PAK3 pathogenic variant associated with sleep‐related hypermotor epilepsy in a family with parental mosaicism
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....
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-04-01
|
| Series: | Epilepsia Open |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/epi4.13124 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849744592013885440 |
|---|---|
| author | Antonio Gambardella Yu‐Chi Liu Mark F. Bennett Timothy E. Green John A. Damiano Francesco Fortunato Matthew J. Coleman Jacqueline Cherfils Jean‐Vianney Barnier Jozef Gecz Melanie Bahlo Samuel F. Berkovic Michael S. Hildebrand |
| author_facet | Antonio Gambardella Yu‐Chi Liu Mark F. Bennett Timothy E. Green John A. Damiano Francesco Fortunato Matthew J. Coleman Jacqueline Cherfils Jean‐Vianney Barnier Jozef Gecz Melanie Bahlo Samuel F. Berkovic Michael S. Hildebrand |
| author_sort | Antonio Gambardella |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-2f14a2c58d27496da9850defd3e18bbf |
| institution | DOAJ |
| issn | 2470-9239 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Epilepsia Open |
| spelling | doaj-art-2f14a2c58d27496da9850defd3e18bbf2025-08-20T03:13:23ZengWileyEpilepsia Open2470-92392025-04-0110259360110.1002/epi4.13124PAK3 pathogenic variant associated with sleep‐related hypermotor epilepsy in a family with parental mosaicismAntonio Gambardella0Yu‐Chi Liu1Mark F. Bennett2Timothy E. Green3John A. Damiano4Francesco Fortunato5Matthew J. Coleman6Jacqueline Cherfils7Jean‐Vianney Barnier8Jozef Gecz9Melanie Bahlo10Samuel F. Berkovic11Michael S. Hildebrand12Institute of Neurology, Department of Medical and Surgical Sciences Magna Graecia University Catanzaro ItalyEpilepsy Research Centre, Department of Medicine The University of Melbourne, Austin Health Heidelberg Victoria AustraliaEpilepsy Research Centre, Department of Medicine The University of Melbourne, Austin Health Heidelberg Victoria AustraliaEpilepsy Research Centre, Department of Medicine The University of Melbourne, Austin Health Heidelberg Victoria AustraliaEpilepsy Research Centre, Department of Medicine The University of Melbourne, Austin Health Heidelberg Victoria AustraliaInstitute of Neurology, Department of Medical and Surgical Sciences Magna Graecia University Catanzaro ItalyEpilepsy Research Centre, Department of Medicine The University of Melbourne, Austin Health Heidelberg Victoria AustraliaUniversité Paris‐Saclay, Ecole Normale Supérieure Paris‐Saclay CNRS Gif‐sur‐Yvette FranceInstitut des Neurosciences Paris Saclay, Université Paris‐Saclay, CNRS Saclay Paris FranceAdelaide Medical School The University of Adelaide Adelaide AustraliaPopulation Health and Immunity Division The Walter and Eliza Hall Institute of Medical Research Parkville Victoria AustraliaEpilepsy Research Centre, Department of Medicine The University of Melbourne, Austin Health Heidelberg Victoria AustraliaEpilepsy Research Centre, Department of Medicine The University of Melbourne, Austin Health Heidelberg Victoria AustraliaAbstract 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.https://doi.org/10.1002/epi4.13124facial dysmorphismgenetic counselingPAK3parental mosaicismsleep‐related hypermotor epilepsy |
| spellingShingle | Antonio Gambardella Yu‐Chi Liu Mark F. Bennett Timothy E. Green John A. Damiano Francesco Fortunato Matthew J. Coleman Jacqueline Cherfils Jean‐Vianney Barnier Jozef Gecz Melanie Bahlo Samuel F. Berkovic Michael S. Hildebrand PAK3 pathogenic variant associated with sleep‐related hypermotor epilepsy in a family with parental mosaicism Epilepsia Open facial dysmorphism genetic counseling PAK3 parental mosaicism sleep‐related hypermotor epilepsy |
| title | PAK3 pathogenic variant associated with sleep‐related hypermotor epilepsy in a family with parental mosaicism |
| title_full | PAK3 pathogenic variant associated with sleep‐related hypermotor epilepsy in a family with parental mosaicism |
| title_fullStr | PAK3 pathogenic variant associated with sleep‐related hypermotor epilepsy in a family with parental mosaicism |
| title_full_unstemmed | PAK3 pathogenic variant associated with sleep‐related hypermotor epilepsy in a family with parental mosaicism |
| title_short | PAK3 pathogenic variant associated with sleep‐related hypermotor epilepsy in a family with parental mosaicism |
| title_sort | pak3 pathogenic variant associated with sleep related hypermotor epilepsy in a family with parental mosaicism |
| topic | facial dysmorphism genetic counseling PAK3 parental mosaicism sleep‐related hypermotor epilepsy |
| url | https://doi.org/10.1002/epi4.13124 |
| work_keys_str_mv | AT antoniogambardella pak3pathogenicvariantassociatedwithsleeprelatedhypermotorepilepsyinafamilywithparentalmosaicism AT yuchiliu pak3pathogenicvariantassociatedwithsleeprelatedhypermotorepilepsyinafamilywithparentalmosaicism AT markfbennett pak3pathogenicvariantassociatedwithsleeprelatedhypermotorepilepsyinafamilywithparentalmosaicism AT timothyegreen pak3pathogenicvariantassociatedwithsleeprelatedhypermotorepilepsyinafamilywithparentalmosaicism AT johnadamiano pak3pathogenicvariantassociatedwithsleeprelatedhypermotorepilepsyinafamilywithparentalmosaicism AT francescofortunato pak3pathogenicvariantassociatedwithsleeprelatedhypermotorepilepsyinafamilywithparentalmosaicism AT matthewjcoleman pak3pathogenicvariantassociatedwithsleeprelatedhypermotorepilepsyinafamilywithparentalmosaicism AT jacquelinecherfils pak3pathogenicvariantassociatedwithsleeprelatedhypermotorepilepsyinafamilywithparentalmosaicism AT jeanvianneybarnier pak3pathogenicvariantassociatedwithsleeprelatedhypermotorepilepsyinafamilywithparentalmosaicism AT jozefgecz pak3pathogenicvariantassociatedwithsleeprelatedhypermotorepilepsyinafamilywithparentalmosaicism AT melaniebahlo pak3pathogenicvariantassociatedwithsleeprelatedhypermotorepilepsyinafamilywithparentalmosaicism AT samuelfberkovic pak3pathogenicvariantassociatedwithsleeprelatedhypermotorepilepsyinafamilywithparentalmosaicism AT michaelshildebrand pak3pathogenicvariantassociatedwithsleeprelatedhypermotorepilepsyinafamilywithparentalmosaicism |