Category: Ataxia
Objective: To foster trial-readiness, we delineate the full phenotypic spectrum and provide piloting longitudinal natural progression data of POLR3A-associated spastic ataxia in a large international cohort.
Background: In recent years, intronic variants in the POLR3A gene have been identified as a cause of autosomal recessive spastic ataxia, with the majority of patients carrying the intronic c.1909+22G>A variant on at least one allele. Due to the rarity of POLR3A-associated spastic ataxia and the only recent description of the disease, data on the phenotypic spectrum and natural history of the disease are missing. This lack of systematic knowledge impedes diagnosis, patient counselling and therapy development.
Method: We conducted a multi-center cohort study of 74 patients with POLR3A-associated spastic ataxia carrying the deep intronic c.1909+22G>A variant, comprising in-depth clinical phenotyping as well as cross-sectional and longitudinal progression data (up to 16.5 years).
Results: Seventy-four patients with biallelic POLR3A variants (intronic c.1909+22G>A variant in combination with truncating (35/74) and missense (23/74) variants or in-frame deletions (16/74)) were identified. POLR3A-associated spastic ataxia was characterized by adolescent- to young adult-onset [19 (13-28) years, median (interquartile range)] progressive cerebellar ataxia (93%), lower limb spasticity (78%) and weakness (79%), with frequent occurrence of sensory deficits (85%), tremor (60%), bladder dysfunction (59%) and reduced lower limb reflexes (52%). Cross-sectional and longitudinal assessments indicated mild progression of symptoms [Scale for the Assessment and Rating of Ataxia (SARA) 0.37/year, Spastic Paraplegia Rating Scale (SPRS) 0.47/year]. Functional impairment increased slowly and was associated with walking aid dependency after 24 years and wheelchair dependency after 43 years in 50% of patients.
Conclusion: Our study characterizes the phenotypic profile and natural history progression of POLR3A-associated spastic ataxia due to the recurrent deep intronic variant c.1909+22G>A. It paves the way towards large-scale natural history studies and treatment trials, which are currently in preparation within the TreatPOLR3A study group.
To cite this abstract in AMA style:
E. Jung, J. Infante, S. Satolli, F. Santorelli, M. Minnerop, S. Klebe, B. Warrenburg, J. Muñoz, A. Fellner, J. de Winter, A. O'Connor, J. Baets, S. Murphy, M. Ruiz Sales, A. Pujol Onofre, L. Ruggiero, G. Coarelli, A. Dürr, X. Kobeleva, C. Stendel, T. Klopstock, F. Nicita, E. Bertini, Q. Thomas, Y. Goldberg, E. Kogan, L. Basel-Salmon, A. Lossos, Z. Argov, A. de Munain, L. Schöls, R. Schüle. Phenotypic spectrum and natural history of POLR3A-associated spastic ataxia [abstract]. Mov Disord. 2024; 39 (suppl 1). https://www.mdsabstracts.org/abstract/phenotypic-spectrum-and-natural-history-of-polr3a-associated-spastic-ataxia/. Accessed June 15, 2025.« Back to 2024 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/phenotypic-spectrum-and-natural-history-of-polr3a-associated-spastic-ataxia/