Under the Umbrella -- FTD with Parkinsonism-17 (FTDP-17)

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Overview

Hereditary Frontotemporal Dementia with Parkinsonism-17 (FTDP-17) is a progressive dementia that can present with a variety of clinical features, including behavioral and cognitive changes, psychiatric symptoms, language disturbances, and/or motor dysfunction. Onset of these symptoms typically occurs between 40 and 60 years of age.

A diagnosis of FTDP-17 relies on three types of data: clinical findings, neuroimaging studies, and family history. Gene testing currently being performed on a research basis may reveal a specific mutation responsible for the disorder in a family. It is important to note that this is the only FTD subtype that has been attributed to mutations in a specific gene (located on chromosome 17), and for which gene testing is currently available. It is also the one subtype for which the cause of brain pathophysiology (disease changes found in the brain upon autopsy) is understood.


Key Clinical Features

Behavioral Symptoms
A progressive deterioration in the patients' ability to control or adjust his/her behavior appropriately in different social contexts is the hallmark of all of these behavior changes, and results in the embarrassing, inappropriate social situations that can be one of the most disturbing facets of FTD.
* Hyperoral behaviors include overeating, dietary compulsions, in which the person restricts himself to eating only specific foods (such as a certain flavor of Lifesaver, or eating food only from one fast food restaurant), or attempts to consume inedible objects. Patients may consume excessive amounts of liquids, alcohol and cigarettes.
* Stereotyped and/or Repetitive behaviors can include re-reading the same book multiple times, hand rubbing and clapping, humming one tune repeatedly, or walking to the same location day after day.
* Personal hygiene habits deteriorate early in the disease progression, as the person fails to perform everyday tasks of bathing, grooming, and appropriate dressing.
* Hyperactive behavior is exhibited by some patients, and can include agitation, pacing, wandering, outbursts of frustration, and aggression.
* Hypersexual behavior can range from a preoccupation with sexual jokes to compulsive masturbation.
* Impulsive acts can include shoplifting, impulsive buying, and grabbing food off of another person's plate.

Emotional Symptoms
* Apathy or an indifference toward events and the surrounding environment can be marked by reduced initiative, and lack of motivation.
* Lack of insight into the person's own behavior develops early. The patient typically does not recognize the changes in his or her own behaviors, nor do they exhibit awareness or concern for the effect these behaviors have on the people around them, including loved ones.
* Emotional blunting develops early in the course of the disorder, and is manifested as a loss of emotional warmth, empathy, and sympathy, and development of what appears to be indifference toward other people, including loved ones.
* Mood changes can be abrupt and frequent.

Cognitive Symptoms
FTD patients typically suffer increasing impairment in “executive functions”, listed below.
* Distractibility and impersistence mean the person has increasing difficulty staying on task mentally.
* Mental rigidity and inflexibility develop as the person may insist on having his or her own way, or have increasing difficulty adapting to new or changing circumstances.
* Planning and problem solving impairments develop as the ability for abstract reasoning decreases. Examples of this would include difficulty planning and coordinating the cooking of a meal, or making a shopping list and performing necessary errands.
* Poor financial judgment can produce additional, troubling situations for families.

Neurological Symptoms
* Movement Dysfunction symptoms may be some of the first to develop, and are similar to those seen in Parkinson disease (in these patients the term “parkinsonism” is used to distinguish the fact that they do not have Parkinson disease, though they do exhibit some of these symptoms). These include: decreased facial expression, bradykinesia (slowness of movements), rigidity (resistance to imposed movement), and postural instability. Less commonly, patients may develop symptoms seen in Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD), including difficulty with eye movements, dystonia (abnormal muscle postures), or alien hand syndrome (in which the person does not recognize his hand as being part of his own body).
* Seizures occur in a minority of patients, those found to have a specific gene mutation (called P301S).

Neuroimaging Studies reveal some characteristic changes in the brain. These may include the following:
* Decreased blood flow in the anterior part of the brain seen early in the disease using SPECT imaging (Single Photon Emission Computed Tomography). This feature may be unilateral or bilateral, but it invariably worsens with the course of the disorder.
* Atrophy of the cerebral cortex and enlargement of the ventricles in the brain seen as the disease progresses, using MRI (magnetic resonance imaging) and CT (computed tomography). This feature may be unilateral or bilateral, but it invariably worsens with the course of the disorder.

Family history of FTD-type dementia and/or parkinsonism in two or more first-degree relatives (children or siblings) is currently a component being used to make a diagnosis of FTDP-17.


Key Pathologic Features

Upon autopsy, all FTDP-17 patients are found to have excess deposits of an irregular form of tau protein in the frontal and temporal lobes of the brain. Neuronal loss, gliosis (overgrowth, or development of tumors), and spongiosis (swelling with excess fluid) are also seen when the tissue of the cortex is viewed under a microscope.


Causes

It is the irregular deposits of tau in the brain of FTDP-17 patients that leads to the clinical symptoms seen in the disorder. The cause of these irregular protein deposits is any one of a variety of mutations in the MAPT gene (Microtubule-Associated Protein Tau gene). The MAPT gene is located on chromosome 17, and contains the instructions the brain needs to produce the protein tau. In a normal brain, the tau protein is present in a couple of different forms, all of which appear necessary to carry out important aspects of normal brain function. In FTDP-17, however, researchers have found both unusual versions of tau (one of these is a hyperphosphorylated version) and/or an imbalance in the relative amounts of normal versions of the protein. A variety of mutations (changes, or “typos” in the genetic instructions) have been identified in the MAPT gene, which produce these irregularities.


Genetics

FTDP-17 is the one FTD that has been associated with mutations in a specific gene. Patients with any FTD diagnosis who have a specific hereditary pattern of dementia or parkinsonism in their family should meet with a genetic counselor, who will take a detailed family history. If analysis of this history suggests an autosomal dominant pattern of inheritance (a clear pattern of FTD-type diagnoses being passed from generation to generation, with virtually every patient having an affected parent and each child of an affected person having a 50% chance to inherit the disorder) families will qualify for a research protocol which performs DNA sequence testing of the MAPT gene. Experience currently shows that 25% - 40% of the families who meet the research testing criteria will be found to have a mutation in the MAPT gene.


Treatment

There is currently no treatment regimen proven effective in FTDP-17 patients. The motor symptoms may be partially responsive to levodopa treatment (typically used in Parkinson patients). Sedative or antipsychotic drugs may help reduce the symptoms of restlessness, roaming, delusions and hallucinations. Anti-epileptic drugs are effective in patients who experience seizures.


Management and Prognosis

Onset of FTDP-17 symptoms typically occurs between 40 and 60 years of age. The course of the disease usually takes 5-10 years, but may extend to 20-30 years. It eventually progresses into profound dementia with mutism.

Behavioral changes and loss of insight and judgment can become a severe burden for caregivers.


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Material prepared by Jennifer M. Farmer, MS, CGC, Website Clinical Consultant and Susan L-J Dickinson, MS, CGC, Website Medical and Science Writer.