Genetics of frontotemporal dementia

Most FTD occurs sporadically, but up to 20% of cases have a known familial cause, and up to 40% of cases have a strong family history without a clear pattern of inheritance.

There are 3 sites of autosomal dominant mutations: C9ORF72, MAPT, and GRN that account for most common known causes of familial FTLD


C9ORF72 (chromosome 9 open reading frame 72), chromosome 9p21.2 (Finger 2016)

  • most common genetic cause of familial FTD (11.7% of familial cases) and familial ALS (Ljubenkov and Miller, 2016)
  • Clinical phenotype bvFTD, ALS, FTLD-ALS (Finger 2016)
  • Healthy patients typically have less than 30 hexanucleotide repeats, patients with 700-1,600 repeats experience nearly 100% penetrance with either FTD, ALS, or FTD-MND syndrome (Ljubenkov and Miller, 2016)
  • Mostly leads to TDP-43 type B pathology (also sometimes type A) (Ljubenkov and Miller, 2016)
  • More likely to exhibit psychotic features, but surprising social warmth and appropriateness on presentation (Ljubenkov and Miller, 2016)
  • Relatively high burden of cerebellar and thalamic atrophy compared to other FTD syndromes (Ljubenkov and Miller, 2016)


MAPT (microtubule associated protein tau), located on chromosome 17q21.32, codes for tau protein

  • Cluster of familial syndromes associated with the MAPT mutations are known as FTD and parkinsonism linked to chromosome 17 (half of patients have parkinsonism features) (Ljubenkov and Miller, 2016)
  • Tend to have younger age of onset (under 50) (Ljubenkov and Miller, 2016)
  • Present with diverse syndromes (bvFTD > PPA, CBS, and PSP) (Ljubenkov and Miller, 2016)
  • Most common clinical phenotype involves mixed features of bvFTD and svPPA with early behavioral disinhibition and temporal lobe atrophy leading to semantic loss (Ljubenkov and Miller, 2016)
  • MND and early apathy are not common in MAPT mutation presentations (Ljubenkov and Miller, 2016)


GRN (progranulin), chromosome 17q21.32

  • Codes for progranulin protein (Finger 2016)
  • Clinical phenotype: bvFTD > PPA, semantic variant PPA, CBS (Finger 2016)
  • TDP-43 type A inclusion pathology (Ljubenkov and Miller, 2016)
  • Tends to have later age of onset (mean of 59 years) and long disease duration (mean of 9 years) (Ljubenkov and Miller, 2016)
  • Distinct radiographic features including asymmetric frontotemporal and parietal atrophy and T2 hyperintense confluent white matter disease affecting periventricular white matter and U-fibers (Ljubenkov and Miller, 2016)


FUS mutations (fused in sarcoma protein), chromosome 16p11.2

  • Strongly associated with ALS, but can also lead to bvFTD presentation (Ljubenkov and Miller, 2016)
  • early age of onset (22 – 46 years) (Ljubenkov and Miller, 2016)
  • significant psychiatric symptoms (Ljubenkov and Miller, 2016)
  • it’s been proposed that von Economo neurons in the ACC and frontoinsular junction may be the site of pathology (Finger 2016)


Other more rare genetic mutations include: (Finger 2016)

  • VCP (valosin-containing protein), chromosome 9p13.3 associated with multisystem proteinopathy and inclusion body myopathy associated with paget disease of bone and frontotemporal dementia
  • TARDBP, chromosome 1p36.21, TDP-43, associated with ALS > FTLD-ALS, FTD
  • SQSTM1 (sequestome 1/p62), chromosome 5q32, associated with Paget disease of bone, ALS, bvFTD
  • CSF1R (colony stimulating factor 1 receptor), chromosome 5q32, associated with bvFTD, CBS, strokelike presentation
  • TREM2 (triggering receptor expressed on myeloid cells), chromosome 6p21.1, associated with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, bvFTD
  • CHMP2B (chromatin-modifying protein 2B), chromosome 3p11.2, associated with bvFTD, FTLD-ALS
  • UBQLN2 (ubiquilin 2), chromosome Xp11.21, associated with ALS > FTLD-ALS
  • hnRNPA2B1 heterogenous nuclear ribonucleoprotein A2/B1), chromosome 7p15, associated with multisystem proteinopathy, inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia


References

Finger, E. C. Frontotemporal Dementias. Contin. Minneap. Minn 22, 464–489 (2016). https://pubmed.ncbi.nlm.nih.gov/27042904/

Ljubenkov, P. A. & Miller, B. L. A Clinical Guide to Frontotemporal Dementias. FOCUS 14, 448–464 (2016). https://pubmed.ncbi.nlm.nih.gov/31975825/

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