The molecular basis of the frontotemporal lobar degeneration–amyotrophic lateral sclerosis spectrum

Abstract

There is increasing evidence that frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) represent a continuum of neurodegenerative diseases. FTLD is complicated by ALS in a significant proportion of patients, and neuropsychological studies have demonstrated frontotemporal dysfunction in up to 50% of ALS patients. More recently, advances in neuropathology and molecular genetics have started to disclose the biological basis for the observed clinical concurrence. TDP-43 and FUS have been discovered as key pathological proteins in both FTLD and ALS. The most recent discovery of a pathological hexanucleotide repeat expansion in the gene C9orf72 as a frequent cause of both FTLD and ALS has eventually confirmed the association of these two at first sight distinct neurodegenerative diseases. Mutations in the TARDBP, FUS, and VCP genes had previously been associated with different phenotypes of the FTLD-ALS spectrum, although in these cases one end of the spectrum predominates. Whilst on the one hand providing evidence for overlap, these discoveries have also highlighted that FTLD and ALS are etiologically diverse. In this review, we review the recent advances that support the existence of an FTLD-ALS spectrum, with particular emphasis on the molecular genetic aspect.

Key words::

• Amyotrophic lateral sclerosis
• C9orf72
• frontotemporal lobar degeneration
• genotype–phenotype correlations
• molecular genetics
• pathology

Acknowledgements

The research in the authors’ group was funded in part by the international consortium of Centers of Excellence in Neurodegenerative Brain Diseases, the Interuniversity Attraction Poles program P6/43 of the Belgian Federal Science Policy Office; the Foundation for Alzheimer Research (SAO/FRMA); the Medical Foundation Queen Elisabeth; the Methusalem excellence program of the Flemish Government; the Research Foundation Flanders (FWO); the Agency for Innovation by Science and Technology Flanders (IWT); and the Special Research Fund of the University of Antwerp, Belgium. The IWT provided a PhD fellowship to T.V.L. and the FWO a postdoctoral fellowship to J.v.d.Z.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.