Frontotemporal Dementia

Frontotemporal dementia, FTD

Autosomal dominant

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 intact^{5, 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.

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:

• 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
• CADASIL

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.