What is the role of genetics in the etiology of frontotemporal lobe dementia with motor neuron disease (FTD/MND)?

Updated: Apr 11, 2017
  • Author: Jasvinder Chawla, MD, MBA; Chief Editor: Jasvinder Chawla, MD, MBA  more...
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A minority of patients have a family history of FTD/MND, but this overlap syndrome may be related to other neurodegenerative overlap syndromes that include variable degrees of dementia, MND, and parkinsonism.

The most common mutation, accounting for 10% of all Western hemisphere ALS, is a hexanucleotide repeat expansion in C9orf72. This and several other genes implicate altered RNA processing and protein-degradation pathways in the core of ALS pathogenesis. [12] The nomenclature MSP1, MSP2, and MSP3 may be used for VCP-, HNRNPA2B1-, and HNRNPA1-associated disease, respectively. Potential relevance has been shown regarding the pathobiology of more common MNDs such as ALS, providing an additional link between ALS and FTD. [13]

Two of the genes causing FTD alone (CHMP2B and GRN) are associated with a damaged autophagy/lysosomal pathway. However, the third FTD gene (MAPT) maps to a different pathway, which perhaps is not surprising, since it is associated with a different (not p62-related) brain pathology. [14] Wang et al recently found relationship between sporadic forms of Alzheimer-type dementia and ALS that is linked to I2(PP2A) and the potential of I2(PP2A)-based therapeutics for these diseases. [15] .

Ubiquilin-2 mouse models provide valuable tools for identifying the mechanisms underlying ALS-FTD pathogenesis and for investigating therapeutic strategies to terminate disease. [16]

C9orf72 repeat expansion has been identified as an important genetic risk factor for both motor neuron disease and frontotemporal dementia. This has helped to confirm that the disease forms part of a spectrum of central neurodegenerative processes. [17, 18]

Overall, the current state of knowledge points to common mechanisms responsible for susceptibilities specific to neuronal classes.

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