PAK1 c.1409 T > a (p. Leu470Gln) de novo variant affects the protein kinase domain, leading to epilepsy, macrocephaly, spastic quadriplegia, and hydrocephalus: Case report and review of the literature

Am J Med Genet A. 2023 Jun;191(6):1619-1625. doi: 10.1002/ajmg.a.63177. Epub 2023 Mar 10.


The p-21-activated kinase 1 (PAK1) protein, encoded by the PAK1 gene, is an evolutionarily conserved serine/threonine-protein kinase that regulates key cellular developmental processes. To date, seven de novo PAK1 variants have been reported to cause the Intellectual Developmental Disorder with Macrocephaly, Seizures, and Speech Delay (IDDMSSD). In addition to the namesake features, other common characteristics include structural brain anomalies, delayed development, hypotonia, and dysmorphic features. Here, we report a de novo PAK1 NM_002576.5: c.1409 T > A variant (p.Leu470Gln) identified by trio genome sequencing (GS) in a 13-year-old boy with postnatal macrocephaly, obstructive hydrocephalus, medically refractory epilepsy, spastic quadriplegia, white matter hyperintensities, profound developmental disabilities, and a horseshoe kidney. This is the first recurrently affected residue identified in the protein kinase domain. Combined assessment of the eight pathogenic PAK1 missense variants reveal that the variants cluster in either the protein kinase or autoregulatory domains. Although interpretation of the phenotypic spectrum is limited by the sample size, neuroanatomical alterations were found more often in individuals with PAK1 variants in the autoregulatory domain. In contrast, non-neurological comorbidities were found more often in individuals with PAK1 variants in the protein kinase domain. Together, these findings expand the clinical spectrum of PAK1-associated IDDMSSD and reveal potential correlations with the affected protein domains.

Keywords: PAK1 gene; autoregulatory domain; delayed development; epileptic encephalopathy; protein kinase domain.

Publication types

  • Review
  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Epilepsy* / diagnosis
  • Epilepsy* / genetics
  • Humans
  • Hydrocephalus* / diagnosis
  • Hydrocephalus* / genetics
  • Intellectual Disability* / genetics
  • Male
  • Megalencephaly* / diagnosis
  • Megalencephaly* / genetics
  • Protein Domains
  • Protein Kinases
  • Quadriplegia / diagnosis
  • Quadriplegia / genetics
  • p21-Activated Kinases / chemistry
  • p21-Activated Kinases / genetics


  • Protein Kinases
  • PAK1 protein, human
  • p21-Activated Kinases