We have confirmed, in an Australian cohort, that the C9ORF72 repeat expansion is a relatively common cause of FTD. Overall, 10.1% of clinically ascertained patients were found to harbor the expansion, but the frequency rose to 28.6% in those with a positive family history of early-onset dementia or ALS, which makes C9ORF72 a priority gene for screening in any newly identified FTD family. The clinical variant associated with the mutation was invariably bvFTD or FTD-ALS. As hypothesized, the mutation was strongly associated with the presence of psychosis. In the pathology cohort, 40.9% of TDP-43-positive cases were found to have the repeat expansion, and all exhibited type B pathology.
The discovery of the C9ORF72
mutation is a major development in the FTD and ALS fields and it is now clear that this defect accounts for a substantial proportion of cases with a strong family history of either FTD or ALS. Families with an autosomal dominant pattern of inheritance and patients with both FTD and ALS are highly likely to harbor the mutation. It should be noted, however, that the strength of family history in expansion-positive patients, as measured by the modified Goldman scale,10
was quite variable. In the clinical cohort, 2 of the expansion-positive patients had no affected family members and for 3 others the family history was rather weak (Goldman score 3–3.5). Screening patients with FTD-ALS but no family history may therefore be indicated, although more prevalence data from larger cohorts with family history–negative patients are required.
Phenotypic presentation of the C9ORF72
expansion appears to be predominantly the behavioral variant of FTD, while 3 of the 9 expansion-positive patients in the clinical cohort had combined FTD and ALS. Notably, none were diagnosed with a language variant of FTD. This finding is in keeping with prior observations, in that the majority of patients with PNFA show tau pathology, and in SMD the histopathologic findings are unique and distinct from those found in FTD-ALS.2
Moreover, ALS has been only very rarely described in association with SMD and the familial rate appears to be extremely low in this variant.16
Our progressive aphasia group (n = 39) included 8 with the newly recognized logopenic variant, which has been associated with underlying Alzheimer pathology.17
They were included because clinical differentiation from the other variants of progressive aphasia requires relatively sophisticated analysis of speech and in most centers such cases would be subsumed under the broad rubric of FTD.
Recent studies have highlighted the high rate of psychosis found in patients with familial and sporadic FTD-ALS.6,15
Delusions are more common than hallucinations and often take bizarre forms, such as delusions of sexual molestation and alien invasion. On the basis of this observation we hypothesized that psychotic phenomena are likely to be associated with the C9ORF72
mutation and might therefore be a clinical marker of those harboring the mutation even when a family history of FTD or ALS is absent. Overall 16 of our 89 clinically ascertained cases met criteria for psychosis, of whom 5 were found to have the expansion. Over half of patients with the expansion were psychotic compared to only 14% of expansion-negative patients. Whether this reflects the speed of progression, the distribution, or the cellular nature of the pathology remains to be established. Psychosis has also been reported as a common feature in patients with FTLD-FUS, although the latter is characterized by a young age at onset (<40 years), no family history, and caudate atrophy,2
all of which distinguish it from the C9ORF72
We identified one healthy individual who harbors an allele with ≥38 hexanucleotide repeats in C9ORF72,
the longest nonexpansion allele identified so far in a cognitively normal aged control. Although it is premature to draw conclusions based on one individual, this finding indicates that the classification of all alleles >30 repeats as pathogenic, as defined by Renton et al.,5
may need revision. In other repeat expansion diseases, such as fragile X syndrome and Huntington disease, healthy people can harbor “premutation” alleles, which are not long enough to lead to a disease phenotype themselves but are prone to expand to a pathogenic length in the next generation.18,19
Large-scale longitudinal cohorts will be required to determine whether such premutation alleles exist for the C9ORF72
locus and if so, how many repeats constitutes such an allele.
One expansion-positive patient was homozygous for the “nonrisk” G allele of rs3849942, a polymorphism that has been used previously as a surrogate marker for the haplotype identified in 9p21-linked FTD-ALS families.4,7
Detection of a repeat expansion on the 9p21 presumed “nonrisk” haplotype suggests that mutation carriers may not all be descended from a common founder, in contrast to previous studies,4,7
and lends support to the hypothesis that the expansion has occurred on multiple occasions on multiple haplotype backgrounds.5
Screening of the neuropathologic cohort revealed that 3 cases with a prior clinical diagnosis of Alzheimer disease (AD) were positive for the C9ORF72
repeat expansion. These patients were not systematically recruited, nor subject to an extensive standardized clinical assessment, thus the details of their clinical presentations are limited. The degree of amnesia led to a diagnosis of AD, although in each case some atypical features were present. In this context, it is of interest that recent studies have highlighted the high prevalence of episodic memory dysfunction in bvFTD that in many instances is of the severity of that seen in AD, although it is accompanied by prominent behavioral symptomatology.20,21
In addition, Murray et al.22
recently reported that 3 C9ORF72
expansion-positive patients in their neuropathologic series were clinically diagnosed with AD. On the basis of these findings it would be prudent to include C9ORF72
in mutation screens for genetic causes of clinically diagnosed AD cases.
There are a number of limitations to this study. The cohorts were determined by availability of DNA samples. Patients with a family history of FTD may have been more motivated to consent to DNA analysis. The frequency of C9ORF72 expansion in this study may therefore be higher than in unselected FTD populations. Secondly, subjects in this study were primarily of European ancestry, as to be expected in an Australian population. Future studies in non-European ancestry populations would be of use in determining the relative contribution of the C9ORF72 expansion to disease in patients with different ethnicities.
We have demonstrated that the C9ORF72 hexanucleotide repeat expansion is a common cause of FTD in Australian populations and is particularly common in patients with FTD-ALS. It is characterized clinically by a high rate of psychosis and neuropathologically by FTLD-TDP type B pathology. The pathogenic mechanism of the repeat expansion in C9ORF72 requires elucidation. It is still not certain whether neuronal loss is wholly a consequence of a pathogenic gain of function of the expansion or if loss of the normal function of C9ORF72 can contribute to disease. If the pathogenic effects are partly due to loss of C9ORF72 function, future studies would benefit from screening other regions of this gene in expansion-negative patients with FTD and ALS to determine whether null mutations are another source of disease.