Distinct clinical characteristics of C9orf72 expansion carriers compared with GRN, MAPT, and nonmutation carriers in a Flanders-Belgian FTLD cohort

JAMA Neurol. 2013 Mar 1;70(3):365-73. doi: 10.1001/2013.jamaneurol.181.


Objective: To characterize patients with frontotemporal lobar degeneration (FTLD) with a repeat expansion mutation in the gene C9orf72, and to determine whether there are differences in the clinical presentation compared with FTLD carriers of a mutation in GRN or MAPT or with patients with FTLD without mutation.

Design: Patient series.

Setting: Dementia clinics in Flanders, Belgium.

Patients: Two hundred seventy-five genetically and phenotypically thoroughly characterized patients with FTLD.

Main outcome measures: Clinical and demographic characteristics of 26 C9orf72 expansion carriers compared with patients with a GRN or MAPT mutation, as well as patients with familial and sporadic FTLD without mutation.

Results: C9orf72 expansion carriers developed FTLD at an early age (average, 55.3 years; range, 42-69 years), significantly earlier than in GRN mutation carriers or patients with FTLD without mutation. Mean survival (6.2 years; range, 1.5-17.0 years) was similar to other patient groups. Most developed behavioral variant frontotemporal dementia (85%), with disinhibited behavior as the prominent feature. Concomitant amyotrophic lateral sclerosis is a strong distinguishing feature for C9orf72 -associated FTLD. However, in most patients (73%), amyotrophic lateral sclerosis symptoms were absent. Compared with C9orf72 expansion carriers, nonfluent aphasia and limb apraxia were significantly more common in GRN mutation carriers.

Conclusions: C9orf72 -associated FTLD most often presents with early-onset behavioral variant frontotemporal dementia with disinhibition as the prominent feature, with or without amyotrophic lateral sclerosis. Based on the observed genotype-phenotype correlations between the different FTLD syndromes and different genetic causes, we propose a decision tree to guide clinical genetic testing in patients clinically diagnosed as having FTLD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Aged
  • Belgium / epidemiology
  • C9orf72 Protein
  • Cohort Studies
  • DNA Repeat Expansion / genetics*
  • Female
  • Frontotemporal Lobar Degeneration / epidemiology
  • Frontotemporal Lobar Degeneration / genetics*
  • Genetic Carrier Screening*
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Male
  • Middle Aged
  • Mutation / genetics
  • Progranulins
  • Proteins / genetics*
  • tau Proteins / genetics*


  • C9orf72 Protein
  • C9orf72 protein, human
  • GRN protein, human
  • Intercellular Signaling Peptides and Proteins
  • MAPT protein, human
  • Progranulins
  • Proteins
  • tau Proteins