Objective: To report the phenotypic spectrum of movement disorders in 5 pediatric patients with TBC1D24 gene variants and provide accompanying video.

Background: The TBC1D24 gene encodes a protein that regulates molecular pathways via GTPase interaction. Gene mutations have been linked to epileptic encephalopathy, hearing loss, and DOORS syndrome. However, the relationship between paroxysmal movement disorders and TBC1D24 variants is unclear.

Method: Charts were retrospectively reviewed for 5 patients seen at Texas Children’s Hospital with known TBC1D24 gene pathogenic variants.

Results: 5 patients (5 male) were included. Mean age at symptom onset was 12 months (range: 4-18 months) and mean age at diagnosis was 3.2 years (range: 2-5 years). All had asymmetrical symptom onset: focal tremor in 3 and hemiplegia in 2. Paroxysmal movement disorders included alternating hemiplegia of childhood (AHC) in 3, focal-segmental myoclonus in 1, paroxysmal exertional dyskinesia (PED) in 1, and paroxysmal exertional ataxia (PEA) in 1. 2 had TBC1D24-related epilepsy. 3 had developmental delay, 1 with developmental regression, and 1 with autism. Parental consanguinity (1) and positive family history (2) was noted. MRI brain was done in 2 patients showing cerebral and cerebellar bi-hemispheric volume loss with FLAIR hyperintensity (1) and cerebellar atrophy in the lateral hemispheres (1). Exome sequencing showed bi-allelic pathogenic changes in all (homozygous: 2, compound heterozygous: 3) with 5 unique variants. 2 patients with AHC were started on flunarizine, where 1 had no symptom improvement and adverse effects (musculoskeletal pain, increased tremor) and 1 refused the medication. Patient with focal-segmental myoclonus and epilepsy trialed levetiracetam, valproic acid and clobazam with complete seizure control, and clonazepam was added with moderately improved myoclonus. Patient with PED, PEA and epilepsy trialed levetiracetam, carbamazepine, and oxcarbazepine which worsened symptoms, so acetazolamide was started with significant improvement in symptoms and seizures. Patient with AHC and epilepsy had complete symptom and seizure control on valproic acid.

Conclusion: This study describes the phenotypic spectrum of movement disorders in 5 pediatric patients with TBCID24 variants. Identified disorders were diverse with varied treatment efficacy. Our findings expand disease understanding and suggest further research need on such emerging variants.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/phenotypic-spectrum-of-movement-disorders-in-tbc1d24-gene-variants-a-case-series/