Frontotemporal dementia, FTD
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.
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|
|ATL1||606439||spastic paraplegia 3A||AD|
|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|
|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|
|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|
|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.
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:
- 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
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
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).
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.