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

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.

Challenges in the Understanding and Treatment of Amyotrophic Lateral Sclerosis/Motor Neuron Disease

“…Perhaps nowhere is this variability in the effect of a single gene mutation more obvious that the impact of a massive GGGGCC (G 4 C 2 ) repeat expansion in C9ORF72 in which ALS, FTD, and ALS-FTD have all been described [97]. Such striking variability also suggests the presence of multiple disease modifiers, not the least of which may be important gene-environment interactions [98].…”

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

“…C9orf72 repeat expansions are involved with a wide spectrum of neurological manifestations 37,38 , involving motor and nonmotor (cognitive and behavioral) phenotypes (syndromes) 38 ( Figure 4). Most clinical data come from populational studies in European countries and in US.…”

“…During a large screening for genetic causes of early-onset autosomal dominant inherited dementia, atypical clinical presentations of C9orf72-related disease were found and disclosed a rare presentation of an olivopontocerebellar degeneration and a corticobasal syndrome-like phenotype 51 . Visuospatial dysfunction has also been described, but the phenotype of pure spastic paraparesis is not associated with repeat expansion 38 . It has also been identified a higher prevalence of multiple sclerosis within families with ALS, mainly those associated with C9orf72 19 .…”

The genetic basis of amyotrophic lateral sclerosis: recent breakthroughs

“…4 Thus, mutations in, at first glance, very different genes induce a very similar (or even identical) clinical picture, but the same mutation may induce quite variable phenotypes both in terms of onset and survival, [20][21][22] or type of involvement. 23,24 This generated an interesting but rather semantic debate on whether ALS is a true disease entity, or rather embodies a heterogeneous group of diseases with motor neuron degeneration as a common characteristic. 4 This progress in genetics has allowed the generation of disease models, which, hopefully, will serve as tools for the rational design and testing of therapeutic approaches.…”

“…111 The G 4 C 2 expansion is associated with a variable phenotype as addressed in recent reviews. 2,24,111 C9orf72-ALS has a high incidence of bulbar onset and cognitive dysfunction is frequent with C9orf72 mutations. 2,24,111 Almost a third of C9orf72 patients have both ALS and FTD.…”