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Relationship Between C9orf72 Repeat Size and Clinical Phenotype

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Relationship Between C9orf72 Repeat Size and Clinical Phenotype Available online at www.sciencedirect.com ScienceDirect Relationship between C9orf72 repeat size and clinical phenotype 1,2,3,4 1,2 1,2 Sara Van Mossevelde , Julie van der Zee , Marc Cruts 1,2 and Christine Van Broeckhoven Patient carriers of a C9orf72 repeat expansion exhibit Patients carrying a C9orf72 repeat expansion are remark- remarkable heterogeneous clinical and pathological able heterogeneous in clinical presentation, not only characteristics suggesting the presence of modifying factors. between families but also within families [3,4 ]. The In accordance with other repeat expansion diseases, repeat majority of the expansion carriers present clinically with length is the prime candidate as a genetic modifier. FTD and/or ALS. 73–100% of C9orf72 FTD patients Observations of earlier onset ages in younger generations of exhibit the behavioral variant (bvFTD) [5–15]. In C9orf72 large families suggested a mechanism of disease anticipation. ALS patients, the relative frequency of a bulbar symptom Yet, studies of repeat size and onset age have led to conflicting onset (29–89% [5,9,11,13,15–18]) is higher than in ALS results. Also, the correlation between repeat size and diagnosis patients without the expansion [13,16–18]. Apart from is poorly understood. We review what has been published FTD and ALS, several other clinical diagnoses have been regarding C9orf72 repeat size as modifier for phenotypic described (Figure 1) [9,19–31]. Parkinsonism is fre- characteristics. Conclusive evidence is lacking, partly due to quently reported in C9orf72 repeat expansion carriers, the difficulties in accurately defining the exact repeat size and but the expansion does not seem to be associated with the presence of repeat variability due to somatic mosaicism. Parkinson’s disease (PD) and is only rarely identified in patients with a clinical typical or atypical PD diagnosis Addresses [15,25–27,32–36]. 1 Center for Molecular Neurology, VIB, Universiteitsplein 1, 2610 Antwerp, Belgium 2 Pathologically, affected regions in the brain and spinal Laboratory of Neurogenetics, Institute Born-Bunge, University of C9orf72 Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium cord of repeat expansion carriers display accu- 3 Department of Neurology and Memory Clinic, Hospital Network mulation of TAR DNA binding protein(TDP)-43 pathol- Antwerp Hoge Beuken, Commandant Weynsstraat 165, 2660 Hoboken, ogy, mostly type B [11,14], although type A also occurs Belgium 4 [3,5,9,16] (Figure 1). Within one single family, different Department of Neurology, Antwerp University Hospital, Wilrijkstraat 10, TDP subtypes can occur [3]. Although most clinical AD 2650 Edegem, Belgium patients with a C9orf72 repeat expansion turn out to be Corresponding author: Van Broeckhoven, Christine FTLD-TDP on neuropathology [7,19], neuropathologi- ([email protected]) cally confirmed AD cases have been described in expan- sion carriers [22]. Furthermore, in one expansion carrier Current Opinion in Genetics & Development 2017, 44:117–124 the disease was neuropathologically characterized as a tauopathy consistent with corticobasal degeneration This review comes from a themed issue on Molecular and genetic pathology without any TDP-43 pathological changes in bases of disease the hippocampus or cerebral cortex [9]. Other neuropath- Edited by Edward Lee and Wilma Wasco ological characteristics in C9orf72 repeat expansion car- riers are the presence of RNA foci and dipeptide repeat protein pathology [58–60]. http://dx.doi.org/10.1016/j.gde.2017.02.008 0959-437X/ã 2017 The Authors. Published by Elsevier Ltd. This is an Apart from the heterogeneity in clinical and pathological open access article under the CC BY-NC-ND license (http://creative- diagnoses, there is also a remarkable variability in onset commons.org/licenses/by-nc-nd/4.0/). age. Onset in C9orf72 repeat expansion carriers is reported to range from 29 to 82 years of age [4 ,10– 12,14,16,29] with a variability up to 22 years in a single Introduction family [3]. A pathogenic expansion of the C9orf72 repeat is the most This marked phenotypical heterogeneity suggests the common genetic cause of frontotemporal lobar degener- presence of genetic modifying factors in C9orf72-related ation (FTLD) and amyotrophic lateral sclerosis (ALS) disease. In accordance with other repeat expansion dis- (Figure 1). The C9orf72 repeat expansion explains 25% of orders, the most obvious candidate to explain the variable familial frontotemporal dementia (FTD), 37% of familial disease expression is the size of the G C expanded ALS and up to 88% of familial patients with both FTD 4 2 repeat. and ALS [1,2]. www.sciencedirect.com Current Opinion in Genetics & Development 2017, 44:117–124 118 Molecular and genetic bases of disease Figure 1 ID S SCA AD CBS PSP HD phenocopy OPCD bvFTD phenocopy PMA C9orf72 FTLD ALS clinical clinical FTD pathological FTLD pathological electrophysiological neuronal loss prominent neuronal loss UMN signs + LMN signs - anterior nerve roots in frontal and / or temporal lobes bvFTD PPA - spasticity - weakness - lower cranial nuclei brainstem prominent prominent - hyperactive reflexes - atrophy - Betz cells motor cortex behavioral / executive language deficits - Babinski sign -fasciculations deficits onset PNFA SD LPA TDP-43 Ta U TDP-43 Type A Type B 4R bulbar spinal CBD - dysarthria - progressive limb weakness - dysphagia - fasciculations limb muscles - tongue fasciculations - hyperreflexia limbs Current Opinion in Genetics & Development C9orf72 disease heterogeneity. Most C9orf72 repeat expansion carriers exhibit frontotemporal lobar degeneration (FTLD) and/or amyotrophic lateral sclerosis (ALS). FTLD presents clinically as frontotemporal dementia (FTD) and has two variants: the behavioral variant of FTD (bvFTD) [56] and primary progressive aphasia (PPA) [57]. This last variant can be further separated into progressive non-fluent aphasia (PNFA), semantic dementia (SD) and logopenic progressive aphasia (LPA), although the latter is frequently associated with underlying atypical Alzheimer’s disease pathology. ALS is the result of a combination of upper motor neuron (UMN) and lower motor neuron (LMN) degeneration. Histopathological, most FTLD and ALS cases due to a C9orf72 repeat expansion are characterized by TAR DNA binding protein-43 (TDP-43) inclusions, although tau-inclusions have also been reported. Apart from ALS and FTLD, several other diagnoses have been described in expansion carriers: Alzheimer’s disease (AD), Huntington’s disease (HD) phenocopy (not carrying a CAG repeat expansion in the HTT gene), progressive supranuclear palsy (PSP), corticobasal syndrome/ degeneration (CBS/CBD), bvFTD phenocopy syndrome (a slowly progressive bvFTD-like phenotype), primary muscular atrophy (PMA), sporadic spinocerebellar ataxia (S SCA), olivopontocerebellar degeneration (OPCD) and intellectual disability (ID). Normal C9orf72 repeat length smaller repeats (Figure 2). Repeat lengths between 24 and The cut-off to discriminate between ‘normal’ repeat 28 units have been observed in ALS patients [17,18,39], alleles and pathogenic expanded repeats is not very well while repeat alleles as short as 20 to 22 repeats have been established. In most healthy control cohorts, normal observed in FTD patients and their affected siblings [37]. repeat lengths up to 24 units were identified [10,11,14, Co-segregation with disease of expansions as short as 17,22,29,32,37–40] (Figure 2). However, two authors 47 units and of expansions between 35 and 100 units have reported slightly larger maximal repeat sizes of 32 and been observed in an FTD/ALS family [46 ] and two AD 35 units, respectively [6,18], and others even observed families respectively [20]. A point of discussion here is large expansions of more than 400 units in unaffected whether these ‘intermediate’ repeat sizes in blood are individuals, probably due to a reduced C9orf72 disease directly associated with pathology, or whether they are penetrance and high variability in onset age [23] associated with fully expanded repeats in disease-relevant (Figure 2). tissue due to increased instability. In patients, the size of most repeat expansions is estimated Effect C9orf72 repeat length on clinical to range between several hundred and several thousand phenotype repeat units [8,23,29,39,41 ,42–44,45 ]. Although most Some authors observed significantly larger pathogenic authors use an arbitrary cut-off of 30 or 60 units (depending expansion sizes in ALS patients than in FTD patients on the upper limit of the repeat-primed PCR detection [47 ,48 ] (Figure 2). However, several Southern blot method), several affected individuals were reported with hybridization studies using different measures of repeat Current Opinion in Genetics & Development 2017, 44:117–124 www.sciencedirect.com Relationship between C9orf72 repeat size and clinical phenotype Van Mossevelde et al. 119 Figure 2 1a 2 3 4 5 6 7 8 9 10 11 C9orf72 GGGGCC n 1 72430 60 80 400 4400 1. increased risk of ALS in comparison with FTD? increased risk of: 2. increase in age at onset? sporadic ALS? ⊕positive correlation between onset age and repeat size 3. Decrease in age at onset? PD / ET? (1) (2) ⊕ arguments for the occurrence of anticipation OA 6 Y 6 U * clinical (1) : 3 5 most healthy individuals 0.09%* earlier onset ages in younger generations * genetic and molecular (2) : OA 54 Y >1100U longer repeat size 0.46%* in younger generations increased CpG methylation* OA 45 Y ⊕ inverse correlation between onset age and repeat size Current
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