Table 2.

Genes in the Differential Diagnosis of GRN Frontotemporal Dementia

Gene(s)DiffDx
Disorder		Clinical Features of DiffDx Disorder
OnsetDisease
Duration		PathologyComment
Most commonly involved genes
C9orf72 ALS & FTD Mean: 54.3 yrs; range: 34-74 yrsMean: 5.3 yrs; range: 1-16 yrsTDP-43 pathology is found in a wide neuroanatomic distribution, w/particular involvement in extramotor neocortex & hippocampus & in lower motor neuronsMay be misdiagnosed as bvFTD, PPA-PNFA, or ALS. 1 Heterogeneity in clinical presentation is common w/in families. Phenotypes tend to converge w/disease progression.
MAPT FTDP-17 (See MAPT-Related Frontotemporal Dementia.)Usually age 40-60 yrs; may occur earlier or laterUsually 5-10 yrs; may be up to 20-30 yrsAt autopsy, all persons w/FTDP-17 show tau-positive inclusion pathology, whereas all persons w/GRN-FTD show ub-ir neuronal intranuclear inclusions. 2Presenile dementia affecting frontal & temporal cortex & some subcortical nuclei. Variable presentation; may present w/slowly progressive behavioral changes, language disturbances, &/or extrapyramidal signs; progresses over a few yrs to profound dementia w/mutism. 25%-40% of families w/AD FTD have mutation of MAPT.
Less commonly involved genes
CHMP2B CHMP2B-FTD Typically in late 50sNeuropathology assoc w/ubiquitin-positive but TDP-43- & FUS-negative inclusionsUsually presents w/a frontal lobe syndrome, parkinsonism, dystonia, pyramidal signs. Myoclonus may occur later in disease course.
TARDBP TARDBP-related ALS or ALS w/FTD 41-60 yrs2-4 yrsTDP-43 inclusions in upper & lower motor neurons & cortexAssoc w/~3% of familial ALS & occasionally FTD w/ALS
VCP Inclusion body myopathy w/Paget disease of bone & FTD (IBMPFD)Muscle disease & PDB: age 42 yrs; FTD: age 55 yrsNumerous intranuclear & infrequent # of neuronal cytoplasmatic inclusions & dystrophic neuritis seen in neuropathologyAdult-onset proximal & distal muscle weakness (clinically LGMD 3), early-onset PDB 4, & FTD. Early-stage FTD: dysnomia, dyscalculia, comprehension deficits, paraphasic errors, & relative preservation of memory. Later stages: inability to speak, auditory comprehension deficits for even 1-step commands, alexia, & agraphia

AD= autosomal dominant; ALS = amyotrophic lateral sclerosis; DiffDx = differential diagnosis; FTD = frontotemporal dementia; bvFTD = behavioral variant FTD; FTDP = frontotemporal dementia with parkinsonism; FUS = fused in sarcoma; LGMD = limb-girdle muscular dystrophy; PNFA = progressive nonfluent aphasia; PDB = Paget disease of bone; PPA = primary progressive aphasia

1.
2.
3.

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

4.

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

From: GRN Frontotemporal Dementia

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