The heritability and genetics of frontotemporal lobar degeneration

Neurology. 2009 Nov 3;73(18):1451-6. doi: 10.1212/WNL.0b013e3181bf997a.


Background: Frontotemporal lobar degeneration (FTLD) is a genetically and pathologically heterogeneous neurodegenerative disorder.

Methods: We collected blood samples from a cohort of 225 patients with a diagnosis within the FTLD spectrum and examined the heritability of FTLD by giving each patient a family history score, from 1 (a clear autosomal dominant history of FTLD) through to 4 (no family history of dementia). We also looked for mutations in each of the 5 disease-causing genes (MAPT, GRN, VCP, CHMP2B, and TARDP) and the FUS gene, known to cause motor neuron disease.

Results: A total of 41.8% of patients had some family history (score of 1, 2, 3, or 3.5), although only 10.2% had a clear autosomal dominant history (score of 1). Heritability varied across the different clinical subtypes of FTLD with the behavioral variant being the most heritable and frontotemporal dementia-motor neuron disease and the language syndromes (particularly semantic dementia) the least heritable. Mutations were found in MAPT (8.9% of the cohort) and GRN (8.4%) but not in any of the other genes. Of the remaining patients without mutations but with a strong family history, 7 had pathologic confirmation, falling into 2 groups: type 3 FTLD-TDP without GRN mutations (6) and FTLD-UPS (1).

Conclusion: These findings show that frontotemporal lobar degeneration (FTLD) is a highly heritable disorder but heritability varies between the different syndromes. Furthermore, while MAPT and GRN mutations account for a substantial proportion of familial cases, there are other genes yet to be discovered, particularly in patients with type 3 FTLD-TDP without a GRN mutation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Aged
  • Aged, 80 and over
  • Cell Cycle Proteins / genetics
  • DNA-Binding Proteins / genetics
  • Dementia / genetics*
  • Dementia / pathology
  • Endosomal Sorting Complexes Required for Transport
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Male
  • Motor Neuron Disease / genetics
  • Mutation*
  • Nerve Tissue Proteins / genetics
  • Neuropsychological Tests
  • Progranulins
  • RNA-Binding Protein FUS / genetics
  • Surveys and Questionnaires
  • Valosin Containing Protein
  • tau Proteins / genetics*


  • CHMP2B protein, human
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Endosomal Sorting Complexes Required for Transport
  • GRN protein, human
  • Intercellular Signaling Peptides and Proteins
  • MAPT protein, human
  • Nerve Tissue Proteins
  • Progranulins
  • RNA-Binding Protein FUS
  • tau Proteins
  • Adenosine Triphosphatases
  • VCP protein, human
  • Valosin Containing Protein