Frontotemporal lobar degeneration —building on breakthroughs Julie van der Zee and Christine Van Broeckhoven

Genetic research in frontotemporal lobar degeneration (FTLD) is gaining momentum. Following the discovery of a repeat expansion in the gene C9 open reading frame 72 (C9orf72), three major genes and associated disease mechanisms and inclusion body pathologies have emerged, paving the way for personalized medicine in FTLD. van der Zee, J. & Van Broeckhoven, C. Nat. Rev. Neurol. advance online publication 7 January 2014; doi:10.1038/nrneurol.2013.270

In less than a decade, immense progress has been made in unravelling the disease mech­ anisms of frontotemporal lobar degener­ ation (FTLD). The discovery 2 years ago of a repeat expansion in the gene C9 open reading frame 72 (C9orf72)1–3 represented a major leap forward in our understanding of FTLD, setting the stage in 2013 for the dis­ covery of a new mutation mechanism and a new inclusion body pathology. Testing of patient cohorts worldwide has established the C9orf72 repeat expan­ sion as the major genetic cause of FTLD, amyotrophic lateral sclerosis (ALS), and the combined syndrome of both diseases (FTLD–ALS), reaching mutation frequen­ cies of up to 29%, 50% and 88%, respec­ tively.4,5 In addition to establishing C9orf72 mutation frequency in disease subtypes, work in 2013 began to elucidate the disease mechanisms of the mutation. The GGGGCC repeat expansion is located in intron 1 fol­ lowing the noncoding exon 1, or in the regulatory region of the C9orf72 gene. Recent studies have shown that the number of repeat units in patients can range up to ­thousands of copies,6 whereas unaffected control individuals harbour two to 24 repeat units.3,5 Interestingly, repeats ranging from seven to 24 units have been suggested to pre­ dispose to disease: in vitro studies demon­ strated an inverse correlation between repeat size and gene expression starting at just nine units compared with the most common two-unit allele, with up to 50% reduction in ­expression for 24-unit alleles.5 Mutations in the granulin (GRN) gene or microtubule-associated protein tau

(MAPT) gene are known to be associated with FTLD. The identification of C9orf72 as a third major gene implicated in FTLD led Van Langenhove and colleagues to perform genotype–phenotype correlation studies in cohorts harbouring mutations in each of the genes, and to design revised guide­ lines for molecular diagnostic testing.7 Of the three genes, only C9orf72 is associated with both FTLD and ALS. Whereas carriers of GRN and MAPT mutations never present with ALS symptoms, 30% of patients with C9orf72-associated FTLD develop con­ current ALS. Importantly, in the group of patients with FTLD–ALS, C9orf72 accounts for up to 88% of patients with familial disease.3 Equally noteworthy, however, is the fact that over 70% of patients with C9orf72associated FTLD will not develop symp­ toms of ALS or other types of motor neuron disease. In the majority of patients with mutated C9orf72, the dementia phenotype is consistent with the behavioural variant of frontotemporal dementia (bvFTD). The other FTLD mutations are also most fre­ quently associated with this form of FTLD, but the bvFTD associated with C9orf72 mutations typically presents as inappropri­ ate behaviour and agitation, in contrast to bvFTD associated with GRN mutations, where apathy dominates the clinical picture. Variability in age of disease onset and disease duration between and within fami­ lies is a recurrent observation in all three major FTLD subtypes, pointing towards genetic or epigenetic modifiers that influ­ ence the clinical manifestation of these causal mutations. In the group of C9orf72


carriers, about 50% were affected by age 60 years, with penetrance reaching 90% by 70 years, although some carriers lived up to 75 years without developing apparent clinical signs of disease. In terms of disease duration, development of ALS was a strong negative prognostic factor, with reduced survival to less than 2 years after the first signs of ALS developed. Overall, the core clinical features of C9orf72-related FTLD were found to be disease onset before age 65 years, a positive family history, predomi­ nance of bvFTD, and co-incidence with ALS. Remarkably, in a Belgian FTLD cohort, up to nine in 10 patients fitting these criteria were carriers of a C9orf72 expansion.7 Clinical differentiation at the individual patient level remains challenging, but these obser­ vations can be translated into a prioritization scheme for gene testing in the framework of medical genetic diagnostics. In patients with FTLD–ALS, testing for C9orf72 repeat expansions should be performed first. C9orf72 is also the most frequent cause of bvFTD without ALS, particularly in patients who present with disinhibition. In contrast to the subtle differences in clinical presentation between C9orf72related and other subtypes of FTLD, Key advances ■■ Genotype–phenotype correlation studies in C9 open reading frame 72 (C9orf72)related frontotemporal lobar degeneration (FTLD) enabled formulation of revised guidelines for genetic diagnostic testing7 ■■ Dipeptide repeat (DPR) aggregation owing to bidirectional RAN translation of the GGGGCC repeat is the key pathological feature of C9orf72-related FTLD8 ■■ DPR-positive cytoplasmic and intranuclear neuronal inclusions show complete overlap with TAR DNA-binding protein 43 (TDP-43)-negative, p62-positive inclusions and are specific to C9orf72-related FTLD and amyotrophic lateral sclerosis9 ■■ Pathological findings suggest that RAN translation and DPR aggregation are early events in FTLD that precede and potentially trigger TDP-43 accumulation5,9 ■■ FTLD is a heterogeneous neurodegenerative brain disease—with three major genes, disease mechanisms and neuropathologies—underscoring the need for personalized medicine tailored to the patient’s molecular signature

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YEAR IN REVIEW C9orf72-related pathology shows some unique, distinctive characteristics. In addi­ tion to the TAR DNA-binding protein 43 (TDP‑43) pathology, patients show abun­ dant TDP‑43-negative, p62-positive dot-like and star-shaped inclusions, predominantly in the cerebellum, hippocampus and fronto­temporal cortex. In 2013, Mori and colleagues went on to further characterize these inclusions, and hypothesized that they may consist of aggregation-prone di­peptide repeat (DPR) proteins resulting from bidirec­tional translation from the noncoding GGGGCC repeat.8 Such bidirectional repeat translation had been described in another repeat expansion disease—spinocerebellar ataxia type 8 (SCA 8)—with a noncoding CAG repeat located in the gene ATXN8, through a mechanism of non-ATG-initiated translation, termed RAN translation. Using antibodies specific to the expected sense and antisense DPRs, the researchers dem­ onstrated that in the absence of an ATG start codon, the GGGGCC expansion is indeed bidirectionally translated into five distinct DPR proteins.8 In-depth analysis of the neuro-­anatomical distribution of the DPR and TDP‑43 pathol­ ogy showed high DPR load in the cerebellum, all neocortical regions and hippocampus, as well as some inclusions in motor neurons.9 Importantly, DPR-positive cytoplasmic and intra­nuclear neur­onal inclusions showed complete overlap with TDP‑43-negative, p62-­positive ­inclusions—in both shape and abundance—and were specific to patients with FTLD–ALS who harbour a C9orf72 repeat expansion. Finally, observation of


Mutation mechanism

DPR pathology in a rare, TDP‑43-negative Belgian carrier of a C9orf72 repeat expan­ sion5 and aggregates composed of a DPR core surrounded by TDP‑43 suggested that RAN translation and DPR aggregation are early pathological events that precede and potentially trigger TDP‑43 accumulation.8,9 As such, Mori and colleagues demon­ strated that DPR inclusion pathology is a direct consequence of the C9orf72 repeat expansion and that DPR aggregation due to RAN translation is the key pathological feature of C9orf72-related FTLD and ALS. Subsequently, they proposed that the current pathological classification and nomenclature should be revised in these patients to FTLDDPR. In addition to DPR accumulation and TDP‑43 pathology, previously proposed disease mechanisms probably also contrib­ ute, in part, to disease. These mechanisms include haplo­insufficiency through loss of gene expression3–5 and RNA toxicity caused by sequestration of RNA-binding proteins.1,10 An important next step will be to be deter­ mine the individual contribution of these four mechanisms to disease, and to charac­ terize the early and late pathological events and how they contribute to the phenotype. Over the years, it has become increas­ ingly clear that FTLD represents one of the most heterogeneous neurodegenera­ tive brain diseases, with three major genes, disease mechanisms and neuropathologies complicating patient diagnosis, care and treatment (Figure 1). This heterogeneity has direct implications for translational research and therapy development, and suggests the potential for personalized medicine on




Gain of function

Loss of function

Repeat expansion

Loss of GRN secretion

Accumulation of defective tau


RAN translation DPR accumulation





Figure 1 | Three subtypes of frontotemporal lobar degeneration. Mutations in three major genes —associated with three distinct disease mechanisms and pathologies—have been identified to cause frontotemporal lobar degeneration. Abbreviations: C9orf72, C9 open reading frame 72; DPR, dipeptide repeat protein; GA, poly-GA DPR; GRN, granulin; MAPT, microtubule-associated protein tau; TDP‑43, TAR DNA-binding protein 43.


the basis of the molecular signature of the FTLD subtype. Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB and Laboratory of Neurogenetics, Institute BornBunge, University of Antwerp, Universiteitsplein 1, B‑2610 Antwerp, Belgium (J. van der Zee, C. Van Broeckhoven). Correspondence to: C. Van Broeckhoven [email protected] Acknowledgements The authors thank J.-J. Martin and A. Sieben for the immunohistochemistry images and expert support. The authors receive funding from the Belgian Science Policy Office Interuniversity Attraction Poles programme, the European Centers of Excellence in Neurodegeneration, the Methusalem Excellence programme, the Alzheimer Research Foundation, the Medical Foundation Queen Elisabeth, the Research Foundation Flanders, the Agency for Innovation by Science and Technology Flanders, the University of Antwerp Research Fund, and the MetLife Foundation Award for Medical Research. Competing interests The authors declare no competing interests. 1.

DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245–256 (2011). 2. Renton, A. E. et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257–268 (2011). 3. Gijselinck, I. et al. A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet 11, 54–65 (2012). 4. Cruts, M., Gijselinck, I., Van Langenhove, T., van der Zee, J. & Van Broeckhoven, C. Current insights into the C9orf72 repeat expansion diseases of the FTLD/ALS spectrum. Trends Neurosci. 36, 450–499 (2013). 5. van der Zee, J. et al. A pan-European study of the C9orf72 repeat associated with FTLD: geographic prevalence, genomic instability, and intermediate repeats. Hum. Mutat. 34, 363–373 (2013). 6. Dols-Icardo, O. et al. Characterization of the repeat expansion size in C9orf72 in amyotrophic lateral sclerosis and frontotemporal dementia. Hum. Mol. Genet. 7. Van Langenhove, T. et al. Distinct clinical characteristics of C9orf72 expansion carriers compared with GRN, MAPT, and nonmutation carriers in a Flanders-Belgian FTLD cohort. JAMA Neurol. 70, 365–373 (2013). 8. Mori, K. et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339, 1335–1338 (2013). 9. Mackenzie, I. R. et al. Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinicopathological correlations. Acta Neuropathol. 126, 859–879 (2013). 10. Lagier-Tourenne, C. et al. Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc. Natl Acad. Sci. USA 110, E4530–E4539 (2013). © 2014 Macmillan Publishers Limited. All rights reserved

Dementia in 2013: frontotemporal lobar degeneration-building on breakthroughs.

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