Frontotemporal Dementia with Parkinsonism linked to Chromosome 17 (FTDP-17)
Overview
Frontotemporal Dementia with Parkinsonism linked to Chromosome 17 (FTDP-17) is a rare, autosomal dominant neurodegenerative disorder characterized by the progressive onset of frontotemporal dementia and parkinsonian features. It is caused by mutations in the [MAPT gene](/genes/mapt) (Microtubule-Associated Protein Tau) located on chromosome 17q21.31[@hutton1998]. FTDP-17 is classified as a 4R-tauopathy, meaning it involves the preferential accumulation of four-repeat (4R) tau isoforms in the brain[@lee2001].
The disease was first recognized as a distinct entity in the mid-1990s when genetic linkage studies mapped the disease locus to chromosome 17q21-22 in several large families with autosomal dominant inheritance of frontotemporal dementia and parkinsonism[@lynch1994].
Genetics
MAPT Gene Mutations
FTDP-17 is caused by pathogenic variants in the MAPT gene, which encodes the microtubule-associated protein tau. Over 50 pathogenic MAPT mutations have been identified in FTDP-17 families, making it one of the most genetically heterogeneous frontotemporal dementia syndromes[@ghetti2015].
The mutations can be broadly categorized into two groups:
Coding region mutations: These alter the amino acid sequence of [tau protein](/proteins/tau), affecting its ability to bind microtubules and promoting aggregation
- P301L, P301S, P301T: Most common, highly penetrant
- V337M, G389R, R406W: Also frequently reported
...Frontotemporal Dementia with Parkinsonism linked to Chromosome 17 (FTDP-17)
Overview
Frontotemporal Dementia with Parkinsonism linked to Chromosome 17 (FTDP-17) is a rare, autosomal dominant neurodegenerative disorder characterized by the progressive onset of frontotemporal dementia and parkinsonian features. It is caused by mutations in the [MAPT gene](/genes/mapt) (Microtubule-Associated Protein Tau) located on chromosome 17q21.31[@hutton1998]. FTDP-17 is classified as a 4R-tauopathy, meaning it involves the preferential accumulation of four-repeat (4R) tau isoforms in the brain[@lee2001].
The disease was first recognized as a distinct entity in the mid-1990s when genetic linkage studies mapped the disease locus to chromosome 17q21-22 in several large families with autosomal dominant inheritance of frontotemporal dementia and parkinsonism[@lynch1994].
Genetics
MAPT Gene Mutations
FTDP-17 is caused by pathogenic variants in the MAPT gene, which encodes the microtubule-associated protein tau. Over 50 pathogenic MAPT mutations have been identified in FTDP-17 families, making it one of the most genetically heterogeneous frontotemporal dementia syndromes[@ghetti2015].
The mutations can be broadly categorized into two groups:
Coding region mutations: These alter the amino acid sequence of [tau protein](/proteins/tau), affecting its ability to bind microtubules and promoting aggregation
- P301L, P301S, P301T: Most common, highly penetrant
- V337M, G389R, R406W: Also frequently reported
Splicing mutations: These affect the alternative splicing of exon 10, leading to altered 3R/4R tau ratio
- S305I, S305N, +3, +12, +14, +16 intronic mutations
Inheritance Pattern
FTDP-17 follows an autosomal dominant inheritance pattern with high penetrance. Affected individuals have a 50% chance of passing the mutation to each offspring. Genetic testing is available for at-risk individuals and families with known mutations[@rascovsky2011].
H1 Haplotype
The H1 haplotype of MAPT serves as a genetic risk factor for sporadic 4R tauopathies including FTDP-17, PSP, and CBD. The H1c sub-haplotype is particularly associated with increased risk[@pittman2004].
Clinical Features
Core Symptoms
The clinical presentation of FTDP-17 is heterogeneous, even within families carrying the same mutation. The two core features are:
Frontotemporal Dementia Symptoms:
- Progressive personality changes
- Disinhibition and inappropriate social behavior
- Apathy and loss of initiative
- Language difficulties (particularly in later stages)
- Executive dysfunction
- Memory impairment (typically less prominent than in AD)
Parkinsonian Features:
- Bradykinesia (slowness of movement)
- Rigidity (often axial, affecting neck and trunk)
- Tremor (less common than in idiopathic PD)
- Postural instability
- Gait disturbance
Phenotypic Variability
Different MAPT mutations are associated with somewhat distinct clinical phenotypes:
| Mutation | Primary Phenotype | Age of Onset |
|----------|------------------|---------------|
| P301L | FTD-Parkinsonism | 45-55 years |
| P301S | FTD with PSP-like features | 50-60 years |
| +3 intronic | CBD-like phenotype | 40-55 years |
| V337M | FTD with parkinsonism | 50-60 years |
| R406W | FTD, prominent memory loss | 55-65 years |
Pathology
Neuropathological Findings
FTDP-17 is characterized by:
- Frontotemporal atrophy: Particularly affecting the frontal and anterior temporal lobes
- Neuronal loss and gliosis: In affected cortical regions and subcortical structures
- Substantia nigra degeneration: Loss of dopaminergic [neurons](/entities/neurons)
- Basal ganglia involvement: Variable involvement of caudate nucleus, putamen, and globus pallidus
Tau Pathology
The defining feature of FTDP-17 is tau protein pathology:
Tau filament inclusions: Neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau
4R tau predominance: Most FTDP-17 cases show predominant 4R tau accumulation, distinguishing it from AD
Distribution: Tau pathology affects both neurons and glia, with variable patterns depending on the specific mutation[@forman2002]Comparison to Other 4R-Tauopathies
FTDP-17 shares overlapping pathological features with other 4R tauopathies:
| Feature | FTDP-17 | PSP | CBD |
|---------|---------|-----|-----|
| Inheritance | Autosomal dominant | Sporadic | Sporadic |
| Primary cause | MAPT mutations | Unknown | Unknown |
| 4R tau | Yes | Yes | Yes |
| Clinical phenotype | FTD + Parkinsonism | Vertical gaze palsy | Cortical signs |
Diagnosis
Clinical Diagnosis
FTDP-17 is diagnosed based on:
Clinical criteria: Presence of frontotemporal dementia plus parkinsonism
Family history: Autosomal dominant pattern suggests FTDP-17
Genetic testing: Identification of pathogenic MAPT mutation confirms diagnosis
Neuroimaging: MRI showing frontotemporal atrophy
FDG-PET: Hypometabolism in frontal and temporal lobesDifferential Diagnosis
FTDP-17 must be distinguished from:
- [Alzheimer's disease](/diseases/alzheimers-disease): Different cognitive profile (memory-first vs. behavioral-first), different tau isoforms
- Progressive supranuclear palsy: Vertical supranuclear gaze palsy is typically absent in FTDP-17
- Corticobasal degeneration: Asymmetric cortical signs are more prominent
- Classic [Parkinson's disease](/diseases/parkinsons-disease): No prominent frontotemporal cognitive changes
- Other frontotemporal dementia subtypes: Behavioral variant FTD without parkinsonism
Genetic Counseling
Given the autosomal dominant inheritance, genetic counseling is essential for:
- At-risk family members
- Individuals considering genetic testing
- Families with known MAPT mutations
- Reproductive planning
Treatment
Symptomatic Management
There is currently no disease-modifying therapy for FTDP-17. Management focuses on symptomatic relief:
For behavioral symptoms:
- Selective serotonin reuptake inhibitors (SSRIs) for disinhibition and depression
- Antipsychotics (with caution due to sensitivity)
- Environmental modifications and caregiver support
For parkinsonism:
- Levodopa/carbidopa: Variable response, often limited
- Dopamine agonists: May provide some benefit
- Physical therapy for mobility maintenance
For cognitive symptoms:
- acetylcholinesterase inhibitors: Generally less effective than in AD
- Speech and occupational therapy
- Supportive care and caregiver education
Emerging Therapies
Several therapeutic approaches are under investigation:
Tau-targeting therapies:
- Anti-tau antibodies (e.g., gosuranemab, tilavonemab)
- Small molecule tau aggregation inhibitors
- ASO (antisense oligonucleotide) therapy targeting MAPT mRNA
Gene therapy approaches:
- AAV-mediated gene delivery
- CRISPR-based editing for future therapeutic applications
Modulation of splicing:
- Splicing modifier compounds to restore normal 3R/4R ratio
Research and Clinical Trials
FTDP-17 provides a unique window into tau biology because:
- It is directly caused by MAPT mutations
- It allows study of how different mutations produce different phenotypes
- It serves as a genetic model for sporadic 4R tauopathies
Clinical trials for tau-targeting therapies often include FTDP-17 patients due to the known genetic cause and 4R tau pathology.
FTDP-17 is part of a spectrum of MAPT-related disorders:
- [Primary 4R tauopathies: PSP, CBD, AGD (argyrophilic grain disease)](/diseases/progressive-supranuclear-palsy)
- [Other frontotemporal dementias: bvFTD, semantic variant PPA, nonfluent variant PPA](/genes/ar)
- [Parkinsonian syndromes: MSA, PD with dementia](/genes/ar)
- [--](/proteins/n--cadherin-protein)
- [MAPT gene](/genes/mapt)
External Links
- [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
- [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)
References
[Hutton M, Lendon CL, Rizzu P, et al, Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17 (1998)](https://doi.org/10.1038/30967)
[Lee VM, Goedert M, Trojanowski JQ, Neurodegenerative tauopathies (2001)](https://doi.org/10.1146/annurev.neuro.24.1.1121)
[Lynch T, Sano M, Marder KS, et al, Clinical characteristics of a family with chromosome 17-linked frontotemporal dementia (1994)](https://pubmed.ncbi.nlm.nih.gov/7966195/)
[Ghetti B, Oblak AL, Boeve BF, et al, Frontotemporal dementia caused by MAPT mutations: a detailed clinical and neuropathological overview (2015)](https://doi.org/10.1093/brain/awv071)
[Rascovsky K, Hodges JR, Knopman D, et al, Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia (2011)](https://doi.org/10.1093/brain/awr179)
[Pittman AM, Myers AJ, Abou-Sleiman P, et al, Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and frontotemporal dementia (2004)](https://doi.org/10.1136/jmg.2004.029421)
[Forman MS, Zhukareva V, Bergeron C, et al, Signature tau neuropathology in gray matter and select white matter regions of three subjects with MAPT mutations P301L, P301S, and V337M (2002)](https://pubmed.ncbi.nlm.nih.gov/11980909/)