Mosaic CLTC pathogenic variant causing focal epilepsy with normal intelligence

CLTC (OMIM 118955) encodes clathrin heavy chain 1 (CLTC), a protein involved in the generation of envelopes that cover the cytoplasmic face of clathrin-covered intracellular organelles, in intracellular trafficking of receptors and endocytosis of many macromolecules, and in the stabilization of kinetochore fibers in the mitotic spindle.^1-3 CLTC is widely expressed in the brain and plays a role in neuronal transmission by facilitating the recycling and release of vesicles at the presynaptic termini of neurons.⁴ Heterozygous CLTC pathogenic variants cause global developmental impairment, often accompanied by dysmorphic features, microcephaly, hypotonia, or ataxia.^5-7 Structural brain abnormalities occur in 80% of individuals, the most common being corpus callosum hypoplasia.⁶ Seizures are reported in 38%, with both generalized and focal semiologies described; age of onset ranges from the neonatal period to adulthood, and seizures are usually pharmacoresponsive.⁶ In this paper, we report the first patient with a mosaic CLTC pathogenic variant, in whom several unique clinical features were observed.

A 6-year-old girl, previously well and with normal developmental milestones, had a 2-week history of episodes of sudden fear and increased heart rate. With a typical event, she would run to a parent, saying she was frightened because monsters or thieves were trying to hurt her. Her heart rate was elevated during the events, and she sometimes had whole-body hyperkinetic movements. Duration of the events was usually 30 s and there was no apparent alteration in awareness. The events occurred from wakefulness or sleep, and frequency progressively increased to the point at which they occurred every 20–30 min.

The patient was initially referred to cardiology; after heart function was found to be normal, the neurology service was consulted. Continuous video EEG monitoring was initiated and 28 seizures were recorded during the first 17 h, despite carbamazepine and levetiracetam being initiated. Clinically, she had ictal hyperkinetic movements and tachycardia up to 200 beats/min. The interictal EEG showed abundant focal spikes, sharp waves, and spike–wave discharges over the frontal regions. During seizures, an evolving ictal rhythm was seen over the frontal regions, without clear laterality (Figure 1). Seizures were initially pharmacoresistant, and she received intravenous doses of midazolam, phenytoin, and phenobarbital. She eventually came under good control on combination therapy of valproic acid and clobazam.

From a developmental perspective, she walked and spoke her first word at 12 months. Motor and language milestones were all normal, though she was subsequently diagnosed with attention deficit disorder. She is of Lebanese background with no known consanguinity and no known family history of epilepsy, intellectual development disorder, or other neurological disorders.

Head CT and MRI were both normal. Lumbar puncture at initial presentation showed normal cell count, glucose, and protein; viral and bacterial testing, as well as an encephalitis antibody panel, were all negative. An epilepsy gene panel including more than 2300 genes (GeneDx EpiXpanded panel) was performed on a peripheral blood sample, and identified a de novo mosaic novel CLTC in-frame deletion (c. 4744_4746del, p.(Val1582del) (NM_004859.3)), present in 23% of 53 sequencing reads. The variant is absent in control databases and classified as pathogenic per American College of Medical Genetics and Genomics criteria (PS2, PM1, PM2, and PM4).⁸ The patient's family provided written consent for this publication.

This patient's presentation expands the phenotypic spectrum for CLTC pathogenic variants, as she is the first individual to be reported with normal intelligence. All 31 previously reported individuals with pathogenic CLTC variants had intellectual disability, ranging from mild to severe.^5-7

The milder developmental phenotype presumably occurred because she has a mosaic pathogenic variant, and not all cells have CLTC dysfunction. However, the impact of the patient's specific variant may be relevant as well. Among the patients reported with CLTC-related disorder, variant types have included frameshift, in-frame, missense, nonsense, and splice site.^5-7 Epilepsy was more commonly reported in patients with missense variants or in-frame deletions, as was the case in the patient we report here; however, the degree of developmental impairment tended to be more severe in those patients as well, and structural brain abnormalities were more frequently observed.⁶

Our patient's seizures were focal aware with fear and tachycardia, with hyperkinetic movements sometimes seen as well. These features suggested a possible ictal focus in the insular-opercular or mesial temporal regions.⁹ The pattern on scalp EEG showed interictal and ictal findings suggestive of an anterior focus, with seizures following an unusual stuttering pattern.

In conclusion, this study expands the phenotypic spectrum associated with CLTC pathogenic variants and demonstrates that this gene should be considered as a cause in patients with epilepsy, even in the absence of intellectual disability.

This study was supported by funding from Fonds de Recherche du Québec—Santé.

M.A. Sveistrup reports no disclosures relevant to the manuscript. K.A. Myers is a site principal investigator for studies sponsored by Ultragenyx and LivaNova, and is on an advisory committee for Jazz Pharmaceuticals.