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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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Pedigree diagram showing affection status and disease haplotype. Squares indicate males and circles females; filled arrow indicates proband; black symbols show individuals clinically diagnosed with dementia, either AD or FTLD; diagonal stripes, individuals diagnosed with MND; and combined black and diagonal stripes, individuals diagnosed with FTLD-MND. A diagonal line marks deceased subjects. Individual I:1, lived until his 80s, but was thought to have had some personality changes. Alleles in parentheses are inferred. 'X' indicates upper and lower recombination breakpoints that define the minimal disease haplotype.
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Figure 1: Pedigree diagram showing affection status and disease haplotype. Squares indicate males and circles females; filled arrow indicates proband; black symbols show individuals clinically diagnosed with dementia, either AD or FTLD; diagonal stripes, individuals diagnosed with MND; and combined black and diagonal stripes, individuals diagnosed with FTLD-MND. A diagonal line marks deceased subjects. Individual I:1, lived until his 80s, but was thought to have had some personality changes. Alleles in parentheses are inferred. 'X' indicates upper and lower recombination breakpoints that define the minimal disease haplotype.

Mentions: We describe an Australian family of Anglo-Celtic origin where eleven family members were affected with FTLD-MND (Figure 1). Over three generations, five family members (II:2, III:3, III:5, III:7, IV:1) presented with symptoms consistent with the behavioural variant of FTLD (Figure 1). Another two family members (III:8, III:12) presented with progressive bulbar and limb weakness consistent with MND. Two family members presented with a combination of FTLD and MND features (II:5, III:6). One of the other family member presented with early-onset dementia (II:7) and had a son with MND (III:12). Of particular interest is the eleventh affected family member. She presented with an amnestic picture and subsequently developed impairment in multiple cognitive domains including visuospatial function, prompting a clinical diagnosis of Alzheimer's disease (III:2). A full description of her clinical presentation is available [see Additional file 1]. Of the eleven affected family members, two also developed paranoid delusions in their middle age, at the beginning of their illnesses (III:6 and III:8). Average age of onset was 53 years (range 43 to 68 years) with a mean disease duration of 9 years (range 1 to 16 years), and mean age of death of 61 years (range 46 to 75 years). An overall clinical summary is provided in Table 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)

Pedigree diagram showing affection status and disease haplotype. Squares indicate males and circles females; filled arrow indicates proband; black symbols show individuals clinically diagnosed with dementia, either AD or FTLD; diagonal stripes, individuals diagnosed with MND; and combined black and diagonal stripes, individuals diagnosed with FTLD-MND. A diagonal line marks deceased subjects. Individual I:1, lived until his 80s, but was thought to have had some personality changes. Alleles in parentheses are inferred. 'X' indicates upper and lower recombination breakpoints that define the minimal disease haplotype.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2553097&req=5

Figure 1: Pedigree diagram showing affection status and disease haplotype. Squares indicate males and circles females; filled arrow indicates proband; black symbols show individuals clinically diagnosed with dementia, either AD or FTLD; diagonal stripes, individuals diagnosed with MND; and combined black and diagonal stripes, individuals diagnosed with FTLD-MND. A diagonal line marks deceased subjects. Individual I:1, lived until his 80s, but was thought to have had some personality changes. Alleles in parentheses are inferred. 'X' indicates upper and lower recombination breakpoints that define the minimal disease haplotype.
Mentions: We describe an Australian family of Anglo-Celtic origin where eleven family members were affected with FTLD-MND (Figure 1). Over three generations, five family members (II:2, III:3, III:5, III:7, IV:1) presented with symptoms consistent with the behavioural variant of FTLD (Figure 1). Another two family members (III:8, III:12) presented with progressive bulbar and limb weakness consistent with MND. Two family members presented with a combination of FTLD and MND features (II:5, III:6). One of the other family member presented with early-onset dementia (II:7) and had a son with MND (III:12). Of particular interest is the eleventh affected family member. She presented with an amnestic picture and subsequently developed impairment in multiple cognitive domains including visuospatial function, prompting a clinical diagnosis of Alzheimer's disease (III:2). A full description of her clinical presentation is available [see Additional file 1]. Of the eleven affected family members, two also developed paranoid delusions in their middle age, at the beginning of their illnesses (III:6 and III:8). Average age of onset was 53 years (range 43 to 68 years) with a mean disease duration of 9 years (range 1 to 16 years), and mean age of death of 61 years (range 46 to 75 years). An overall clinical summary is provided in Table 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