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Frontotemporal Dementia

December 14, 2017

Disease synonyms

Frontotemporal dementia, FTD

Inheritance pattern

Autosomal dominant

Clinical features

Frontotemporal dementia (FTD) is a clinically and pathologically heterogeneous group of non-Alzheimer dementias characterized by selective and progressive atrophy involving the frontal or temporal lobes1. It typically develops in the sixth decade of life 2, but some cases manifest at younger ages, where it may mimic psychiatric disorders such as schizophrenia, bipolar affective disorder, and major depression. The estimated prevalence of FTD ranges between 15 and 22 in 100,000, with 25% of all cases with late-life onset3. Population studies show nearly equal distribution by gender.

Frontotemporal dementia Infographics

FTD has three main clinical manifestation groups based on the dominant symptoms at diagnosis:

  • The first is the frontal variant or behavioral variant, which may represent 70% of FTD 4. Frontal variant FTD results in alterations in interpersonal skills and behavior. Persons may show uninhibited behavior, disinhibition, apathy, or new obsessions or rituals, usually first noticed by a close contact of the patient 5, 6.
  • Progressive nonfluent aphasia variant is another manifestation group in which patients present with word-finding difficulty. Speech can become nonfluent, but comprehension remains intact5, 6. A semantic subtype of dementia is characterized by the loss of semantic memory. Patients may present with loss of word understanding and the inability to use or recall certain words. Instead, patients use less precise substitute terms and phrases 5, 6.
  • Movement disorder-related frontotemporal dementia: The following disorders, which are a part of the frontotemporal degeneration spectrum, produce changes in muscle functions with or without behavior or language problems:
    • Amyotrophic lateral sclerosis (ALS), which causes muscle weakness or wasting. ALS is a motor neuron disease also known as Lou Gehrig’s disease.
    • Corticobasal syndrome, which causes the arms and legs to become uncoordinated or stiff.
    • Progressive supranuclear palsy (PSP), which causes muscle stiffness, difficulty walking and changes in posture. It also affects eye movements.

In a small proportion of patients, extrapyramidal signs, such as rigidity or parkinsonian syndrome, may develop. These cases may overlap with Lewy body dementia, in which fluctuating mental status, early visual hallucinations, and sleep behavior disorder are characteristic, along with mild parkinsonian motor symptoms. Widespread muscle atrophy, bulbar signs, fasciculations, muscle weakness and hyperreflexia may ensue in patients with motor neuron disease.

Approximately 20–40% of FTD cases have a family history of disease, and 10% of FTD cases are inherited in an autosomal dominant fashion 8. The most notable variants are found in MAPT (microtubule-associated protein tau), C9ORF72, and PGRN (progranulin) 7. Genes associated with frontotemporal dementia are listed in the table.

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance
ALS2 606352 amyotrophic lateral sclerosis 2; Spastic paralysis, infantile onset ascending AR
ANG 105850 amyotrophic lateral sclerosis 9
APOE 107741 Alzheimer Disease 2; Sea-blue histiocyte disease; Macular Degeneration, Age-Related, 1; early-onset familial Alzheimer disease-3; Lipoprotein glomerulopathy AD, AR
APP 104760 Alzheimer Disease; Cerebral Amyloid Angiopathy, App-Related AD
ARSA 607574 metachromatic leukodystrophy AR
ATL1 606439 spastic paraplegia 3A AD
ATP7B 606882 Wilson disease AR
ATXN2 601517 Susceptibility to late-onset Parkinson disease; spinocerebellar ataxia 2 AD
BSCL2 606158 Lipodystrophy, congenital generalized, type 2; spastic paraplegia 17; Neuropathy, distal hereditary motor, type V; Encephalopathy, progressive, with or without lipodystrophy AD, AR
C9orf72 614260 frontotemporal dementia and/or amyotrophic lateral sclerosis AD
CHCHD10 615903 Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 AD
CHMP2B 609512 Dementia, familial, nonspecific; amyotrophic lateral sclerosis 17 AD
CP 117700 aceruloplasminemia AR
CSF1R 164770 hereditary diffuse leukoencephalopathy with axonal spheroids and pigmented glia AD, AR
DCTN1 601143 amyotrophic lateral sclerosis 1; Perry syndrome; Neuronopathy, Distal Hereditary Motor, Type Viib AD, AR
ERBB4 600543 Amyotrophic lateral sclerosis 19 AD
FIG4 609390 Yunis-Varon syndrome; type 4J Charcot-Marie-Tooth disease; amyotrophic lateral sclerosis 11; Polymicrogyria, bilateral temporooccipital AD, AR
FTL 134790 Hyperferritinemia With Or Without Cataract; neurodegeneration with brain iron accumulation 3 AD, AR
FUS 137070 amyotrophic lateral sclerosis 6; Tremor, hereditary essential, 4 AD
GRN 138945 frontotemporal lobar degeneration with ubiquitin-positive inclusions; neuronal ceroid lipofuscinosis type 11 AD, AR
HEXA 606869 Tay-Sachs disease/ GM2-gangliosidosis AR
HNRNPA1 164017 Amyotrophic lateral sclerosis 20 AD
HSPD1 118190 spastic paraplegia 13; hypomyelinating leukodystrophy-4 AD, AR
ITM2B 603904 Cerebral amyloid angiopathy, itm2b-related, 2; Cerebral amyloid angiopathy, itm2b-related, 1 AD
KIF5A 602821 spastic paraplegia 10; Neonatal intractable myoclonus AD
MAPT 157140 Susceptibility to late-onset Parkinson disease; Pick disease; Dementia, frontotemporal AD, AR
MATR3 164015 Myopathy, Distal, 2 AD
NEFH 162230 amyotrophic lateral sclerosis 1; Charcot-Marie-Tooth disease, axonal, type 2CC AD, AR
NOTCH3 600276 CADASIL; Lateral meningocele syndrome AD
NPC1 607623 Niemann-Pick disease type C/D AR
OPTN 602432 Adult-onset primary open angle glaucoma; Glaucoma, normal tension, susceptibility to; amyotrophic lateral sclerosis 12 AD
PANK2 606157 neurodegeneration with brain iron accumulation type 1; HARP syndrome AR
PFN1 176610 amyotrophic lateral sclerosis 18
PRNP 176640 Creutzfeldt-Jakob disease; Gerstmann-Straussler disease; Kuru, susceptibility to; Insomnia, fatal familial; Huntington disease-like 1; Prion disease with protracted course AD
PRPH 170710 amyotrophic lateral sclerosis 1 AD, AR
PSEN1 104311 Pick disease; Dementia, frontotemporal; early-onset familial Alzheimer disease-3; dilated cardiomyopathy-1U; Acne inversa, familial, 3 AD
PSEN2 600759 Alzheimer disease, type 4; dilated cardiomyopathy-1V AD
REEP1 609139 spastic paraplegia 31; Neuronopathy, distal hereditary motor, type VB AD
SETX 608465 amyotrophic lateral sclerosis 4; autosomal recessive spinocerebellar ataxia 1 AD, AR
SIGMAR1 601978 distal spinal muscular atrophy type 2; amyotrophic lateral sclerosis 16 AR
SLC52A3 613350 Fazio-Londe disease; Brown-Vialetto-Van Laere syndrome 1 AR
SNCA 163890 Lewy body dementia; Parkinson disease 1 AD
SOD1 147450 amyotrophic lateral sclerosis 1 AD, AR
SORL1 602005
SPAST 604277 spastic paraplegia-4 AD
SPG11 610844 Amyotrophic lateral sclerosis 5, juvenile; spastic paraplegia type 11; Charcot-Marie-Tooth disease, axonal, type 2X AR
SQSTM1 601530 Frontotemporal dementia and/or amyotrophic lateral sclerosis 3; Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset AD, AR
TARDBP 605078 amyotrophic lateral sclerosis 10 AD
TBK1 604834 Frontotemporal dementia and/or amyotrophic lateral sclerosis type 4; Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8 AD
TREM2 605086 polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy type 2 AD
TUBA4A 191110 amyotrophic lateral sclerosis 22 AD
TYROBP 604142 polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy type 1 AR
UBE3A 601623 Angelman syndrome AD
UBQLN2 300264 amyotrophic lateral sclerosis 15 XLD
VAPB 605704 Finkel type late-onset spinal muscular atrophy; amyotrophic lateral sclerosis 8 AD
VCP 601023 inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1; amyotrophic lateral sclerosis 14; Charcot-Marie-Tooth disease type 2Y AD
WASHC5 610657 Ritscher-Schinzel syndrome; spastic paraplegia 8 AD, AR

There is no specific treatment for frontotemporal dementia. There are medications which can reduce agitation and other behavioral problems and/or depression. These treatments should be used to help improve the quality of life.

Differential diagnosis

The differential diagnosis of Alzheimer disease-related disorders includes the following diseases - depending on the major presenting symptoms:

Other causes of dementia, especially treatable forms of cognitive decline including:

  • Depression
  • Chronic drug intoxication
  • Chronic CNS infection
  • Thyroid disease
  • Vitamin B12 and thiamine deficiencies

Other degenerative disorders associated with dementia, such as:

  • Amyotrophic lateral sclerosis
  • Alzheimer´s disease
  • Picks disease
  • Parkinson disease
  • Diffuse Lewy body disease
  • Creutzfeldt-Jakob disease

Testing strategy

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for frontotemporal dementia:

Step 1: NGS Panel (including repeat expansion testing)

Step 2: Whole genome sequencing

Referral reasons

The following individuals are candidates for Frontotemporal dementia gene panel testing:

  • Individuals with a family history of frontotemporal dementia and presentation of the most common symptoms
  • Individuals without a positive family history, but with symptoms resembling frontotemporal dementia
  • Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).

Test utility

Sequencing, deletion/duplication of frontotemporal dementia related genes should be performed in all individuals suspected of having this condition. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of pathogenic variants, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of frontotemporal dementia, identify at-risk family members, provide information on reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.