Epileptic spasms and RNA analysis in a new case of Kabuki syndrome type 2

Abstract

Kabuki syndrome (KS; Online Mendelian Inheritance in Man [OMIM] #147920, #300867) is a rare genetic syndrome characterized by postnatal growth retardation, distinctive facial dysmorphisms, and mild-to-moderate intellectual disability (ID).¹ Approximately 55%–75% of KS cases are caused by autosomal dominant pathogenic variants in KMT2D (OMIM *602113); an X-linked inheritance has also been described, in association with variants in the KDM6A (OMIM *300128) gene.^2-4 Epilepsy is often reported in KS, but the detailed clinical characteristics are often partial in the KDM6A-related forms probably because of their lower general prevalence. Here, we present a 19-year-old girl showing severe ID, speech delay, facial dysmorphisms (Figure 1A–C), and drug-resistant epilepsy, mostly characterized by epileptic spasms. Her clinical features were generally attributable to a chromatinopathy, and a diagnosis of Cornelia De Lange syndrome was initially entertained.

Seizure onset was reported at 3 years, as unrecognized nocturnal epileptic spasms. The diagnosis of epilepsy was established when also diurnal clusters of spasms occurred, either spontaneous or reflex (induced by skin touch). Multiple antiseizure medications were attempted with poor efficacy (i.e., valproate, vigabatrin, rufinamide, clobazam, clonazepam). The seizure semiology was constantly stereotypical: initial fixed tonic asymmetric posturing—right arm elevation and ipsilateral head version—followed by brisk axorhizomelic adduction spasms leading to forehead banging or falls (Figure 1F). Electroencephalographic features consisted of slow background activity with bilateral independent epileptiform discharges over frontotemporal regions in wake, and spike–polyspike/wave discharges in drowsiness and sleep (Figure 1G). Brain magnetic resonance imaging was normal at age 5 years.

Whole exome sequencing (WES) on the family trio showed a novel de novo variant in KDM6A, c.3549-3C>G (NM_021140.4), predicted to alter the splicing process at 3' untranslated region of exon 25 (MobiDetails, https://mobidetails.iurc.montp.inserm.fr/MD/). A similar splicing variant in KDM6A, c.3549-1G>A (NM_021140.4),⁵ previously reported in association with KS type 2, and the use of phenotyping applications such as Face2Gene (https://www.face2gene.com/), shifted our focus on this condition rather than on other chromatinopathies. The c.3549-3C>G was initially reported as a variant of uncertain origin according to the current American College of Medical Genetics and Genomics guidelines (criteria PP3 + PM1).⁶ Skipping of exon 25 observed by RNA analysis in blood (Figure 1D) allowed us to predict a premature protein truncation through bioinformatic tools (Figure 1E) and the replacement of Lys1183 in Asn in the highly conserved JmjC domain.⁴ This led us to consider the variant as likely pathogenic (PS2+ PM1)⁶ and to assess the right diagnosis of KS.

In the present case, we have recently used cenobamate as an add-on drug to valproate/lamotrigine therapy, obtaining a reduction of spasm severity. After 6 months of treatment, seizures are limited to asymmetric tonic posturing; they occur exclusively when falling asleep and waking up. Epileptic spasms have very rarely been described in KS with KMT2D mutations. A general history of seizures has been reported in 36% of patients harboring KDM6 variants,⁵ yet the specific seizure type has not yet been addressed. Epilepsy expressivity may be variable. Lederer et al.⁷ described febrile seizures only in a 3-year-old child, and unspecified seizures associated with a hypsarrhythmic pattern in his 6-month-old affected brother.⁷ Epileptic spasms have been cited in a single case in Chinese language, with no longitudinal observation.⁸ Seizures have been better characterized in other chromatinopathies. For instance, epilepsy arises with an encephalopathic phenotype that may include epileptic spasms in Wiedemann–Steiner syndrome (OMIM #605130). However, the long-term prognosis of this type of seizure remains unknown.⁹

Our experience provides the first comprehensive description of epileptic spasms in association with alteration in the KDM6A gene, delving into a more precise seizure semiology and further confirming WES trio as a first-line approach to be adopted in diagnostic studies of childhood idiopathic epilepsies, ID, and dysmorphic features.

Conceptualization: Flavia Privitera. Investigation: Flavia Privitera, Camilla Meossi, Emanuele Bartolini, and Filippo Maria Santorelli. Project administration: Filippo Maria Santorelli. Resources: Flavia Privitera and Camilla Meossi. Writing—original draft preparation: Flavia Privitera. Supervision: Filippo Maria Santorelli, Emanuele Bartolini, and Camilla Meossi. Funding acquisition: Filippo Maria Santorelli. All authors have read and agreed to the published version of the manuscript.

This work is supported by the Italian Ministry of Health Ricerca Corrente 2024.

The authors declare no conflict of interest. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

The study was approved by the Tuscany Region Ethics Committee (154/2020).

The patient gave informed consent for diagnostic testing, pictures, and research studies. The study was conducted in accordance with the Helsinki Declaration of 1964, as revised in October 2013 in Fortaleza, Brazil.