Characterization of Childhood Neurodegeneration and Associated Ataxia in UBTF-Related Disorder (P12-9.011)

Abstract

<h3>Objective:</h3> To clarify the natural history of neurodegeneration related to a heterozygous missense de novo mutation in the upstream binding transcription factor (<i>UBTF</i>) gene and to understand the movement patterns extracted from continuous wrist and ankle accelerometer data. <h3>Background:</h3> <i>UBTF</i>-related childhood-onset neurodegeneration is characterized by a period of typical or mildly delayed development followed by regression. Affected individuals frequently experience movement disorders, including ataxia. <h3>Design/Methods:</h3> An online REDCap survey of families of patients with a pathogenic variant in <i>UBTF</i> was conducted. Between March 2021 and February 2022, 52 surveys were started. Duplicate and incomplete responses were excluded. Ten unique responses were fully submitted, and these were included for analysis. Patients with <i>UBTF</i>-related disorder evaluated in a neurogenetics clinic were enrolled for data collection using wearable wrist and ankle accelerometers. Longitudinal data during typical daily activities was collected remotely for continuous one-week periods. These findings were compared to similar data collected from patients with Ataxia-Telangiectasia (A-T) and control subjects. Motor activity was compared with clinical severity using the Brief Ataxia Rating Scale (BARS). <h3>Results:</h3> Median age of the survey subjects was 12.5 years (range 5–20 years), with symptom onset at a median of 2.5 years. All participants reported motor regression (median 3.75 years at onset), with 90% reporting ataxia. Motor activity data was collected from 5 participants (median age 12 years, range 8–12 years), with 3 time points included for one participant (2 with wrist data only) and 1 time point for the other 4 participants. Data from both sensors had high test-retest reliability. Motor activity showed similarities to A-T over controls across multiple measures and correlated with BARS scores. <h3>Conclusions:</h3> Ataxia is frequent in <i>UBTF-</i>related disorder. Motor activity data collected via wrist and ankle accelerometers is a highly reliable measure correlated to disease severity with results resembling other hereditary ataxias, indicating potential use as a motor biomarker. <b>Disclosure:</b> Dr. Nagy has nothing to disclose. Ms. Gupta has nothing to disclose. Ms. Molay has nothing to disclose. Miss De la Rosa Abreu has nothing to disclose. Catherine Becker has nothing to disclose. Dr. Gupta has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Biogen. The institution of Dr. Gupta has received research support from Biogen. An immediate family member of Dr. Eichler has received personal compensation for serving as an employee of UpToDate. Dr. Eichler has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for SwanBio Therapeutics. Dr. Eichler has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alnylam. Dr. Eichler has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Origin Biosciences. Dr. Eichler has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Orchard Therapeutics. Dr. Eichler has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Autobahn Therapeutics. Dr. Eichler has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bluebird Bio. Dr. Eichler has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for UpToDate. Dr. Eichler has received stock or an ownership interest from SwanBio Therapeutics. The institution of Dr. Eichler has received research support from Bluebird Bio. The institution of Dr. Eichler has received research support from Minoryx Therpeutics. The institution of Dr. Eichler has received research support from Sio Therapeutics. Dr. Eichler has received intellectual property interests from a discovery or technology relating to health care.