Table 3.

Genes of Interest in the Differential Diagnosis of MAPT-Related Frontotemporal Dementia

Gene(s)DiffDx
Disorder		Clinical Features of DiffDx Disorder
OnsetDisease
duration		PathologyComment
Familial FTD: Most commonly involved genes
C9orf72 C9orf72-ALS/FTD Mean: 58.2 yrs; range: 20-91 yrs 1Mean: 6.4 yrs; range: 0-36 yrs 1TDP-43 pathology in wide neuroanatomic distribution, w/particular involvement of extramotor neocortex, hippocampus, & lower motor neuronsMay be diagnosed as bvFTD, ALS, FTD/ALS, or PPA. 2 Parkinsonism can develop as disease progresses. Rarely a Huntington disease-like phenotype is seen. Heterogeneity in clinical presentation is common w/in families. Phenotypes may overlap w/disease progression. C9orf72 is involved in ~5%-10% of all FTD. 3
GRN GRN-FTD Mean: 61.3 yrs; range: 25-90 yrs 1Mean: 7.1 yrs; range: 0-27 yrs 1TDP-43 pathology in neocortex & striatum; widespread & often asymmetric atrophy in frontal, temporal, &/or parietal lobes; characteristic parietal involvementMost common presentation is bvFTD. Can also present as PPA, CBS, atypical PD, or (very rarely) ALS. May be misdiagnosed as AD. GRN is involved in ~5%-10% of all FTD. 3
Familial FTD: Less commonly involved genes (<5% of all FTD) 3
CCNF CCNF-FTD/ALS (OMIM 619141)Mean: 55.3 yrs; range: 42-66 yrsMean: 2.5 yrs; range: 1-54 yrsTDP-43 type 1 pathologyAssoc w/ALS, FTD/ALS, or PLS
CHCHD10 CHCHD10-related disorders Approximately 50 yrs1-27 yrsPathology not yet availablePresentation is highly variable; assoc w/ALS, FTD, cerebellar ataxia, & myopathy.
CHMP2B CHMP2B-FTD Typically in late 50s
Mean: 57 yrs; range 46-70 yrs		3-20+ yrsNeuropathology assoc w/ubiquitin- & p62-positive inclusions, & TDP-43-, MAPT-, & FUS-negative inclusionsUsually presents w/bvFTD but parkinsonism can be seen as disease progresses
FUS FUS-ALS ± FTD 2 (OMIM 608030)Onset frequently <35 yrs
Median: 39 yrs; range: 11-80 yrs		Median: 2.1 yrsFUS pathology in neuronal cytoplasm & dendrites. Severe caudate atrophy may differentiate FTLD-FUS from FTLD-Tau & FTLD-TDP.Assoc w/ALS & occasionally FTD/ALS or bvFTD
OPTN OPTN-ALS ± FTD 2 (OMIM 613435)Mean: 51.9 yrs; range: 23-83 yrsRange: 1-24 yrsOPTN-positive cytoplasmic inclusions in CNSAssoc w/ALS & occasionally FTD/ALS
SQSTM1 SQSTM1-ALS/FTD 2 (OMIM 616437)Range: 48-73 yrsRange: 2-29 yrsTDP-43 pathologyAssoc w/ALS, bvFTD, ALS/FTD, &/or PDB 4
TARDBP ALS or ALS w/FTD (See TARDBP-ALS.)41-60 yrs
Range: 29-77 yrs		Range: 2-4 yrsTDP-43 inclusions in upper & lower motor neurons & cortex; can be assoc w/focal temporal lobe atrophyAssoc w/ALS & occasionally FTD/ALS or bvFTD; more rarely can cause PPA
TBK1 TBK1-ALS/FTD 2 (OMIM 616439)Mean: 63.3 yrs; range: 56-70 yrsRange: 1-10+ yrs 1TDP-43 pathology; can be assoc w/focal temporal lobe atrophyCan cause bvFTD, PPA, CBS, FTD/ALS, ALS; assoc w/1%-2% of all FTD
TIA1 TIA1-ALS ± FTD (OMIM 619133)Mean: 58.9 yrs; range: 28-86 yrs1-11 yrsTDP-43 type B pathology in extramotor neocortex, motor cortex, spinal cordAssoc w/ALS w/or w/o bvFTD
TUBA4A TUBA4A-ALS/FTD (OMIM 616208)Median: 65.5 yrs; range: 59-70 yrsMedian: 7 yrs; range: 6-11 yrsTDP-43 pathologyAssoc w/ALS & occasionally FTD/ALS or bvFTD
UBQLN2 UBQLN2-ALS/FTD (OMIM 300857)Mean: 42 yrs; range: 16-71 yrsMean: 4 yrs; range: 1-15+ yrsTDP-43-positive inclusionsAssoc w/ALS & occasionally FTD/ALS. X-linked inheritance.
VCP Inclusion body myopathy w/Paget disease of bone &/or FTD (IBMPFD)Mean: 40 yrs; range: 35-66 yrsMean: 6 yrs after dementia diagnosisNumerous intranuclear & rare neuronal cytoplasmatic inclusions; dystrophic neuritis seen in neuropathology; TDP-43 type D pathologyAdult-onset proximal & distal muscle weakness (clinically LGMD 5), early-onset PDB, & FTD. Can also present as ALS.
Non-FTD spectrum disorders
HTT Huntington disease Range: 35-44 yrsMedian:15-18 yrsDegeneration of neurons in caudate, putamen, & cerebral cortexBehavioral & psychiatric manifestations of MAPT-FTD can be confused w/those of HD.
APP
PSEN1
PSEN2 6		Early-onset familial Alzheimer disease (See Alzheimer Disease Overview.)APP: usually 40s & 50s (range: 30-65 yrs)
PSEN1: usually 40s or early 50s (range: 30s-early 60s)
PSEN2: 40-75 yrs		PSEN1: relatively rapid progression over 6-7 yrs is common.
PSEN2: mean: 11 yrs		β-amyloid plaques, intraneuronal neurofibrillary tangles (containing tau protein), & amyloid angiopathyCan sometimes present w/prominent behavioral syndrome similar to bvFTD, particularly PSEN1-related Alzheimer disease, & therefore may be confused w/MAPT-FTD

AD= Alzheimer disease; ALS = amyotrophic lateral sclerosis; bvFTD = behavioral variant FTD; CBS = corticobasal syndrome; CNS = central nervous system; DiffDx = differential diagnosis; FTD = frontotemporal dementia; FUS = fused in sarcoma; HD = Huntington disease; LGMD = limb-girdle muscular dystrophy; PD = Parkinson disease; PDB = Paget disease of bone; PLS = primary lateral sclerosis; PPA = primary progressive aphasia

1.
2.
3.
4.

Paget disease of bone (PDB) involves focal areas of increased bone turnover that typically leads to spine and/or hip pain and localized enlargement and deformity of the long bones.

5.

Muscle weakness progresses to involve other limb and respiratory muscles; cardiac failure and cardiomyopathy have been observed in later stages of IBMPFD.

6.

It is likely that pathogenic variants in other genes causative of early-onset familial Alzheimer disease will be identified because kindreds with autosomal dominant familial Alzheimer disease with no known pathogenic variants in PSEN1, PSEN2, or APP have been described (see Alzheimer Disease Overview).

From: MAPT-Related Frontotemporal Dementia

Cover of GeneReviews®
GeneReviews® [Internet].
Adam MP, Feldman J, Mirzaa GM, et al., editors.
Seattle (WA): University of Washington, Seattle; 1993-2024.
Copyright © 1993-2024, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2024 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.