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.

Isoform‐specific antibodies reveal distinct subcellular localizations of C9orf72 in amyotrophic lateral sclerosis

“…In contrast, C9-S antibody gave a very specific labeling of the nuclear membrane, clearly showing that C9-L and C9-S have different subcellular localizations in Purkinje cells. Previously published reports using commercial antibodies against C9orf72 protein have noted diffuse and granular staining in neuronal cytoplasm and neurites; however, these antibodies show high levels of nonspecific staining and are either unable to discriminate between C9-L and C9-S or are solely directed against C9-L. 11,12,15,16,40,44 Thus, our antibodies provide greatly improved detection of C9orf72 protein isoforms and have revealed distinct subcellular localizations of C9-L and C9-S. Immunohistochemical labeling of spinal cord tissue showed that the subcellular localization of C9-L in diseased motor neurons appeared unchanged in c9-ALS and non-c9-ALS cases compared to controls. However, changes in the relative intensity of staining between cases were apparent, with some c9-ALS cases showing a relative increase in labeling and others a decrease.…”

“…1,2,5,6 Patients carrying the expansion can show heterogeneous clinical presentation, and the expansion has been identified in patients with other neurological diseases. 1,2,[7][8][9][10][11][12][13][14][15][16][17][18][19] Three potential pathomechanisms have been proposed to arise from the repeat expansion in C9orf72: RNAmediated toxicity through generation of RNA foci and sequestration of RNA-binding proteins from their normal targets; expression of dipeptide repeat proteins by repeatassociated non-ATG (RAN) translation; and haploinsufficiency. 1,2,[20][21][22][23] C9orf72 generates three transcripts through alternative splicing that encode 2 protein isoforms; a long isoform of approximately 54 kDa (termed C9-L), corresponding to variants 2 (V2) and 3 (V3), and a short isoform of approximately 24 kDa (termed C9-S) corresponding to variant 1 (V1).…”

Neuron-Microglia Interactions in Motor Neuron Degeneration. The Inflammatory Hypothesis in Amyotrophic Lateral Sclerosis Revisited

“…In a diversity of phenotypes, the extrapyramidal, cerebellar, sensory or autonomic systems are also affected [12]. (See per cent of ALS patients who develop frontotemporal dementia (FTD), adds another dimension the disease's genetic and phenotypic variability [14][15][16][17]. Together with its large clinical heterogeneity (Figure 1a) even within the familiar forms [18][19][20] the absence of specific biomarkers delays ALS diagnosis and strongly limits an early neuronal therapeutic approach.…”

C9orf72-related disorders: expanding the clinical and genetic spectrum of neurodegenerative diseases

“…The finding of TDP-43 (TAR/transactive response DNA-binding protein 43) positive cytoplasmic inclusions in spinal motor neurons and eventually in glial cells, commonly associated with cytoplasmic neuronal ubiquitin-positive and Tau-negative inclusions in the cortex and spinal cord 19,31,32 . The absence of FUS and Ubiquilin 2 positive inclusions differentiate C9orf72 spectrum from other genetic forms of FTD-ALS disorders 14 .…”