{"doi":"10.1101/2023.07.30.23293380","title":"Intronic <i>FGF14</i> GAA repeat expansions are a common cause of downbeat nystagmus syndromes: frequency, phenotypic profile, and 4-aminopyridine treatment response","abstract":"Abstract The cause of downbeat nystagmus (DBN) remains unknown in approximately 30% of patients (idiopathic DBN). Here, we hypothesized that: (i) FGF14 (GAA) ≥250 repeat expansions represent a frequent genetic cause of idiopathic DBN syndromes, (ii) are treatable with 4-aminopyridine (4-AP), and (iii) FGF14 (GAA) 200-249 alleles are potentially pathogenic. We conducted a multi-modal cohort study of 170 patients with idiopathic DBN that comprised: in-depth ocular motor, neurological, and disease evolution phenotyping; assessment of 4-AP treatment response, including re-analysis of placebo-controlled video-oculography treatment response data from a previous randomized double-blind 4-AP trial; and genotyping of the FGF14 repeat. Frequency of FGF14 (GAA) ≥250 expansions was 48% (82/170) in the entire idiopathic DBN cohort. Additional cerebellar ocular motor signs were observed in 100% (82/82), cerebellar ataxia in 43% (35/82), and extracerebellar features in 21% (17/82) of (GAA) ≥250 - FGF14 patients. Alleles of 200 to 249 GAA repeats were enriched in patients with DBN (12%; 20/170) compared to controls (0.87%; 19/2,191; OR, 15.20; 95% CI, 7.52-30.80; p =9.876e-14). The phenotype of (GAA) 200-249 - FGF14 patients closely mirrored that of (GAA) ≥250 - FGF14 patients. (GAA) ≥250 - FGF14 and (GAA) 200-249 - FGF14 patients had a significantly greater clinician-reported (80% vs 31%; p =0.0011) and self-reported (59% vs 11%; p =0.0003) response rate to 4-AP treatment compared to (GAA) &lt;200 - FGF14 patients. This included a treatment response with high relevance to everyday living, as exemplified by an improvement of 2 FARS stages in some cases. Placebo-controlled video-oculography data of four (GAA) ≥250 - FGF14 patients previously enrolled in a 4-AP randomized double-blind trial showed a significant decrease in slow phase velocity of DBN with 4-AP, but not placebo. This study shows that FGF14 GAA repeat expansions are a highly frequent genetic cause of DBN syndromes, especially when associated with additional cerebellar features. Moreover, they genetically stratify a subgroup of patients with DBN that appear to be highly responsive to 4-AP, thus paving the way for a “theranostics” approach in DBN syndromes.","journal":"medRxiv","year":2023,"id":390566,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9611,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1162355,"name":"Felix Heindl","orcid":"0000-0002-5484-2575","position":1,"is_corresponding":false},{"id":746335,"name":"Carlo Wilke","orcid":"0000-0002-7250-8597","position":2,"is_corresponding":false},{"id":298704,"name":"Matt C. Danzi","orcid":"0000-0003-1568-5965","position":3,"is_corresponding":false},{"id":301262,"name":"Andreas Traschütz","orcid":"0000-0002-8165-5898","position":4,"is_corresponding":false},{"id":842962,"name":"Catherine Ashton","orcid":null,"position":5,"is_corresponding":false},{"id":842961,"name":"Marie‐Josée Dicaire","orcid":null,"position":6,"is_corresponding":false},{"id":1162356,"name":"Alexanne Cuillerier","orcid":"0000-0001-8505-3758","position":7,"is_corresponding":false},{"id":1009653,"name":"Giulia Gobbo","orcid":"0000-0001-7368-0033","position":8,"is_corresponding":false},{"id":403079,"name":"Kym M. Boycott","orcid":"0000-0003-4186-8052","position":9,"is_corresponding":false},{"id":1162357,"name":"Jens Claaßen","orcid":"0000-0002-2131-3511","position":10,"is_corresponding":false},{"id":256441,"name":"Dan Rujescu","orcid":"0000-0002-1432-313X","position":11,"is_corresponding":false},{"id":62368,"name":"Annette M. Hartmann","orcid":"0000-0003-0689-4335","position":12,"is_corresponding":false},{"id":88911,"name":"Stephan Züchner","orcid":"0000-0002-8498-5235","position":13,"is_corresponding":false},{"id":841745,"name":"Bernard Brais","orcid":"0000-0003-1394-3561","position":14,"is_corresponding":false},{"id":671844,"name":"Michael Strupp","orcid":null,"position":15,"is_corresponding":false},{"id":65630,"name":"Matthis Synofzik","orcid":"0000-0002-2280-7273","position":16,"is_corresponding":false},{"id":841726,"name":"David Pellerin","orcid":"0000-0002-5807-995X","position":0,"is_corresponding":true}],"reference_count":32,"raw_metadata":null,"created_at":"2026-07-19T01:18:37.743462Z","pmid":"37577458","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}