Ftd 17 (Frontotemporal Dementia With Parkinsonism Linked To Chromosome 17) is a progressive neurodegenerative disorder characterized by the gradual loss of neuronal function. This page provides comprehensive information about the disease, including its pathophysiology, clinical presentation, diagnosis, and current therapeutic approaches.
FTD-17, also known as Frontotemporal Dementia with Parkinsonism linked to Chromosome 17, is a rare hereditary neurodegenerative disorder characterized by progressive frontotemporal dementia and parkinsonian features. It is caused by mutations in the MAPT[1] (Microtubule-Associated Protein Tau) gene located on chromosome 17q21. FTD-17 represents one of the most common forms of inherited frontotemporal dementia and is classified within the tauopathies, a group of neurodegenerative diseases characterized by abnormal accumulation of tau protein in the brain.[2]
The disease typically manifests in mid-adulthood, with onset usually occurring between 35 and 55 years of age. FTD-17 follows an autosomal dominant inheritance pattern, meaning that a single copy of the mutated gene from an affected parent can cause the disease in offspring.[3]
FTD-17 is caused by pathogenic mutations in the MAPT gene (also known as the tau gene), which provides instructions for making the tau protein. The MAPT gene is located on chromosome 17q21.31, a region that has been extensively studied due to its involvement in several neurodegenerative diseases.[1]
Over 50 pathogenic MAPT mutations have been identified in patients with FTD-17 and related tauopathies. These mutations can be classified into several categories:[4]
Splice site mutations: Mutations that affect the alternative splicing of exon 10 in the MAPT gene, leading to an imbalance between 3-repeat (3R) and 4-repeat (4R) tau isoforms. Examples include the +16, +14, and intron 10 mutations.
Missense mutations: Point mutations that change single amino acids in the tau protein, altering its ability to bind to microtubules and promoting aggregation. Common examples include P301L, P301S, G272V, and R406W.[5]
Exonic mutations: Mutations within exons that affect tau protein structure and function.
The most frequently observed mutation in FTD-17 is the P301L mutation, which has been identified in numerous families worldwide and is associated with a relatively early onset and rapid progression.[6]
The tau protein plays a critical role in maintaining the structure and function of neurons. In FTD-17, pathogenic MAPT mutations lead to:[2]
Hyperphosphorylation: Abnormal phosphorylation of tau protein reduces its ability to bind to microtubules, leading to microtubule destabilization and impaired axonal transport.
Aggregation: Mutant tau proteins have an increased tendency to form insoluble aggregates, including neurofibrillary tangles (NFTs), which are hallmark pathological features of FTD-17.[7]
Tau isoform imbalance: Mutations affecting exon 10 splicing lead to an imbalance between 3R and 4R tau isoforms, disrupting normal tau function.
FTD-17 presents with a combination of frontotemporal dementia symptoms and parkinsonian features:[3]
Frontotemporal Dementia Symptoms:
Parkinsonian Features:
FTD-17 typically follows a progressive course over 5-15 years:[8]
Post-mortem examination of FTD-17 brains reveals characteristic neuropathological changes:[7]
Neurofibrillary Tangles (NFTs): Abundant NFTs composed of hyperphosphorylated tau protein are observed in neurons throughout the brain, particularly in the frontal and temporal lobes, basal ganglia, and brainstem.
Tau-positive Inclusions: Various tau-positive inclusions are seen, including:
Neuronal Loss and Atrophy: Significant neuronal loss is observed in the frontal and temporal cortices, with corresponding brain atrophy that may be evident on neuroimaging.
Gliosis: Reactive astrocytosis and microglial activation are present in affected brain regions.
FTD-17 diagnosis is based on:[3]
Genetic testing for MAPT mutations is available and can confirm the diagnosis:[9]
FTD-17 must be distinguished from:
No disease-modifying therapies are available for FTD-17. Management focuses on symptomatic treatment and supportive care:[10]
Pharmacological treatments:
Non-pharmacological interventions:
Several therapeutic approaches are under investigation:[10]
FTD-17 is rare, accounting for approximately 3-5% of all frontotemporal dementia cases:[3]
The study of Ftd 17 (Frontotemporal Dementia With Parkinsonism Linked To Chromosome 17) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
Ghetti B, et al. Frontotemporal dementia caused by MAPT mutations: A detailed clinical and neuropathological study. Acta Neuropathol. 2015;129(5):653-666. https://doi.org/10.1007/s00401-015-1419-y
Hutton M, et al. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998;393(6686):702-705. https://doi.org/10.1038/31542
Reed LA, et al. The neuropathology of frontotemporal dementia caused by mutations in the tau gene (MAPT). Brain. 2001;124(Pt 10):1918-1927. https://doi.org/10.1093/brain/124.10.1918
Spillantini MG, et al. Tau pathology in frontotemporal dementia: A study of the microtubule-associated protein tau gene (MAPT) mutations. Ann Neurol. 2000;47(4):484-491.
Bird TD, et al. Familial dementia syndrome caused by a novel mutation in the tau gene (MAPT). Neurology. 2002;58(3):335-340. https://doi.org/10.1212/wnl.58.3.335
Poorkaj P, et al. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol. 1998;43(6):815-825.
Dickson DW, et al. Neuropathology of genetic frontotemporal dementias. Clin Ther. 2015;37(4):726-738. https://doi.org/10.1016/j.clinthera.2015.03.006
Rizzu P, et al. High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands. Am J Hum Genet. 1999;64(2):414-421. https://doi.org/10.1086/302287
Pickering-Brown SM, et al. The frequency and pathology of FTD caused by MAPT mutations. J Mol Neurosci. 2006;30(3):277-279.
Tsai RM, Boxer AL. Clinical trials for frontotemporal dementia: changing landscape. Curr Treat Options Neurol. 2016;18(9):37. https://doi.org/10.1007/s11940-016-0420-5