We read with great interest the article by Mondragon et al. regarding clinical trajectories in TBC1D24-related epilepsies. 1 Their longitudinal analysis of 15 patients offers critical insights into clinical trajectories and medication responses—an important step toward clinical trial readiness. Following their publication, we reviewed five cases of TBC1D24-related epilepsy from our dataset of 623 cases with epilepsy-related variants at the Children's Hospital of Chongqing Medical University. The genetic and clinical features in our cohort differ somewhat from those reported by Mondragon et al. , 1 thereby expanding longitudinal trajectory and genotypes of TBC1D24-related epilepsy. As summarized in Table 1, our cohort includes five unrelated children (four males, one female), followed for a median of 47. 6 months (range = 17–125 months). Seizures were the initial presentation in all cases. Four patients had seizure onsets at between 3 and 7 months of age and experienced status epilepticus (SE) weekly to monthly (Figure 1A, B). One exceptional case (P4) had the first seizure at 38 months and only one episode of SE. During follow-up, jerk as nonepileptic myoclonus was the most common movement disorder (n = 5; Figure 1C), followed by tremor (n = 3) and dystonia (n = 3; Figure 1D). Ataxia was observed in two patients and episodic hemiplegia in one (Figure 1E). Three patients experienced frequent SE episodes starting before 6 months of age, with a subsequent reduction in frequency by approximately 1 (P1, P3) or 4 (P5) years of age. Conversely, one exceptional case (P2) exhibited a contrasting trajectory. In this patient, SE frequency followed an opposite trend, beginning at 7 months of age and peaking between 6 and 10 years, highlighting the significant clinical heterogeneity in the trajectory of TBC1D24-related epilepsy. Two patients were diagnosed with drug-resistant epilepsy and were treated with ≥2 antiseizure medications (ASMs), including oxcarbazepine, valproic acid (VPA), clobazam (CLB), carbamazepine, and phenytoin. One patient (P3) responded partly to a combination of VPA, lacosamide, CLB, and zonisamide. Notably, one patient (P4) with infrequent seizures did not receive any ASMs by the last visit. All five patients were diagnosed with developmental and epileptic encephalopathy (DEE). During follow-up, 10 electroencephalographic (EEG) recordings from four patients were obtained; six were normal, two showed slow background activity, one revealed frontomidline epileptic discharges, and one showed bilateral discharges with frontal and occipital predominance. Brain magnetic resonance imaging demonstrated cerebellar atrophy in one patient and widened extra-axial spaces in three and was normal in one. Interestingly, serial images in P5 revealed progressive cerebellar atrophy by 47 months of age. Genetically, we identified eight novel variants—p. Ser336Leu, p. Ser372Phe, p. Glu31*, p. Ala244Thr, p. Lys80*, p. Ile77Lys80del, p. Pro221Ser, and p. Gln400*—that have not been reported previously (Table 1, Figure 2). Among of them, eight were classified as pathogenic or likely pathogenic by American College of Medical Genetics and Genomics criteria; the other two variants of uncertain significance in P3 and P4 were established through detailed correlation with distinct TBC1D24-associated clinical presentations. The TBC1D24 protein architecture comprises two primary functional domains: the Tre2/Bub2/Cdc16 (TBC) domain, involved in vesicle trafficking, and the neuroprotective TBC/lysin motif domain/ catalytic (TLDc) domain, which is critical for oxidative stress resistance. 2-4 In the two patients (P1 and P2) presenting with drug-resistant epilepsy, all four identified variants were mapped directly to these critical functional domains, likely accounting for the observed clinical severity (Figure 2). Expanding on Mondragon et al. 's findings, 1 four variants in our cohort were situated in the TLDc domain. Our study delineates additional clinical trajectories characterized by a later age of onset, reduced seizure burden, and milder neurodevelopmental delay (P4). Combining ours with the findings of Lüthy et al. , we propose that later childhood onset may delineate a more self-limited seizure course. 2 However, other manifestations, such as movement disorders and neurodevelopmental delay, appear to persist chronically. In line with reported data, the observation of cerebellar atrophy in two cases suggests an underlying progressive disorder profile. 5, 6 Specifically, three of our cases present clear myoclonic seizures at onset despite normal EEG findings. This clinicoelectrical dissociation, when observed in conjunction with neurodevelopmental delay and cerebellar atrophy, may serve as a diagnostic red flag for TBC1D24-related DEE. Collectively, the cases in this study expand the longitudinal trajectory and genotypes of TBC1D24-related disorders. Given the marked heterogeneity in neurological conditions over time and genotypes inherent to this condition, large-scale, multicenter, prospective cohort studies are imperative to further delineate the neurological trajectories and therapeutic responses to ASMs. Songyang Xiang: Data collection; visualization; writing—original draft. Lu Fei: Data collection. Tingsong Li: Conceptualization; supervision; data curation; draft revision—review registration No. MR-50-24-018246). The data that support the findings of this study are available from the corresponding author upon reasonable request.
Xiang et al. (Thu,) studied this question.