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narrative_review·neurology, genetics, psychiatry, reproductive endocrinology, neurodegenerative disease·PMC10529056

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

Cells · 46 authors, 48 centres

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This comprehensive review from the 2023 International Conference on FMR1 Premutation summarizes the full spectrum of fragile X-premutation-associated conditions (FXPAC), including FXTAS, FXPOI, and FXAND. Key findings highlight that premutation carriers are at increased risk for a wide range of neurological, psychiatric, and medical conditions, with severity influenced by CGG repeat length, X-inactivation, and genetic/environmental modifiers. The clinical significance lies in recognizing these risks to enable early diagnosis, management, and potential lifestyle interventions to improve outcomes.

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**Background:** The fragile X premutation (PM), defined as 55–200 CGG repeats in the FMR1 gene, was initially thought to be clinically benign. However, research over the past two decades has revealed a spectrum of associated conditions, including fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND). The Fifth International Conference on FMR1 Premutation, held in New Zealand in 2023, brought together experts to review the current state of knowledge and provide clinical recommendations.

**Methods:** This paper is a narrative review summarizing presentations and discussions from the conference. It synthesizes findings from molecular, clinical, neuroimaging, and treatment studies, as well as community perspectives. No new experimental data are presented; rather, the paper consolidates existing evidence and expert consensus.

**Key Results:** The molecular basis of FXPAC involves RNA toxicity from elevated FMR1 mRNA (2–8 times normal), repeat-associated non-AUG (RAN) translation producing toxic polyglycine (FMRpolyG), and mitochondrial dysfunction. CGG repeat length correlates with disease severity, with mid-range repeats (80–110) conferring highest risk for FXPOI and FXTAS. Somatic instability and X-inactivation ratios modulate phenotype in females. Clinically, FXTAS affects 75% of male carriers by their 80s, presenting with intention tremor, gait ataxia, parkinsonism, and executive dysfunction, with 50% developing dementia. Female carriers have lower motor symptom penetrance (14–16%) but higher rates of anxiety, depression, and chronic pain. FXPOI affects approximately 20% of female carriers, with highest risk at 85–100 CGG repeats. Psychiatric conditions (anxiety, depression, ADHD, social phobia) occur in up to 50% of carriers. Neuroimaging shows characteristic white matter hyperintensities in the middle cerebellar peduncles (MCP sign), cerebellar and brainstem atrophy, and iron accumulation. Neuropathology reveals intranuclear inclusions in neurons and astrocytes, activated microglia, and white matter disease. Treatment remains symptomatic, with no FDA-approved disease-modifying therapies. Open-label trials of allopregnanolone, citicoline, and sulforaphane have shown some cognitive benefits. Lifestyle modifications (exercise, diet, avoidance of toxins) are recommended. Newborn screening pilot studies (e.g., Early Check) have identified PM infants, enabling prospective natural history studies.

**Clinical Implications:** Clinicians should be aware that PM carriers are at increased risk for a broad range of conditions beyond FXTAS and FXPOI, including anxiety, depression, ADHD, hypertension, autoimmune disease, chronic pain, and sleep apnea. Early diagnosis through cascade testing and increased awareness can facilitate management. Genetic counseling should include discussion of CGG repeat size, AGG interruptions, and X-inactivation. Lifestyle interventions and symptomatic treatments (e.g., SSRIs for anxiety, propranolol for tremor) may improve quality of life. The term 'fragile X-premutation-associated conditions' (FXPAC) is proposed as an umbrella term to encompass all PM-related health issues, with FXAND and FXTAS as subcategories. Consistent terminology and patient-centered communication are essential.

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neurology

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ORIGINAL PAPER

PMC10529056

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

Cells

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ABSTRACT

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. Keywords: FMR1 premutation, FXPAC, FXTAS, FXAND, FXPOI, FMR1 molecular and clinical

CITATION EXPORT

Flora Tassone, Dragana Protic, Emily Graves Allen et al.. Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation. Cells. (2023). https://doi.org/10.3390/cells12182330

AUTHORS

46 · 48 CENTRES

Flora Tassone, Dragana Protic, Emily Graves Allen, Alison D Archibald, Anna Baud, Ted W Brown, Dejan B Budimirovic, Jonathan Cohen, Brett Dufour, Rachel Eiges, Nicola Elvassore, Lidia V Gabis, Samantha J Grudzien, Deborah A Hall, David Hessl, Abigail Hogan, Jessica Ezzell Hunter, Peng Jin, Poonnada Jiraanont, Jessica Klusek, R Frank Kooy, Claudine M Kraan, Cecilia Laterza, Andrea Lee, Karen Lipworth, Molly Losh, Danuta Loesch, Reymundo Lozano, Marsha R Mailick, Apostolos Manolopoulos, Veronica Martinez-Cerdeno, Yingratana McLennan, Robert M Miller, Federica Alice Maria Montanaro, Matthew W Mosconi, Sarah Nelson Potter, Melissa Raspa, Susan M Rivera, Katharine Shelly, Peter K Todd, Katarzyna Tutak, Jun Yi Wang, Anne Wheeler, Tri Indah Winarni, Marwa Zafarullah, Randi J Hagerman

1Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817, USA; [email protected]
2MIND Institute, University of California Davis, Davis, CA 95817, USA; [email protected] (B.D.); [email protected] (D.H.); [email protected] (V.M.-C.)
3Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, 11129 Belgrade, Serbia; [email protected]
4Fragile X Clinic, Special Hospital for Cerebral Palsy and Developmental Neurology, 11040 Belgrade, Serbia
5Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA; [email protected] (E.G.A.); [email protected] (P.J.); [email protected] (K.S.)
6Victorian Clinical Genetics Services, Royal Children’s Hospital, Melbourne, VIC 3052, Australia; [email protected]
7Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3052, Australia; [email protected]
8Genomics in Society Group, Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC 3052, Australia
9Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University, Uniwersytetu Poznańskiego 6, 61-614 Poznan, Poland; [email protected] (A.B.); [email protected] (K.T.)
10Central Clinical School, University of Sydney, Sydney, NSW 2006, Australia; [email protected]
11Fragile X Association of Australia, Brookvale, NSW 2100, Australia; [email protected]
12NYS Institute for Basic Research in Developmental Disabilities, New York, NY 10314, USA
13Department of Psychiatry, Fragile X Clinic, Kennedy Krieger Institute, Baltimore, MD 21205, USA; [email protected]
14Department of Psychiatry & Behavioral Sciences-Child Psychiatry, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
15Fragile X Alliance Clinic, Melbourne, VIC 3161, Australia; [email protected]
16Department of Pathology and Laboratory Medicine, Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children of Northern California, School of Medicine, University of California Davis, Sacramento, CA 95817, USA; [email protected]
17Stem Cell Research Laboratory, Medical Genetics Institute, Shaare Zedek Medical Center Affiliated with the Hebrew University School of Medicine, Jerusalem 91031, Israel; [email protected]
18Veneto Institute of Molecular Medicine (VIMM), 35129 Padova, Italy; [email protected] (N.E.); [email protected] (C.L.)
19Department of Industrial Engineering, University of Padova, 35131 Padova, Italy
20Keshet Autism Center Maccabi Wolfson, Holon 5822012, Israel; [email protected]
21Faculty of Medicine, Tel-Aviv University, Tel Aviv 6997801, Israel
22Department of Neurology, University of Michigan, 4148 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA; [email protected] (S.J.G.); [email protected] (P.K.T.)
23Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA
24Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA
25Department of Neurological Sciences, Rush University, Chicago, IL 60612, USA; [email protected]
26Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California Davis, Sacramento, CA 95817, USA
27Department of Communication Sciences and Disorders, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA; [email protected] (A.H.); [email protected] (J.K.)
28RTI International, Research Triangle Park, NC 27709, USA; [email protected] (J.E.H.); [email protected] (S.N.P.); [email protected] (M.R.); [email protected] (A.W.)
29Faculty of Medicine, King Mongkut’s Institute of Technology Ladkrabang, Bangkok 10520, Thailand; [email protected]
30Department of Medical Genetics, University of Antwerp, 2000 Antwerp, Belgium; [email protected]
31Diagnosis and Development, Murdoch Children’s Research Institute, Melbourne, VIC 3052, Australia
32Fragile X New Zealand, Nelson 7040, New Zealand; [email protected]
33Roxelyn and Richard Pepper Department of Communication Sciences and Disorders, Northwestern University, Evanston, IL 60201, USA; [email protected]
34School of Psychology and Public Health, La Trobe University, Melbourne, VIC 3086, Australia; [email protected]
35Departments of Genetics and Genomic Sciences and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; [email protected]
36Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA; [email protected]
37Intramural Research Program, Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD 21224, USA; [email protected]
38National Fragile X Foundation, Washington, DC 20005, USA; [email protected]
39Child and Adolescent Neuropsychiatry Unit, Department of Neuroscience, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; [email protected]
40Department of Education, Psychology, Communication, University of Bari Aldo Moro, 70121 Bari, Italy
41Schiefelbusch Institute for Life Span Studies, University of Kansas, Lawrence, KS 66045, USA; [email protected]
42Clinical Child Psychology Program, University of Kansas, Lawrence, KS 66045, USA
43Kansas Center for Autism Research and Training (K-CART), University of Kansas, Lawrence, KS 66045, USA
44Department of Psychology, University of Maryland, College Park, MD 20742, USA; [email protected]
45Ann Arbor Veterans Administration Healthcare, Ann Arbor, MI 48105, USA
46Center for Mind and Brain, University of California Davis, Davis, CA 95618, USA; [email protected]
47Center for Biomedical Research (CEBIOR), Faculty of Medicine, Universitas Diponegoro, Semarang 502754, Central Java, Indonesia; [email protected]
48Department of Pediatrics, School of Medicine, University of California Davis, Sacramento, CA 95817, USA