Cognitive and behavioral features of c9FTD/ALS.

Bradley F Boeve,Neill R Graff-Radford

doi:10.1186/alzrt132

Abstract

Numerous kindreds with familial frontotemporal dementia or amyotrophic lateral sclerosis or both have been linked to chromosome 9 (c9FTD/ALS), and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 (C9ORF72) was identified in the summer of 2011 as the pathogenic mechanism. An avalanche of papers on this disorder is in progress, and a relatively distinctive phenotype is taking form. In this review, we present an illustrative case and summarize the demographic, inheritance, clinical, and behavioral aspects and presumed pathologic underpinnings of c9FTD/ALS on the basis of the available data on more than 250 patients with frontotemporal lobar degeneration syndromes, parkinsonism, or ALS or a combination of these disorders.

Highlights

Familial frontotemporal dementia (FTD) with or without parkinsonism has been associated with mutations in genes encoding microtubule-associated protein tau (MAPT), progranulin (PGRN), and less commonly valosin-containing protein (VCP), TAR DNA-binding protein (TARDBP), and fused in sarcoma (FUS), whereas familial amyotrophic lateral sclerosis (ALS) has been associated with mutations in genes encoding Cu/Zn superoxide dismutase-1 (SOD1), TARDBP, and FUS [1,2,3,4,5,6,7,8,9]
The phenotype of familial FTD or ALS linked to chromosome 9 or both has been appreciated for many years [10,11,12,13,14,15,16,17], the pathogenic genetic mutation remained elusive until two teams of investigators discovered the mechanism in the summer of 2011 and published their findings shortly thereafter [18,19]. e mutation is an expansion of the GGGGCC hexanucleotide repeat in the non-coding intronic region of the chromosome 9 open reading frame 72 (C9ORF72) gene [18,19], and the disease is known as frontotemporal
He is patient III.2 in the report by Boxer and colleagues [16]. His father developed ALS at age 35 and died after a two-and-a-half-year course. His paternal aunt presented with behavioral variant frontotemporal dementia features at age 46 and shortly thereafter with parkinsonism and ALS and died after a nine-year course

Summary

Introduction

Familial frontotemporal dementia (FTD) with or without parkinsonism has been associated with mutations in genes encoding microtubule-associated protein tau (MAPT), progranulin (PGRN), and less commonly valosin-containing protein (VCP), TAR DNA-binding protein (TARDBP), and fused in sarcoma (FUS), whereas familial amyotrophic lateral sclerosis (ALS) has been associated with mutations in genes encoding Cu/Zn superoxide dismutase-1 (SOD1), TARDBP, and FUS [1,2,3,4,5,6,7,8,9]. Abbreviations ALS, amyotrophic lateral sclerosis; bvFTD, behavioral variant frontotemporal dementia; c9FTD/ALS, frontotemporal dementia or amyotrophic lateral sclerosis (or both) linked to chromosome 9; C9ORF72, (gene encoding the mutation in) chromosome 9 open reading frame 72; FDG-PET, flourodeoxyglucose positron emission tomography; FTD, frontotemporal dementia; FTD/ALS, frontotemporal dementia or amyotrophic lateral sclerosis or both; FTLD-MND, frontotemporal lobar degeneration with motor neuron disease; FUS, fused in sarcoma; GGGGCC, (the hexanucleotide expansion of ) guanine-guanine-guanine-guanine-cytosine-cytosine; MAPT, microtubuleassociated protein tau; MRI, magnetic resonance imaging; PET, positron emission tomography; PGRN, progranulin; PPA, primary progressive aphasia; TARDBP, TAR DNA-binding protein.

38. Schmahmann JD

Findings

44. Grossman M