Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p

Abstract

Frontotemporal dementia and amyotrophic lateral sclerosis are closely related clinical syndromes with overlapping molecular pathogenesis. Several families have been reported with members affected by frontotemporal dementia, amyotrophic lateral sclerosis or both, which show genetic linkage to a region on chromosome 9p21. Recently, two studies identified the FTD/ALS gene defect on chromosome 9p as an expanded GGGGCC hexanucleotide repeat in a non-coding region of the chromosome 9 open reading frame 72 gene (C9ORF72). In the present study, we provide detailed analysis of the clinical features and neuropathology for 16 unrelated families with frontotemporal dementia caused by the C9ORF72 mutation. All had an autosomal dominant pattern of inheritance. Eight families had a combination of frontotemporal dementia and amyotrophic lateral sclerosis while the other eight had a pure frontotemporal dementia phenotype. Clinical information was available for 30 affected members of the 16 families. There was wide variation in age of onset (mean = 54.3, range = 34-74 years) and disease duration (mean = 5.3, range = 1-16 years). Early diagnoses included behavioural variant frontotemporal dementia (n = 15), progressive non-fluent aphasia (n = 5), amyotrophic lateral sclerosis (n = 9) and progressive non-fluent aphasia-amyotrophic lateral sclerosis (n = 1). Heterogeneity in clinical presentation was also common within families. However, there was a tendency for the phenotypes to converge with disease progression; seven subjects had final clinical diagnoses of both frontotemporal dementia and amyotrophic lateral sclerosis and all of those with an initial progressive non-fluent aphasia diagnosis subsequently developed significant behavioural abnormalities. Twenty-one affected family members came to autopsy and all were found to have transactive response DNA binding protein with M(r) 43 kD (TDP-43) pathology in a wide neuroanatomical distribution. All had involvement of the extramotor neocortex and hippocampus (frontotemporal lobar degeneration-TDP) and all but one case (clinically pure frontotemporal dementia) had involvement of lower motor neurons, characteristic of amyotrophic lateral sclerosis. In addition, a consistent and relatively specific pathological finding was the presence of neuronal inclusions in the cerebellar cortex that were ubiquitin/p62-positive but TDP-43-negative. Our findings indicate that the C9ORF72 mutation is a major cause of familial frontotemporal dementia with TDP-43 pathology, that likely accounts for the majority of families with combined frontotemporal dementia/amyotrophic lateral sclerosis presentation, and further support the concept that frontotemporal dementia and amyotrophic lateral sclerosis represent a clinicopathological spectrum of disease with overlapping molecular pathogenesis.

Figure 1

Age of onset by generation. There was a trend for the age of onset in each subsequent generation to be younger (ANOVA, P = 0.14). Boxes represent the 25–75th percentile, whiskers represent 95% confidence interval and circles are individual outliers.

Figure 2

Evolution of clinical diagnoses. There was a tendency for the clinical phenotypes to converge with disease progression. AD = Alzheimer's disease; bvFTD = behavioural variant frontotemporal dementia; EtOH = alcohol related; MCI = mild cognitive impairment.

Figure 3

Neuroimaging on illustrative Family member 3. MRI at the age of 54 (A). Top: T₁ axial images at the level of hippocampus (left) and corona radiata (right), demonstrating anterior frontal and temporal lobar atrophy (left > right). Bottom: T₂ coronal images at the level of the hippocampus (left) and cerebellum (right), further demonstrating the asymmetric atrophy and showing hippocampal atrophy that is mild compared to the degree of cortical involvement. FDG-PET at the age of 54 years (B) shows hypometabolism in the frontal lobes relative to the occipital cortex at the level of the basal ganglia (left) and the cerebellum (right).

Figure 4

Neuropathological features associated with the C9ORF72 mutation. All cases showed compact and granular TDP-43-immunoreactive neuronal cytoplasmic inclusions in the neocortex, typical of FTLD-TDP type B (A). Granular neuronal pre-inclusions in neocortex layer II were common (B). A subset of cases had compact neuronal cytoplasmic inclusions, short neurites and rare lentiform neuronal intranuclear inclusions (inset) in layer II neocortex, consistent with FTLD-TDP type A (C). Compact and granular neuronal cytoplasmic inclusions in hippocampal dentate granule cells were a consistent feature (D). Lower motor neurons contained neuronal cytoplasmic inclusions with granular, filamentous (E) or compact Lewy body-like morphology (F). Small neuronal cytoplasmic inclusions and short neurites in the granule cell layer of the cerebellar cortex were immunoreactive for ubiquitin and p62, but negative for TDP-43 (G). Increased cytoplasmic staining of some lower motor neurons was seen in cases of ALS, both with and without the C9ORF72 mutation (H). In all cases of FTLD (with and without the C9ORF72 mutation) hippocampal pyramidal neurons were surrounded by coarse punctate staining, consistent with enlarged presynaptic terminals (I). Immunohistochemistry for TDP-43 (A–F), ubiquitin (G) and C9ORF72 (H and I). Scale bars: A, D–F, H and I = 25 µm; B and C = 30 µm; G = 12 µm.