Genotype-phenotype links in frontotemporal lobar degeneration

Area of Science:

• Neuroscience
• Genetics
• Neuropathology

Background:

• Frontotemporal lobar degeneration (FTLD) exhibits significant heterogeneity in clinical, neuropathological, and genetic features.
• This diversity stems from multiple underlying molecular disease processes, complicating the development of a universal therapy.
• Effective therapeutic strategies require tools for selecting patients likely to respond to specific treatments.

Purpose of the Study:

• To define phenotypic characteristics in patients with different FTLD subtypes sharing common disease processes.
• To aid in stratifying patients into homogeneous groups for targeted therapies.
• To provide a comprehensive overview of FTLD with TAR DNA-binding protein 43 (TDP43) pathology (FTLD-TDP) and its genetic mutations.

Main Methods:

• Review and synthesis of existing literature on FTLD-TDP.
• Analysis of phenotypic data from patients with FTLD-TDP.
• Comparison of patient groups with mutations in C9orf72, GRN, TBK1, and VCP genes.

Main Results:

• FTLD-TDP is the most common FTLD subtype.
• Pathogenic mutations in C9orf72, GRN, TBK1, and VCP are associated with FTLD-TDP.
• Shared and distinct phenotypic features exist among patients with mutations in these four genes.

Conclusions:

• Understanding FTLD-TDP phenotypic variability is crucial for patient stratification.
• Identifying specific genetic mutations aids in categorizing FTLD subtypes.
• This knowledge supports the development of personalized therapeutic approaches for FTLD.