Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family

Abstract

Background: Frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) is a heritable form of FTD, but the gene(s) responsible for the majority of autosomal dominant FTD-ALS cases have yet to be found. Previous studies have identified a region on chromosome 9p that is associated with FTD and ALS.

Methods: The authors report the clinical, volumetric MRI, neuropathological and genetic features of a new chromosome 9p-linked FTD-ALS family, VSM-20.

Results: Ten members of family VSM-20 displayed heterogeneous clinical phenotypes of isolated behavioural-variant FTD (bvFTD), ALS or a combination of the two. Parkinsonism was common, with one individual presenting with a corticobasal syndrome. Analysis of structural MRI scans from five affected family members revealed grey- and white-matter loss that was most prominent in the frontal lobes, with mild parietal and occipital lobe atrophy, but less temporal lobe atrophy than in 10 severity-matched sporadic bvFTD cases. Autopsy in three family members showed a consistent and unique subtype of FTLD-TDP pathology. Genome-wide linkage analysis conclusively linked family VSM-20 to a 28.3 cM region between D9S1808 and D9S251 on chromosome 9p, reducing the published minimal linked region to a 3.7 Mb interval. Genomic sequencing and expression analysis failed to identify mutations in the 10 known and predicted genes within this candidate region, suggesting that next-generation sequencing may be needed to determine the mutational mechanism associated with chromosome 9p-linked FTD-ALS.

Conclusions: Family VSM-20 significantly reduces the region linked to FTD-ALS on chromosome 9p. A distinct pattern of brain atrophy and neuropathological findings may help to identify other families with FTD-ALS caused by this genetic abnormality.

Figure 1

Pedigree of family VSM-20. Black symbols represent patients affected with behavioural-variant frontotemporal dementia (left side filled), amyotrophic lateral sclerosis (right side filled) or both. White symbols represent unaffected individuals or at-risk individuals with unknown phenotype. The Roman numeral to the left of the pedigree denotes the generation; Arabic numbers above the individuals denote individuals. The Arabic numbers below the individuals denote age at onset for patients and either age at last examination or age at death for unaffected or at-risk individuals with unknown phenotype. The ‘+’ sign indicates individuals included in the linkage analysis. For generation IV, only individuals included in the linkage analysis are shown.

Figure 2

Patterns of brain atrophy in two VSM-20 clinical phenotypes: coronal T1-weighted MRI section at MNI coordinate y=14, and Freesurfer-derived cortical thickness maps in (A) a 54-year-old behavioural-variant frontotemporal dementia subject (II-8) as compared with 20 male normal control subjects (mean age 55.5) and (B) a 40-year-old pure amyotrophic lateral sclerosis subject (III-9) as compared with 25 female normal control subjects (mean age 59.8) displayed on rendered normal control MRI template. Coloured areas indicate cortical thickness reductions p<0.05 to p<0.001, uncorrected, versus controls.

Figure 3

Post-mortem neuropathology in affected members of VMS-20. Cerebral atrophy was most consistent in the frontal lobes (A, case II-8). The corticospinal tracts showed loss of myelin staining (B, case III-7). Ubiquitin- and TDP-43-immunoreactive neuronal cytoplasmic inclusions (NCI) were present in all layers of the frontal and temporal neocortex (arrows, C) and either had a smooth round contour or appeared to be an aggregate of coarse granules (D). TDP-43-positive granular preinclusions were most common in the upper neocortical layers (E). Swollen dystrophic neurites in the neocortex were best demonstrated with ubiquitin immunoistochemistry (F). Moderate numbers of TDP-43-immunoreactive glial cytoplasmic inclusions were present in the subcortical white matter (G). In the hippocampus, compact neuronal cytoplasmic inclusions (NCI) were numerous in the dentate granule cells (H), while hippocampal pyramidal neurons often contained more ill-defined NCI (I). NCI were present in lower motor neurons of the brainstem and spinal cord, and had a granular, filamentous (J) or compact (K) morphology. There were numerous round NCI and neurites in the cerebellar granular layer that were immunoreactive ubiquitin but not TDP-43 (L). (A) gross photograph; (B) haematoxylin and eosin with luxol fast blue; (C, F, H–L), ubiquitin immunohistochemistry; (D, E and G) TDP-43 immunohistochemistry. Scale bar: (A) 6 cm; (B) 300 μm; (C, F, H and I) 50 μm; (D, E and G) 12 μm; (J and K) 30 μm; (L) 20 μm.

Figure 4

Disguised linkage pedigree of family VSM-20. Black symbols represent patients affected with behavioural-variant frontotemporal dementia (left side filled), amyotrophic lateral sclerosis (right side filled) or both. White symbols represent unaffected individuals or at-risk individuals with unknown phenotype. The Roman numeral to the left of the pedigree denotes the generation; Arabic numbers above the individuals denote individuals. Haplotypes are based on 16 informative markers at chromosome 9p. Haplotypes for individuals I-1, I-2, II-3 and II-4 are inferred from genotype data of siblings and offspring. Detailed pedigree is shown in Figure 1.

Figure 5

Schematic presentation of chromosome 9p FTD-ALS locus. Grey bars indicate the minimal candidate regions on chromosome 9p in family VSM-20 and all other previously reported 9p-linked FTD-ALS families. Together, these studies define a 3.7 Mb interval between D9S169 and D9S251 containing 10 genes (shown in detail on the right). The five protein coding genes analysed in detail in this study are highlighted in bold.