PAK3 pathogenic variant associated with sleep-related hypermotor epilepsy in a family with parental mosaicism

Gambardella, A; Liu, YC; Bennett, MF; Green, TE; Damiano, JA; Fortunato, F; Coleman, MJ; Cherfils, J; Barnier, JV; Gecz, J; Bahlo, M; Berkovic, SF; Hildebrand, MS

Author(s): Gambardella, A; Liu, YC; Bennett, MF; Green, TE; Damiano, JA; Fortunato, F; Coleman, MJ; Cherfils, J; Barnier, JV; Gecz, J; Bahlo, M; Berkovic, SF; Hildebrand, MS;
Details: Publication Year 2025-04,Volume 10,Issue #2,Page 593-601
Journal Title: Epilepsia Open
Abstract: Protein-activated kinases mediate spine morphogenesis and synaptic plasticity. PAK3 is part of the p21-activated kinases (PAKs) family of Ras-signaling serine/threonine kinases. Pathogenic variants in the X-linked gene PAK3 have been described in patients with neurodevelopmental syndromes. We analyzed an Italian family with sleep-related hypermotor epilepsy, intellectual disability, psychiatric and behavioral problems, and dysmorphic facial features. A novel PAK3 c.342_344del (p.Lys114del) inframe deletion was detected in the family. Protein structure analysis supported deleterious impact of p.Lys114 deletion through loss or partial loss of autoinhibition of PAK3 protein kinase activity. The male proband had drug-resistant hypermotor seizures and moderate intellectual disability. His brother had drug-responsive hypermotor seizures and mild intellectual disability. Both brothers were hemizygous and had psychiatric and behavioral problems as well as dysmorphic facial features. Their mother had never had seizures but was shown to be mosaic for the PAK3 pathogenic variant. She had normal intellect but did have short stature and dysmorphic facial features similar to her sons. This is the first reported association of a PAK3 pathogenic variant with sleep-related hypermotor epilepsy. PAK3 testing should be considered in families with suspected X-linked sleep-related hypermotor epilepsy and intellectual disability, including for mosaicism in mildly affected females. PLAIN LANGUAGE SUMMARY: We studied an Italian family with sleep-related hypermotor epilepsy, intellectual disability, psychiatric and behavioral problems, and dysmorphic facial features. A novel PAK3 c.342_344del (p.Lys114del) inframe deletion was detected in the family. Protein structure analysis supported deleterious impact of p.Lys114 deletion through loss or partial loss of autoinhibition of PAK3 protein kinase activity. This is the first reported association of a PAK3 pathogenic variant with sleep-related hypermotor epilepsy. PAK3 testing should be considered in families with suspected X-linked sleep-related hypermotor epilepsy and intellectual disability, including for mosaicism in mildly affected females.
Publisher: Wiley
Keywords: Humans; Male; *p21-Activated Kinases/genetics; *Mosaicism; Female; Pedigree; Intellectual Disability/genetics; Adult; Child; Adolescent; Pak3; facial dysmorphism; genetic counseling; parental mosaicism; sleep-related hypermotor epilepsy
Research Division(s): Genetics and Gene Regulation
PubMed ID: 39806575
Publisher's Version: https://doi.org/10.1002/epi4.13124
Open Access at Publisher's Site: https://doi.org/ 10.1002/epi4.13124.
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-02-07 11:22:09

Last Modified: 2025-05-06 09:18:30