Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation

Abstract

The premutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5’ untranslated region and increased levels of FMR1 mRNA. Molecular mechanisms leading to fragile X-premutation-associated conditions (FXPAC) include cotranscriptional R-loop formations, FMR1 mRNA toxicity through both RNA gelation into nuclear foci and sequestration of various CGG-repeat-binding proteins, and the repeat-associated non-AUG (RAN)-initiated translation of potentially toxic proteins. Such molecular mechanisms contribute to subsequent consequences, including mitochondrial dysfunction and neuronal death. Clinically, premutation carriers may exhibit a wide range of symptoms and phenotypes. Any of the problems associated with the premutation can appropriately be called FXPAC. Fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND) can fall under FXPAC. Understanding the molecular and clinical aspects of the premutation of the FMR1 gene is crucial for the accurate diagnosis, genetic counseling, and appropriate management of affected individuals and families. This paper summarizes all the known problems associated with the premutation and documents the presentations and discussions that occurred at the International Premutation Conference, which took place in New Zealand in 2023.

A holistic approach to fragile X syndrome integrated guidance for person‐centred care

“…Research in FXPAC is burgeoning, as evidenced in the comprehensive review and papers published in summary of the 5th International Conference on the FMR1 Premutation (Tassone et al, 2023).…”

Potential Prodromal Digital Postural Sway Markers for Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) Detected via Dual-Tasking and Sensory Manipulation

“…It is caused by a 55–200 CGG repeat expansion (termed a “premutation”) in the promotor region of the fragile X messenger ribonucleoprotein 1 ( FMR1 ) gene located on the X chromosome [ 3 ]. Premutation alleles are associated with elevated levels of expanded CGG repeat-containing FMR1 mRNA, which causes the activation of cellular stress pathways and RNA-mediated toxicity with CGG binding protein sequestration, repeat-associated non-AUG-initiated (RAN) translation [ 4 ], and subsequent neurodegeneration, especially in the cerebellum, cerebral cortex, and cerebellar–cortical pathways [ 5 , 6 , 7 , 8 , 9 , 10 ]. FXTAS is not fully penetrant and occurs in approximately 50% of men carriers and 16% of women carriers, generally beginning after age 50, with incidence increasing with age [ 11 ].…”

Unmethylated Mosaic Full Mutation Males without Fragile X Syndrome

“…Those with PM repeat expansions have elevated levels of FMR1 -mRNA and normal to decreased FMRP compared to individuals without expanded CGG repeats. This elevation in mRNA expression levels can lead to the development of fragile X premutation-associated conditions (FXPAC) [ 6 ], including fragile X-associated tremor/ataxia syndrome (FXTAS) [ 6 ], fragile X-associated primary ovarian insufficiency (FXPOI) [ 7 ], and fragile X-associated neuropsychiatric disorder (FXAND) [ 6 ].…”

“…PM alleles are relatively common, with 1 in 200 females and 1 in 400 males possessing the premutation in the general population [ 2 , 13 , 14 , 15 , 16 ]. Due to the RNA toxicity of elevated levels of FMR1 -mRNA, those with PM alleles are at increased risk of developing FXPAC, and especially FXTAS, a late-onset neurodegenerative syndrome with prominent features of gait ataxia, intention tremor, and cognitive decline [ 6 ]. Furthermore a higher CGG repeat in the premutation range is associated with higher mRNA levels-- leading to earlier onset and faster progression of FXTAS [ 17 , 18 ].…”

“…These disorders are termed the fragile X-associated neuropsychiatric disorder (FXAND) [ 24 ]. Although anxiety is the most common psychiatric problem among PM carriers, additional problems include insomnia, obsessive compulsive disorder, chronic pain and chronic fatigue [ 6 ]. As PM carriers age, approximately 40–85% of males and 16% of females develop FXTAS which manifests as tremors, ataxia, white matter hyperintensities (especially in the middle cerebellar peduncles, known as the MCP sign), CNS atrophy, and progressive cognitive decline [ 6 ].…”