Review article
The clinical and pathological phenotypes of frontotemporal dementia with C9ORF72 mutations

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Abstract

An expanded hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72), on chromosome 9p21, has recently been identified as a major cause of familial frontotemporal dementia (FTD). The neuropathology and clinical characteristics associated with C9ORF72 mutations are heterogeneous with the unknown pathomechanism. These cases were reported with a series of neuropathology, including TDP-43 pathology, ubiquilin (UBQLN) pathology, p62 pathology, microglial pathology, RNA-binding protein pathology and pathology associated with dipeptide-repeat (DPR) proteins. TDP-43 positive neuropathology was important in FTD patients with the mutations. Nevertheless, the majority of reports agree with a special pattern of neuropathology with p62 positive, TDP-43-negative inclusions being a consistent feature. Although subjects with the C9ORF72 mutations more frequently present with earlier onset age, earlier death, a shortened survival and a positive family history, most of the subjects present with typical clinical features of FTD. All these findings support that the C9ORF72 mutations become important newly recognized causes of FTD, providing a more detailed characterization of the associated clinical and pathological features. The following review summarizes the pathological development of FTD associated with C9ORF72, the clinical and pathological features of this cohort, some pathological mechanism hypotheses, and describes their phenotypic range and overlap with other neurodegenerative diseases.

Introduction

Frontotemporal dementia (FTD) is the most common form of primary degenerative dementia after Alzheimer's disease that affects people in middle age, accounting for up to 20% of presenile dementia cases [1], [2]. FTD is a term for a class of neurodegenerative disorders characterized by significant atrophy of the frontal and temporal lobes of the brain, which has been called frontotemporal lobar degeneration (FTLD). It presents with a spectrum of clinical manifestations: progressive changes in personality, behavior, insight, judgment, reasoning abilities, or language, with relative perseveration of episodic memory. There are several major clinical presentations of FTD, including behavioral variant frontotemporal dementia (bvFTD), progressive nonfluent aphasia, semantic dementia and corticobasal syndrome, as well as FTD with motor neuron disease (FTD-MND) [3], [4]. BvFTD is the most frequent FTD phenotype, which is present with insidious changes in personality and interpersonal conduct [5]. Currently, FTD is pathologically classified based on three main proteins which aggregated in the central nervous systems, microtubule-associated protein tau, transactive response (TAR) DNA binding protein (TDP-43), and fused in sarcoma [6]. Thus, FTD can be pathologically divided into FTD-tau, FTD-TDP and the rarest type, FTD-FUS [7]. Besides, there are a small number of FTD patients with unknown inclusions which is referred to as FTD-ubiquitin proteasome system (FTD-UPS). The majority of FTD cases are sporadic and more likely caused by multiple factors including genetic and environmental factors. Thus, no genes are identified that sufficiently explained the growing class of families in which affected members developed FTD. A significant proportion of patients with FTD-TDP develop features of motor neuron dysfunctions, especially amyotrophic lateral sclerosis (ALS) [8], [9], [10], [11]. On the other hand, frontal executive deficits and cognitive impairment are also reported in a number of ALS patients [12]. The overlap in TDP-43 pathology between ALS and FTD-TDP identified the linkage. FTD and ALS may form a disease spectrum, and the discovery of C9ORF72 mutations tied them together.

About 40% of the patients have at least one extra family member with dementia and in 13.4%, family history is consistent with an autosomal dominant inheritance [1], [13], [14], [15]. The presence of familial aggregation suggested a genetic cause for FTD. To date, molecular genetic studies identified several genes associated with FTD, including microtubule-associated-protein-tau (MAPT) gene, the progranulin (GRN) gene, the gene fused in sarcoma (FUS), charged multivesicular body protein 2B (CHMP2B) gene, the 43-kDa transactive response (TAR)-DNA-binding protein (TARDBP) gene, valosin containing protein (VCP) gene and C9ORF72 gene [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31] (Table 1). The majority of families with autosomal dominant FTD have a mutation in one of the three most important genes for FTD including GRN, MAPT, and C9ORF72. A large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72, a gene located on the short arm of chromosome 9, had recently been identified as the most common hereditary cause of chromosome 9p-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) [8], [9]. In the past two years, significant advances have been seen in the etiology, pathogenesis, pathology and clinical phenotype of FTD related with C9ORF72 gene. In this review, we summarize recent advances on the neuropathology and clinical phenotypes of FTD associated with C9ORF72 mutations.

Section snippets

Brief characterizations of C9ORF72 and underlying mechanisms

C9ORF72 is a gene of unknown function on chromosome 9p21 first detected in Finnish and North American familial FTD and ALS cohorts, and identified by two separate groups of researchers [8], [9]. The C9ORF72 gene structure spans 27, 546, 543–27, 573, 864 base pair (bp) on chromosome 9p21 and encodes eleven exons (Fig. 1). In these two studies, the C9ORF72 mutation was particularly frequent in patients and families with FTD-ALS. Based on the analysis of this region, normal individuals usually

Neuropathology

The neuropathology associated with clinical FTD is heterogeneous. Furthermore, Murray and colleagues highlighted the pathological heterogeneity of patients with the C9ORF72 mutations [11]. Information about pathology in FTD with C9ORF72 mutations is limited. In many forms of neurodegenerative diseases, neuronal aggregations of dysfunctional proteins are regarded as an important neuropathological feature. It has also been identified that FTD is proteinopathy in which the toxic aggregation and

Clinical phenotypes

To date, the spectrum of frontotemporal dementia with C9ORF72 mutations includes the behavioral variant (bvFTD), primary progressive aphasia (PPA; further sub-categorized as progressive non-fluent aphasia PNFA, semantic dementia SD), FTD-ALS, and movement disorders with extrapyramidal features such as Parkinsonism and corticobasal syndrome. The first reported linkage between 9p21-22 and FTD comes from a study carried out in families with FTD-MND patients in 2000 [78]. After more than a decade

Concluding remarks

Although the mutation was detected in September 2011, in this short space of time, further clinical and pathological details on neurodegenerative diseases related with C9ORF72 mutations were reported all over the world. The TDP-43 pathology is regarded as an important pathology in the initial researches. However, the relevance of TDP-43 accumulation in C9ORF72 mutations carriers has recently been challenged by the new identification of TDP-43 negative, ubiquitin-positive pathology which is more

Conflicts of Interest

No conflicts of interest.

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (81000544, 81171209), the Shandong Provincial Natural Science Foundation, China (ZR2010HQ004, ZR2011HZ001), and the Shandong Provincial Outstanding Medical Academic Professional Program.

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