Expanding the phenotype of PIGS-associated early onset epileptic developmental encephalopathy.

Stéphanie Efthymiou ,Joseph G Gleeson,Maha S Zaki,Barbara Vona,Marilena Christoforou,Kshitij Mankad,Thi Tuyet Mai Nguyen,Philippe M Campeau,Reza Maroofian,Marina Dutra‐Clarke,Tipu Sultan,Javeria Reza Alvi,Pasquale Striano,Henry Houlden,Rauan Kaiyrzhanov,Vincenzo Salpietro,Marcello Scala,Bianca Russell ,Abolfazl Rad ,María J Guillen Sacoto

doi:10.1111/epi.16801

Abstract

The phosphatidylinositol glycan anchor biosynthesis class S protein (PIGS) gene has recently been implicated in a novel congenital disorder of glycosylation resulting in autosomal recessive inherited glycosylphosphatidylinositol‐anchored protein (GPI‐AP) deficiency. Previous studies described seven patients with biallelic variants in the PIGS gene, of whom two presented with fetal akinesia and five with global developmental delay and epileptic developmental encephalopathy. We present the molecular and clinical characteristics of six additional individuals from five families with unreported variants in PIGS. All individuals presented with hypotonia, severe global developmental delay, microcephaly, intractable early infantile epilepsy, and structural brain abnormalities. Additional findings include vision impairment, hearing loss, renal malformation, and hypotonic facial appearances with minor dysmorphic features but without a distinctive facial gestalt. Four individuals died due to neurologic complications. GPI anchoring studies performed on one individual revealed a significant decrease in GPI‐APs. We confirm that biallelic variants in PIGS cause vitamin pyridoxine‐responsive epilepsy due to inherited GPI deficiency and expand the genotype and phenotype of PIGS‐related disorder. Further delineation of the molecular spectrum of PIGS‐related disorders would improve management, help develop treatments, and encourage the expansion of diagnostic genetic testing to include this gene as a potential cause of neurodevelopmental disorders and epilepsy.

Highlights

Congenital disorders of glycosylation (CDGs) are a rapidly growing heterogeneous group of genetic conditions
Inherited glycosylphosphatidylinositol-anchored protein (GPI-AP) deficiencies (IGDs) are a subset of CDGs that account for 0.15% of all neurodevelopmental disorders.[1]
There are more than 150 human GPI-APs, which often play a role in synaptic function, development of the central nervous system (CNS), and plasticity; defects in several of these proteins have been implicated in various neurological disorders.[2]

Summary

| INTRODUCTION

Congenital disorders of glycosylation (CDGs) are a rapidly growing heterogeneous group of genetic conditions. Inherited glycosylphosphatidylinositol-anchored protein (GPI-AP) deficiencies (IGDs) are a subset of CDGs that account for 0.15% of all neurodevelopmental disorders.[1] In many cases, IGDs result from the failure of the GPI anchor to regulate APs on the external cell surface This has consequences for early human neurogenesis and neurodevelopment.[2,3,4,5] To date, 17 known IGDs lead to a wide range of symptoms, including variable intellectual disabilities and developmental impairment, seizures, hypotonia, weakness, ataxia, congenital malformations, and dysmorphic facial features. We describe six individuals (from five unrelated families) carrying biallelic variants in PIGS and presenting with hypotonia, severe global developmental delay, infantile onset (intractable) seizures, and different CNS anomalies identified on brain imaging Two patients in this cohort are responsive to pyridoxine. Fluorescence-activated cell sorting analysis to assess for reduction in cell-surface expression of GPI-APs was done for Patient 6 and performed as previously described.[15]

| RESULTS

Findings

| DISCUSSION