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Review
. 2014 Mar;127(3):333-45.
doi: 10.1007/s00401-014-1251-9. Epub 2014 Feb 4.

The widening spectrum of C9ORF72-related disease; genotype/phenotype correlations and potential modifiers of clinical phenotype

Johnathan Cooper-Knock  1 , Pamela J Shaw, Janine Kirby
Affiliations
Review

The widening spectrum of C9ORF72-related disease; genotype/phenotype correlations and potential modifiers of clinical phenotype

Johnathan Cooper-Knock et al. Acta Neuropathol. 2014 Mar.

Abstract

The GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common cause of familial amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTLD) and ALS-FTLD, as well as contributing to sporadic forms of these diseases. Screening of large cohorts of ALS and FTLD cohorts has identified that C9ORF72-ALS is represented throughout the clinical spectrum of ALS phenotypes, though in comparison with other genetic subtypes, C9ORF72 carriers have a higher incidence of bulbar onset disease. In contrast, C9ORF72-FTLD is predominantly associated with behavioural variant FTD, which often presents with psychosis, most commonly in the form of hallucinations and delusions. However, C9ORF72 expansions are not restricted to these clinical phenotypes. There is a higher than expected incidence of parkinsonism in ALS patients with C9ORF72 expansions, and the G4C2 repeat has also been reported in other motor phenotypes, such as primary lateral sclerosis, progressive muscular atrophy, corticobasal syndrome and Huntington-like disorders. In addition, the expansion has been identified in non-motor phenotypes including Alzheimer's disease and Lewy body dementia. It is not currently understood what is the basis of the clinical variation seen with the G4C2 repeat expansion. One potential explanation is repeat length. Sizing of the expansion by Southern blotting has established that there is somatic heterogeneity, with different expansion lengths in different tissues, even within the brain. To date, no correlation with expansion size and clinical phenotype has been established in ALS, whilst in FTLD only repeat size in the cerebellum was found to correlate with disease duration. Somatic heterogeneity suggests there is a degree of instability within the repeat and evidence of anticipation has been reported with reducing age of onset in subsequent generations. This variability/instability in expansion length, along with its interactions with environmental and genetic modifiers, such as TMEM106B, may be the basis of the differing clinical phenotypes arising from the mutation.

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Figures

Fig. 1
Fig. 1
Clinical phenotypes associated with G4C2 repeat expansion of C9ORF72: both motor and non-motor phenotypes are associated with C9ORF72 expansions. The primary phenotype in each case is amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). Other phenotypes have been noted in very small numbers of patients: motor phenotypes in this group are parkinsonism, olivopontocerebellar degeneration, corticobasal syndrome and Huntington’s disease phenocopies. The only non-motor phenotype identified in more than a few individuals is Alzheimer’s disease
Fig. 2
Fig. 2
Proposed pathogenic mechanisms and modifiers in C9ORF72 disease. Three prominent mechanisms of pathogenesis have been proposed in C9ORF72 disease: (1) Haploinsufficiency, (2) RAN translation of the expansion to form dipeptide repeats and (3) the formation of toxic RNA foci. Poly-(Gly-Ala)- dipeptide repeat protein is shown (stained in green, arrowed) aggregated in the cytoplasm of a cerebellar granule cell from a C9ORF72-ALS patient. RNA foci containing the G4C2 repeat sequence are shown (stained red, arrowed) within a fibroblast obtained from a C9ORF72-ALS patient. There is some evidence that the repeat length is a modifier of the disease phenotype which would be consistent with mechanisms (2) and (3). However, case reports suggest that disease phenotype is not directly proportional to the number of affected alleles which goes against mechanism (1). The function of the C9ORF72 protein is unknown, but a role in membrane trafficking has been proposed which is consistent with the modifier effect of the TMEM106B genotype: both C9ORF72 and TMEM106B are postulated to be involved in lysosome function
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