Dual pathogenic mutations in SQSTM1 and C9orf72 as a cause of frontotemporal dementia

Abstract

AbstractBackgroundHexanucleotide repeat expansions in the C9orf72 gene have been found to be the leading genetic cause of both familial frontotemporal dementia (FTD) and motor neuron disease (MND). However there are a number of other genetic causes of both FTD and MND including, less commonly, mutations in sequestosome 1 (SQSTM1) which codes for the cargo protein p62. Occasionally, people with FTD or MND have been described with dual pathogenic mutations, although this is rare.MethodWe describe the clinical and imaging features of a woman who presented with FTD and motor neurone involvement who was found to carry both a pathogenic C9orf72 expansion and a deleterious c.1185dup, p.Glu396* heterozygous SQSTM1 mutation.ResultSymptoms started at the age of 60 with change in personality and impaired behaviour followed at the age of 63 by prosopagnosia and semantic impairment. Brain magnetic resonance imaging showed right‐sided predominant temporal more than frontal lobe atrophy, and she was initially diagnosed with behavioural variant FTD. However at the age of 66 she developed asymmetrical limb weakness and stiffness, with upper motor neurone features only on examination, suggestive of primary lateral sclerosis (PLS). She deteriorated rapidly over the next couple of years, although never developed lower motor neurone features when subsequently examined. She died at the age of 69.ConclusionThe co‐presence of both a SQSTM1 mutation and C9orf72 expansion is rare. It remains unclear which mutation accounts for which of the features seen. Focal right temporal lobe atrophy is more common with SQSTM1 mutations, but PLS is uncommon with both mutations. It may be therefore that it is the dual mutations together that explain the altered phenotype. It is paramount to better understand the roles which SQSTM1 and C9orf72 mutations have on cellular pathways and how their combination results in rare phenotypes.