Intronic <i>FGF14</i> GAA repeat expansions impact progression and survival in multiple system atrophy

Partial phenotypic overlap has been suggested between multiple system atrophy and spinocerebellar ataxia 27B, the autosomal dominant ataxia caused by an intronic GAA•TTC repeat expansion in FGF14. In this study, we investigated the frequency of FGF14 GAA•TTC repeat expansion in clinically diagnosed and pathologically confirmed multiple system atrophy cases. We screened 657 multiple system atrophy cases (193 clinically diagnosed and 464 pathologically confirmed) and 1003 controls. The FGF14 repeat locus was genotyped using long-range PCR and bidirectional repeat-primed PCRs, and expansions were confirmed with targeted long-read Oxford Nanopore Technologies sequencing. We identified 19 multiple system atrophy cases carrying an FGF14 GAA≥250 expansion (2.89%, n = 19/657), a significantly higher frequency than in controls (1.40%, n = 12/1003) (P = 0.04). Long-read Oxford Nanopore Technologies sequencing confirmed repeat sizes and polymorphisms detected by PCR, with high concordance (Pearson's r = 0.99, P < 0.0001). Seven multiple system atrophy patients had a pathogenic FGF14 GAA≥300 expansion (five pathologically confirmed and two clinically diagnosed), and 12 had intermediate GAA250-299 expansion (six pathologically confirmed and six clinically diagnosed). A similar proportion of cerebellar-predominant and parkinsonism-predominant multiple system atrophy cases had FGF14 expansions. Multiple system atrophy patients carrying an FGF14 GAA≥250 expansion exhibited severe gait ataxia, autonomic dysfunction and parkinsonism, in keeping with a multiple system atrophy phenotype, with a faster progression to falls (P = 0.03) and regular wheelchair use (P = 0.02) in comparison to the multiple system atrophy cases without FGF14 GAA expansion. The length of the GAA•TTC repeat expansion lengths was inversely correlated with survival in multiple system atrophy patients (r = -0.67; P = 0.02) but not with age of onset. Therefore, screening for FGF14 GAA•TTC repeat expansion should be considered for multiple system atrophy patients with rapid loss of mobility and for complete diagnostic accuracy at inclusion in disease-modifying multiple system atrophy drug trials.

Authors

Institutions

Publication Details

Journal
Brain
Published
2025-04-16
DOI
https://doi.org/10.1093/brain/awaf134
Citations
4
Primary Topic
Genetic Neurodegenerative Diseases
Type
article
Field-Weighted Citation Impact
3.64

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Intronic FGF14 GAA repeat expansions impact progression and survival in multiple system atrophy

Joanne Trinh, Thomas T. Warner, Annarita Scardamaglia, Nirosen Vijiaratnam et al.
4 citations
Brain
Genetic Neurodegenerative Diseases
3.64
article

Intronic FGF14 GAA repeat expansions impact progression and survival in multiple system atrophy

Joanne Trinh, Thomas T. Warner, Annarita Scardamaglia, Nirosen Vijiaratnam, M. Renaud, David Crosiers, James Benedict Rowe, Timothy Rittman, Tomi Pastinen, Stéphane Lehéricy, Bernard Brais, Yen Yee Goh, Thomas Foltynie, Stephan Züchner, Matthis Synofzik, Matt C. Danzi, Bart De Vil, Danielle Seilhean, Patrick Cras, David Pellerin, Catherine Ashton, Warren Cheung, Djordje Gverić, David Murphy, Pablo Iruzubieta, Matthew James Farrer, Marios Hadjivassiliou, Céline Bonnet, Virginie Roth, Miriam Ostrožovičová, Eleanor Self, Lauren Brown, Zane Jaunmuktane, Christine Girges, Joshua Laβ, Emil Karl Gustavsson, Anne Sieben, Huw R. Morris, Henry Houlden, Jordan Follett, Marion Wandzel, Wassilios G. Meissner, Lukas Beichert, Toby J Curless, Hamin Lee, Cameron Lee, Marie‐Josée Dicaire, Sara Sambin, P. Nigel Leigh, Rahema Mohammad, Neil Archibald, Jean-Christophe Corvol
article en
4 citations

Abstract

Partial phenotypic overlap has been suggested between multiple system atrophy and spinocerebellar ataxia 27B, the autosomal dominant ataxia caused by an intronic GAA•TTC repeat expansion in FGF14. In this study, we investigated the frequency of FGF14 GAA•TTC repeat expansion in clinically diagnosed and pathologically confirmed multiple system atrophy cases. We screened 657 multiple system atrophy cases (193 clinically diagnosed and 464 pathologically confirmed) and 1003 controls. The FGF14 repeat locus was genotyped using long-range PCR and bidirectional repeat-primed PCRs, and expansions were confirmed with targeted long-read Oxford Nanopore Technologies sequencing. We identified 19 multiple system atrophy cases carrying an FGF14 GAA≥250 expansion (2.89%, n = 19/657), a significantly higher frequency than in controls (1.40%, n = 12/1003) (P = 0.04). Long-read Oxford Nanopore Technologies sequencing confirmed repeat sizes and polymorphisms detected by PCR, with high concordance (Pearson's r = 0.99, P < 0.0001). Seven multiple system atrophy patients had a pathogenic FGF14 GAA≥300 expansion (five pathologically confirmed and two clinically diagnosed), and 12 had intermediate GAA250-299 expansion (six pathologically confirmed and six clinically diagnosed). A similar proportion of cerebellar-predominant and parkinsonism-predominant multiple system atrophy cases had FGF14 expansions. Multiple system atrophy patients carrying an FGF14 GAA≥250 expansion exhibited severe gait ataxia, autonomic dysfunction and parkinsonism, in keeping with a multiple system atrophy phenotype, with a faster progression to falls (P = 0.03) and regular wheelchair use (P = 0.02) in comparison to the multiple system atrophy cases without FGF14 GAA expansion. The length of the GAA•TTC repeat expansion lengths was inversely correlated with survival in multiple system atrophy patients (r = -0.67; P = 0.02) but not with age of onset. Therefore, screening for FGF14 GAA•TTC repeat expansion should be considered for multiple system atrophy patients with rapid loss of mobility and for complete diagnostic accuracy at inclusion in disease-modifying multiple system atrophy drug trials.

BrainVol. 148(9)
Brighton and Sussex Medical School (GB), Montreal Neurological Institute and Hospital (CA), Centre National de la Recherche Scientifique (FR), Children's Mercy Hospital (US), University College London Hospitals NHS Foundation Trust (GB), University of Miami (US), University of Antwerp (BE), Université de Bordeaux (FR), Inserm (FR), Queen Mary University of London (GB), MRC Cognition and Brain Sciences Unit (GB), University of Cambridge (GB), Royal Perth Hospital (AU), Instituto de Salud Carlos III (ES), German Center for Neurodegenerative Diseases (DE), Royal Hallamshire Hospital (GB), Cambridge University Hospitals NHS Foundation Trust (GB), South Tees Hospitals NHS Foundation Trust (GB), Centre Hospitalier Universitaire de Bordeaux (FR), University of Florida (US), Sorbonne Université (FR), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Institut des Maladies Neurodégénératives (FR), Cambridge School (PT), Bridge University (SS), Assistance Publique – Hôpitaux de Paris (FR), New Zealand Brain Research Institute (NZ), Biogipuzkoa Health Research Institute (ES), Centre Hospitalier Régional et Universitaire de Nancy (FR), Antwerp University Hospital (BE), Centre d’Investigation Clinique Innovation Technologique de Nancy (FR), Centre for Movement Disorders (CA), Institut de Myologie (FR), Monash Health (AU), Pitié-Salpêtrière Hospital (FR), Nicolae Testemițanu State University of Medicine and Pharmacy (MD), UK Dementia Research Institute (GB), Dr. John T. Macdonald Foundation (US), Institute of Child Health (IN), Hertie Institute for Clinical Brain Research (DE), Mercy Research (US), National Hospital for Neurology and Neurosurgery (GB), Institut du Cerveau (FR), Institute of Neurobiology (BG), Nutrition-Génétique et Exposition aux Risques Environnementaux (FR), University College London (GB), Imperial College London (GB), McGill University (CA), Monash University (AU), University of Otago (NZ), University of Tübingen (DE), Université de Lorraine (FR), University of Lübeck (DE)
Multiple Sclerosis Society, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, International Centre for Bamboo and Rattan
Good health and well-being
Openalex Percentile: Top 7%
Genetic Neurodegenerative Diseases
3.64
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.