Genetic forms of frontotemporal lobar degeneration: Current diagnostic approach and new directions in therapeutic strategies

Abstract

Recent advances in the genetics of neurodegenerative diseases have substantially improved our knowledge about the genetic causes of Frontotemporal lobar degeneration (FTLD). Three major genes, namely progranulin (GRN), C9orf72 and MAPT, as well as several less common genes, are responsible of the majority of familial cases and of a significant proportion of sporadic forms, including FTLD with or without associated amyotrophic lateral sclerosis and some rarer clinical presentations. Plasma progranulin dosage and next-generation sequencing are currently available tools which allow the detection of a genetic cause in a more rapid and efficient way. This has important consequences for clinical practice and genetic counselling for patients and families. The ongoing investigations on some therapeutic candidates targeting different biological pathways involved in the most frequent genetic forms of FTLD, as well as a better understanding of the early pathophysiological modifications occurring during the presymptomatic phase of the disease could hopefully contribute to develop effective disease modifying therapies. The identification of a causal mutation in a family is of outmost importance indeed to propose to presymptomatic carriers the inclusion in clinical trials with the aim to prevent or delay the onset of disease.

Cerebrospinal Fluid Biomarker Profile in TDP-43-Related Genetic Frontotemporal Dementia

“…TDP-43 aggregation appears in approximately 50% of all FTLD cases (familial and sporadic) and in 97% of all ALS cases [ 37 ]. Mutations associated with TDP-43 histopathology have been documented for C9orf72 , GRN , VCP , and TARDBP genes for FTLD and the FTD-ALS spectrum [ 38 ]. TDP-43 was initially considered as an intracellular/intranuclear protein; however, it is now recognized as an important protein for the existence and wellbeing of cells, through its various functions in RNA metabolism and homeostasis.…”

How can we define the presymptomatic C9orf72 disease in 2022? An overview on the current definitions of preclinical and prodromal phases

“…Notably, no such overlap exists with other relatively frequent genes after C9orf72, such as progranulin gene (GRN) and microtubule associated protein tau gene (MAPT), identified in FTD phenotypes, or superoxide dysmutase 1 (SOD1), responsible of pure ALS. Less common disease-causing genes can be involved in both cognitive, motor, or complex phenotypes [7].…”

Molecular Dissection of TDP-43 as a Leading Cause of ALS/FTLD

“…FTLD-TDP type D correlates with mutations in the VCP gene and has many lentiform neuronal TDP-43 intranuclear inclusions throughout the cortical layers [ 3 , 179 ]. The genetic analysis shows that mutations in C9orf72 , GRN , CHMP2b , and TARDBP genes are also associated with FTLD-TDP [ 181 ]. Although the subtypes of TDP-43 pathology do not always accord with genetics or clinical profiles, mutations in the GRN gene typically correlate with type A pathology.…”