This international observational study focuses on individuals with genetic forms of [Frontotemporal Dementia](/diseases/frontotemporal-dementia) and related disorders, including [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy), [Corticobasal Degeneration](/diseases/corticobasal-degeneration), and [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)[@roehr_2024]. The study aims to characterize phenotype-genotype correlations, develop biomarkers for genetic carriers, establish natural history data, and enable prevention trials["@greaves_2022"].
Frontotemporal dementia (FTD) represents a group of clinically and genetically heterogeneous disorders characterized by progressive degeneration of the frontal and temporal lobes["@seelaar_2021"]. Approximately 20-30% of FTD cases have an autosomal dominant inheritance pattern, with mutations in several key genes identified["@sieben_2012"].
Study Details
| Parameter | Value | |-----------|-------| | NCT Number | NCT05653778 | | Status | Recruiting | | Study Type | Observational | | Conditions | FTD, PSP, CBS, ALS, Alzheimer's Disease | | Sites | International |
Genetic Architecture of FTD
Major Genetic Causes
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Overview
Mermaid diagram (expand to render)
This international observational study focuses on individuals with genetic forms of [Frontotemporal Dementia](/diseases/frontotemporal-dementia) and related disorders, including [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy), [Corticobasal Degeneration](/diseases/corticobasal-degeneration), and [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)[@roehr_2024]. The study aims to characterize phenotype-genotype correlations, develop biomarkers for genetic carriers, establish natural history data, and enable prevention trials["@greaves_2022"].
Frontotemporal dementia (FTD) represents a group of clinically and genetically heterogeneous disorders characterized by progressive degeneration of the frontal and temporal lobes["@seelaar_2021"]. Approximately 20-30% of FTD cases have an autosomal dominant inheritance pattern, with mutations in several key genes identified["@sieben_2012"].
Study Details
| Parameter | Value | |-----------|-------| | NCT Number | NCT05653778 | | Status | Recruiting | | Study Type | Observational | | Conditions | FTD, PSP, CBS, ALS, Alzheimer's Disease | | Sites | International |
Genetic Architecture of FTD
Major Genetic Causes
MAPT Gene (Tau)
Mutations in the [MAPT](/genes/mapt) (Microtubule-Associated Protein Tau) gene cause familial FTD, often with parkinsonism[@gomez_tortosa_2020]:
Over 60 pathogenic mutations identified
Autosomal dominant inheritance
Typically presents with behavioral changes and language impairment
Neuropathology: Tau-positive inclusions (3R and 4R tau)
GRN Gene (Progranulin)
Loss-of-function mutations in the [GRN](/genes/grn) gene lead to haploinsufficiency[@cruts_2013]:
Autosomal dominant inheritance with complete penetrance
Often presents with language impairment (aphasia)
Neuropathology: TDP-43 inclusions (type A)
C9orf72 Gene
The hexanucleotide repeat expansion in the [C9orf72](/genes/c9orf72) gene is the most common genetic cause of FTD and ALS[@le_ber_2023]:
Can present with behavioral, language, or motor phenotypes
Neuropathology: TDP-43 inclusions with characteristic "star" pathology
Additional Genetic Causes
TARDBP: TAR DNA-binding protein gene mutations
FUS: Fused in Sarcoma gene mutations
TBK1: TANK-binding kinase 1 gene mutations
VCP: Valosin-containing protein gene mutations (inclusion body myopathy with FTD)
Background
Genetic forms of FTD account for approximately 30-50% of all FTD cases. Unlike sporadic FTD, genetic forms offer unique opportunities for:
Studying disease mechanisms
Identifying biomarkers
Developing targeted therapies
Pre-symptomatic intervention
The study addresses how specific genetic mutations influence:
Disease presentation
Progression rate
Response to emerging treatments
Objectives
Primary Objectives
Phenotype-Genotype Correlation: Characterize how specific genetic mutations influence clinical presentation, disease progression, and imaging findings
Biomarker Development: Identify fluid and imaging biomarkers for:
Early detection
Disease progression tracking
Treatment response monitoring
Natural History Documentation: Establish comprehensive natural history data for each genetic subtype
Trial Readiness: Create infrastructure for preventive therapeutic trials in pre-symptomatic carriers
Secondary Objectives
Understanding modifier genes and environmental factors