Homozygosity for the C9orf72 GGGGCC repeat expansion in frontotemporal dementia.

Pietro Fratta,Sarah Mizielinska,James M Polke,Jon Beck,Tania F Gendron,John Collinge,Simon Mead,Adrian M Isaacs,Mark Poulter,Jason D Warren,Adrian J Waite,Natalie Ryan,Mang-Ching Lai,Tamas Revesz,Jonathan D Rohrer,Davina Hensman,Leonard Petrucelli,Tammaryn Lashley,Elizabeth M C Fisher

doi:10.1007/s00401-013-1147-0

Abstract

An expanded hexanucleotide repeat in the C9orf72 gene is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). We now report the first description of a homozygous patient and compare it to a series of heterozygous cases. The patient developed early-onset frontotemporal dementia without additional features. Neuropathological analysis showed c9FTD/ALS characteristics, with abundant p62-positive inclusions in the frontal and temporal cortices, hippocampus and cerebellum, as well as less abundant TDP-43-positive inclusions. Overall, the clinical and pathological features were severe, but did not fall outside the usual disease spectrum. Quantification of C9orf72 transcript levels in post-mortem brain demonstrated expression of all known C9orf72 transcript variants, but at a reduced level. The pathogenic mechanisms by which the hexanucleotide repeat expansion causes disease are unclear and both gain- and loss-of-function mechanisms may play a role. Our data support a gain-of-function mechanism as pure homozygous loss of function would be expected to lead to a more severe, or completely different clinical phenotype to the one described here, which falls within the usual range. Our findings have implications for genetic counselling, highlighting the need to use genetic tests that distinguish C9orf72 homozygosity.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-013-1147-0) contains supplementary material, which is available to authorized users.

Highlights

Frontotemporal dementia (FTD) is the most common form of early-onset dementia, second only to Alzheimer’s disease, and is characterised clinically by changesJ
We report the first FTD patient carrying a homozygous C9orf72 hexanucleotide repeat expansion
Our finding that the clinicopathological features were severe, but within the range of reported heterozygous cases, suggests that the condition is truly dominant; we provide evidence in favour of a gain-of-function mechanism

Summary

Introduction

Frontotemporal dementia (FTD) is the most common form of early-onset dementia, second only to Alzheimer’s disease, and is characterised clinically by changes. D. Warren Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK. An expanded hexanucleotide repeat in the C9orf gene has been identified recently as the most common known genetic cause of both FTD and ALS [9, 20, 25]. C9orf positive FTD (c9FTD) cases may show clinically typical FTD features and have been described to most commonly present with behavioural variant frontotemporal dementia, often with prominent psychiatric and amnestic symptoms [19]. The pathogenic mechanisms by which the hexanucleotide repeat expansion causes disease are unclear and both gainand loss-of-function mechanisms have been proposed to play a role [3, 9, 10, 22]. Neuropathology and expression data that we describe below carry important implications for disease pathogenesis and genetic counselling

Materials and methods

Results

Discussion

6: Hom TDP-43 p62