, E and G; 20 μm in F.
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Figure 3: The neuropathology of case III:12. (A) C7 cervical cord showing symmetrical Wallerian degeneration of lateral corticospinal tracts and anterior corticospinal tract. Note atrophy of anterior nerve roots in comparison to dorsal nerve roots. TDP-43 immunopositive skein-like (B) and punctate (C) cytoplasmic inclusions within anterior horn cells of the spinal cord. (D) Normal TDP-43 positive nuclear staining of the anterior horn cell. (E) Anterior horn cell showing Bunina bodies. (F) Spongiosis in layers 2 and 3 of parasagittal motor cortex. (G) Residual Betz cell in motor cortex. Bar = 10 μm in B, C, D, E and G; 20 μm in F.

Mentions: The location of the abnormal TDP-43-immunoreactive protein deposits within layer II neurons of the frontal cortex and hippocampal granule cells was identified as either cytoplasmic, intranuclear or neuritic. These features were used to classify the cases into histological subtypes according Cairns et al. [5] Histopathological examination was available for one family member with FTLD (III:3), finding TDP-43 inclusions consistent with type 2 FTLD-U [9] (Figure 2). Histopathological examination was available for one family member with MND (III:12), again finding TDP-43 inclusions in the dentate gyrus and anterior horn cells (Figure 3). The individual (III:2) with clinical Alzheimer's disease was found to have TDP-43 inclusions consistent with type 2 FTLD-U (Figure 2), with co-existing hippocampal sclerosis, as well as sufficient densities of cortical plaques and tangles but insufficient CA1 hippocampal neuritic pathology to fulfil criteria for Alzheimer's disease. Overall the severity of the FTLD-U histology for III:2 was more severe than the Alzheimer's disease histology. A detailed description of the clinical and pathological presentation of affected pedigree members is presented in Additional file 1.


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

Luty AA, Kwok JB, Thompson EM, Blumbergs P, Brooks WS, Loy CT, Dobson-Stone C, Panegyres PK, Hecker J, Nicholson GA, Halliday GM, Schofield PR - BMC Neurol (2008)

The neuropathology of case III:12. (A) C7 cervical cord showing symmetrical Wallerian degeneration of lateral corticospinal tracts and anterior corticospinal tract. Note atrophy of anterior nerve roots in comparison to dorsal nerve roots. TDP-43 immunopositive skein-like (B) and punctate (C) cytoplasmic inclusions within anterior horn cells of the spinal cord. (D) Normal TDP-43 positive nuclear staining of the anterior horn cell. (E) Anterior horn cell showing Bunina bodies. (F) Spongiosis in layers 2 and 3 of parasagittal motor cortex. (G) Residual Betz cell in motor cortex. Bar = 10 μm in B, C, D, E and G; 20 μm in F.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 3: The neuropathology of case III:12. (A) C7 cervical cord showing symmetrical Wallerian degeneration of lateral corticospinal tracts and anterior corticospinal tract. Note atrophy of anterior nerve roots in comparison to dorsal nerve roots. TDP-43 immunopositive skein-like (B) and punctate (C) cytoplasmic inclusions within anterior horn cells of the spinal cord. (D) Normal TDP-43 positive nuclear staining of the anterior horn cell. (E) Anterior horn cell showing Bunina bodies. (F) Spongiosis in layers 2 and 3 of parasagittal motor cortex. (G) Residual Betz cell in motor cortex. Bar = 10 μm in B, C, D, E and G; 20 μm in F.
Mentions: The location of the abnormal TDP-43-immunoreactive protein deposits within layer II neurons of the frontal cortex and hippocampal granule cells was identified as either cytoplasmic, intranuclear or neuritic. These features were used to classify the cases into histological subtypes according Cairns et al. [5] Histopathological examination was available for one family member with FTLD (III:3), finding TDP-43 inclusions consistent with type 2 FTLD-U [9] (Figure 2). Histopathological examination was available for one family member with MND (III:12), again finding TDP-43 inclusions in the dentate gyrus and anterior horn cells (Figure 3). The individual (III:2) with clinical Alzheimer's disease was found to have TDP-43 inclusions consistent with type 2 FTLD-U (Figure 2), with co-existing hippocampal sclerosis, as well as sufficient densities of cortical plaques and tangles but insufficient CA1 hippocampal neuritic pathology to fulfil criteria for Alzheimer's disease. Overall the severity of the FTLD-U histology for III:2 was more severe than the Alzheimer's disease histology. A detailed description of the clinical and pathological presentation of affected pedigree members is presented in Additional file 1.

Bottom Line: 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.This provides the highest reported LOD scores from a single FTLD-MND pedigree.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Prince of Wales Medical Research Institute, Sydney, NSW, Australia. a.luty@powmri.edu.au

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.

Show MeSH
Related in: MedlinePlus