Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17).

The term frontotemporal dementia and parkinsonism linked to chromosome 17 was defined during the International Consensus Conference in Ann Arbor, Michigan, in 1996 1. At the time, affected individuals with frontotemporal dementia and parkinsonism linked to the wld locus on chromosome 17 had been identified within 13 families. This syndrome is a familial disorder with autosomal dominant inheritance. The three major clinical features include behavioral disturbances, cognitive impairment, and parkinsonism. There are no strict diagnostic criteria for FTDP-17. Nevertheless, FTDP-17 should be considered in the differential diagnosis in the presence of one or more of the following 2:

• Age of onset of neurological symptoms between the third and fifth decades;

• Progressive neuropsychiatric syndrome including personality and behavioral abnormalities and/or frontotemporal dementia;

• Parkinsonism-plus syndrome (bradykinesia, rigidity, postural instability, paucity of resting tremor, and poor or no response to dopaminergic therapy) frequently associated with falls and supranuclear gaze palsy and less commonly associated with apraxia, dystonia, and lateralization;

• Progressive speech difficulties from the onset of the illness;

• Seizure disorder poorly controlled by standard anticonvulsant therapy;

• Positive family history suggestive of autosomal dominant inheritance of a neurodegenerative disorder, even if there has been variability in clinical presentations.

FTDP-17 is an extremely rare condition. Its prevalence and incidence remain unknown. Over 100 families with FTDP-17 have been reported to date in numerous countries (USA, Great Britain, Japan, Netherlands, France, Canada, Australia, Italy, Germany, Israel, Ireland, Spain and Sweden). Some of these families share a common founder 3. We estimate that there have been about 50–600 patients described, with fewer than 70 individuals still living. Molecular genetic studies have identified 38 unique mutations in these families (Figure 1). The most common mutations, accounting for approximately 60% of known cases, are P301L, N279K and a splice site mutation (exon 10 +16) 4.

Mutations in the tau gene account for the vast majority of FTDP-17 cases. Tau is a microtubule-binding protein abundant in neurons and glia. In neurons, it is predominantly expressed in axons. Tau binds to and stabilizes microtubules and promotes microtubule assembly. The majority of the currently known mutations in coding region occur within the microtubule-binding region of tau gene. Most known mutations in non-coding regions affect the splicing of exon 10 4. The pathogenetic mechanisms in FTDP-17 are thought to be related to the altered proportion of tau isoforms or to the ability of tau to bind microtubules and to promote microtubule assembly.

Mutations in tau gene associated with FTDP-17 fall into two broad mechanistic groups. One group contains coding mutations (missense and two deletions) that, in recombinant protein studies and in transfected cell assays, have been shown to disrupt the binding of tau to microtubules. In addition, the majority of these mutations have also been shown to accelerate the aggregation of recombinant tau in the presence of polyanions. Thus, overall, these mutations are predicted both to increase the proportion of tau that is unbound to microtubules and available for aggregation and also to increase directly the tendency of the unbound tau to form filaments. The second group of tau mutations appears to cause disease by disrupting the alternative splicing of exon 10 and hence the ratio of 4R: 3R tau. These mutations comprise a mixture of coding changes, within exon 10 (N279K, delK280, L284L, N296N/H, delN296, P301L/S, G303V, and S305S/N) and also intronic mutations close to the 5' splice site of exon 10 (at positions +3, +11, +12, +13, +14, +16, +19, and +29). All but three of these mutations have been demonstrated to increase the splicing-in of exon 10 and hence the proportion of 4R tau. The exceptions are delK280, +19, and, +29 mutations that show increased 3R: 4R ratio as compared with normal condition 5. The +29 mutation has been detected in both affected individuals with the FTD phenotype and normal controls 678. Therefore, it is still unclear whether this splicing mutation contributes to disease development.

Characteristic clinical and pathological features of FTDP-17 coupled with a molecular genetic analysis of the tau gene are essential steps for a diagnosis.

Imaging studies such as computerized tomography (CT) and magnetic resonance imaging (MRI) can assist in establishing a diagnosis, mainly by excluding other diagnostic possibilities such as the presence of a brain tumor, abscess, multi-infarct state, or hydrocephalus.

Clinically, FTDP-17 may mimic several neurodegenerative diseases. The differential diagnosis of FTDP-17 includes disorders with initial signs such as behavioral and personality abnormalities, parkinsonism, lower motor neuron dysfunction or cognitive impairments. In the absence of a positive family history or molecular genetic data, FTDP-17 is most frequently confused with Pick's disease, sporadic progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD). Other familial frontotemporal dementias, parkinson-plus syndromes, dementia with Lewy bodies (DLB), Parkinson's disease (PD), multiple system atrophy (MSA) should be excluded. A neuropathologic examination coupled with molecular genetic analysis of the tau gene are essential steps towards distinguishing FTDP-17 from other neurodegenerative diseases associated with tau deposition. The pathologic analysis should include immunohistochemical studies using multiple anti-tau antibodies.

Affected individuals should be counseled regarding the estimated probability of passing the genetic bases for their illness on to their offspring. As FTDP-17 is an autosomal dominantly inherited condition, each offspring of an affected individual will carry a 50% risk of inheriting the abnormal gene. Some of these mutations can be detected through genetic testing. The individual who inherits a mutation will not necessarily develop the same clinical syndrome as the parent, because penetrance may be incomplete, neurologic manifestations vary greatly even within families, or the individual might die from unrelated causes. In the case of the pallido-ponto-nigral degeneration (PPND) subtype of FTDP-17, however, penetrance is complete and virtually all individuals who inherit the mutation will become symptomatic during middle age.

At-risk individuals may sometimes choose to adopt rather than bear their own children. When faced with the option of genetic testing, some people prefer the greater certainty that a genetic diagnosis may afford when planning life decisions, while others find not knowing to be a lesser emotional burden as well as a lesser risk of being denied healthcare should their insurance carrier learn the test result. In either case the patient's choice should be respected.

Inquiring into the family history can also identify relatives who may be at risk of having inherited the genetic basis for FTDP-17 and who thus may be presymptomatic.

Clinical genetic testing of affected and presymptomatic individuals is commercially available for some mutations. However, there tends to be little interest among at-risk family members to undergo clinical genetic testing 29.

Once a genetic basis for a subtype of FTDP-17 is discovered and testing for that gene becomes commercially available, it becomes possible, in principle, to identify that gene antenatally by sampling amniotic fluid or by preimplantation genetic diagnosis. Genetic counseling should accompany antenatal genetic diagnosis.

Currently, a curative treatment for FTDP-17 does not exist, and most patients respond poorly, if at all, to levodopa. Palliative and symptomatic interventions are the mainstay of treatment. Physical therapy can be helpful to preserve some measure of mobility and independence in activities of daily living and to reduce the risk of falling. Stool softening agents are recommended for constipation. Speech therapy, swallowing assessment, and switching to a softer diet may be helpful for dysphagia. Anticholinergics may be helpful for sialorrhea or urinary frequency but carry the risk of aggravating mental confusion. Clozapine or quetiapine may be helpful for psychosis not explained by systemic infection or responsive to medication withdrawal. Antidepressant medications may be indicated for concurrent depression. Bed-bound patients will require frequent repositioning or air flow mattresses. Patients should be encouraged to discuss their treatment preferences with their families and their physicians and to indicate their choices by advance directives.

The prognosis varies considerably. Most patients with FTDP-17 will experience several months to one or two years of moderate impairment followed by an unremitting downward course of physical and cognitive decline. The rate of progression varies greatly among individual patients and genetic kindreds, ranging from life expectancies of several months to several years, and, in exceptional cases, as long as two decades. In addition to the clinical features described above, in the late stages of illness these patients often develop secondary medical problems associated with immobility including falling injuries and respiratory and urinary tract infections.

It is hoped that further research will identify the genetic modifiers and environmental factors that influence the variable penetrance and clinical expression of FTDP-17. The development of transgenic mice may provide an opportunity to test novel therapeutic agents in the near future.