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 (Microtubule-Associated Protein Tau) located on chromosome 17q21.31[1]. FTDP-17 is classified as a 4R-tauopathy, meaning it involves the preferential accumulation of four-repeat (4R) tau isoforms in the brain[2].
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[3].
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[4].
The mutations can be broadly categorized into two groups:
Coding region mutations: These alter the amino acid sequence of tau protein, affecting its ability to bind microtubules and promoting aggregation
Splicing mutations: These affect the alternative splicing of exon 10, leading to altered 3R/4R tau ratio
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[5].
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[6].
The clinical presentation of FTDP-17 is heterogeneous, even within families carrying the same mutation. The two core features are:
Frontotemporal Dementia Symptoms:
Parkinsonian Features:
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 |
FTDP-17 is characterized by:
The defining feature of FTDP-17 is tau protein pathology:
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 |
FTDP-17 is diagnosed based on:
FTDP-17 must be distinguished from:
Given the autosomal dominant inheritance, genetic counseling is essential for:
There is currently no disease-modifying therapy for FTDP-17. Management focuses on symptomatic relief:
For behavioral symptoms:
For parkinsonism:
For cognitive symptoms:
Several therapeutic approaches are under investigation:
Tau-targeting therapies:
Gene therapy approaches:
Modulation of splicing:
FTDP-17 provides a unique window into tau biology because:
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)
Other frontotemporal dementias: bvFTD, semantic variant PPA, nonfluent variant PPA
Hutton M, Lendon CL, Rizzu P, et al. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998. ↩︎
Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annual Review of Neuroscience. 2001. ↩︎
Lynch T, Sano M, Marder KS, et al. Clinical characteristics of a family with chromosome 17-linked frontotemporal dementia. Neurology. 1994. ↩︎
Ghetti B, Oblak AL, Boeve BF, et al. Frontotemporal dementia caused by MAPT mutations: a detailed clinical and neuropathological overview. Brain. 2015. ↩︎
Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011. ↩︎
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. Journal of Medical Genetics. 2004. ↩︎
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. Journal of Neuropathology & Experimental Neurology. 2002. ↩︎