A Treatable Cause of Seizures and Hyperphosphatasia: Patients with PGAP2 and PGAP3 Mutations.

Abstract

Introduction: Hyperphosphatasia with mental retardation syndrome (HPMRS) is characterized by intellectual impairment, seizures, hypotonia, facial dysmorphism, and elevated serum alkaline phosphatase (ALP) level. HPMRS has been linked to mutations in several genes including PGAP2 and PGAP3. Here, we report 2 patients of HPMRS3 and HPMRS4 and highlight the genetic and phenotypic diversity of this disorder.

Case reports: Patient 1, a 1-year-old male with developmental delay, generalized tonic-clonic seizures, and dysmorphic facial features, was found to have a pathogenic variant in the PGAP3 gene. Patient 2, a 1-year-old female with seizures, hypotonia, joint hypermobility, and facial dysmorphism, was found to have a pathogenic variant in the PGAP2 gene. Both patients exhibited elevated ALP levels. Brain MRI of patient 1 revealed periventricular hyperintense signal foci, while patient 2 showed cerebral atrophy and basal ganglia diffusion restriction.

Discussion: HPMRS3 and HPMRS4 share clinical features including elevated ALP levels, developmental delay, seizures, and facial dysmorphisms. Although joint hypermobility is not a common feature of HPMRS3, it was observed in our patients. Both patients responded well to high-dose pyridoxine, suggesting a potential therapeutic benefit for seizure management. This report expands the understanding of HPMRS by presenting novel genetic findings and providing insights into the clinical presentation of PGAP2- and PGAP3-related conditions.