Genetic Semantic Dementia? Twins’ Data and Review of Autosomal Dominant Cases

Background

Amongst different subtypes of frontotemporal dementia (FTD), semantic dementia (SD, also known as the semantic variant of primary progressive aphasia, svPPA), is the least likely to have a genetic basis.

Methods

Our study had two aims: (i) to describe two SD cases and detailed assessments of their unaffected monozygotic (MZ) twins, and (ii) to review cases with FTD-associated mutations or known family history classified as SD/svPPA either in the Genetic Frontotemporal dementia Initiative (GENFI) or in the published literature.

Results

The two affected twins displayed characteristic features of SD, both in neuroimaging and cognition, whereas their MZ twins exhibited no abnormalities in either regard, even up to 15 years of follow-up for one affected twin. Only five cases out of more than 1300 people in GENFI were classified as svPPA, with a genetic mutation. The systematic review revealed 29 cases with sufficient clinical and language details regarding ‘genetic’ SD/svPPA. A comparison of these five GENFI and 29 literature cases to the patterns observed in a large number of sporadic cases revealed critical differences in presentation.

Conclusions

Both parts of our study suggest that true SD/svPPA is unlikely to have an autosomal dominant genetic aetiology and that, while mutation carriers may resemble SD/svPPA in some respects, they may not meet current clinical diagnostic criteria for this condition.

What is already known on this topic : Approximately 30% of all frontotemporal dementia cases are associated with an autosomal dominant pattern of inheritance but the reported prevalence of mutation in semantic dementia/semantic variant of primary progressive aphasia (SD/svPPA) is very low.

What this study adds : From (a) outlining the discordance for SD/svPPA in two pairs of monozygotic twins and (b) comparing the clinical and cognitive profiles of people who had been classified as SD/svPPA with an FTD-associated genetic mutation versus sporadic SD/svPPA, we conclude that true SD/svPPA is unlikely to have an autosomal dominant genetic aetiology.

How this study might affect research, practice or policy : Our study highlights gaps in the understanding of environmental and epigenetic influences on sporadic SD/svPPA and a need for further unbiased genotyping and phenotyping of SD/svPPA and “SD-like” syndromes.

Open access: For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.