Childhood-onset neurodegeneration and brain atrophy: defining <i>UBTF</i> -related developmental regression and progressive ataxia

BACKGROUND: (upstream binding transcription factor) causes childhood-onset neurodegeneration with brain atrophy (CONDBA) (OMIM # 600673), characterised by early normal or mildly delayed development followed by regression, with individuals frequently experiencing movement disorders. This study defines the natural history of this rare disorder and explores potential biomarkers in humans and mice. METHODS: Caregivers of individuals with CONDBA completed cross-sectional surveys detailing genetic, developmental and clinical features. Patients evaluated in a neurogenetics clinic underwent Brief Ataxia Rating Scale (BARS) assessments compared with remotely collected wrist and ankle accelerometry data. Neurofilament light chain (NFL) levels were assessed in the clinic cohort and in a Ubtf E210K knock-in mouse model. RESULTS: All 11 caregiver surveys reported onset of neurodevelopmental regression (median 3.5 years, range 0.5-5 years), at times following anaesthesia or illness and 82% developed ataxia. Motor activity data from five participants (median 11.8 years, range 8.1-12.5 years) had high test-retest reliability, correlated with ataxia severity as measured by the BARS, and showed declines across multiple measures over the study period. NFL was abnormally elevated in both humans and the mouse model. CONCLUSION: -related CONDBA presents with early normal or mildly delayed development followed by regression and progressive ataxia. Wearable accelerometers provide a reliable measure of disease severity, and elevated NFL may serve as a biomarker of neuronal injury in both humans and animal models.