Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ: Report of seven new subjects and review of the literature

Abstract

We investigated seven children from six families to expand the phenotypic spectrum associated with an early infantile epileptic encephalopathy caused by biallelic pathogenic variants in the phosphatidylinositol glycan anchor biosynthesis class Q (PIGQ) gene. The affected children were all identified by clinical or research exome sequencing. Clinical data, including EEGs and MRIs, was comprehensively reviewed and flow cytometry and transfection experiments were performed to investigate PIGQ function. Pathogenic biallelic PIGQ variants were associated with increased mortality. Epileptic seizures, axial hypotonia, developmental delay and multiple congenital anomalies were consistently observed. Seizure onset occurred between 2.5 months and 7 months of age and varied from treatable seizures to recurrent episodes of status epilepticus. Gastrointestinal issues were common and severe, two affected individuals had midgut volvulus requiring surgical correction. Cardiac anomalies including arrythmias were observed. Flow cytometry using granulocytes and fibroblasts from affected individuals showed reduced expression of glycosylphosphatidylinositol (GPI)anchored proteins. Transfection of wildtype PIGQ cDNA into patient fibroblasts rescued this phenotype. We expand the phenotypic spectrum of PIGQ-related disease and provide the first functional evidence in human cells of defective GPI-anchoring due to pathogenic variants in PIGQ.

GPI-AP: Unraveling a New Class of Malignancy Mediators and Potential Immunotherapy Targets

“…In addition, compound heterozygous variants in PIG-S:c.148C > T and c.1141_1164 resulted in infantile spasms (ISs), severe global developmental delay, hearing loss, visual impairment (cortical blindness), hypotonia, and intellectual disability (24). Furthermore, two subsets of mutations were associated with early infantile epileptic-dyskinetic encephalopathy; first is the homozygous c.384del variant of PIG-P gene (25), which led to the frame shift of 6 codons before the expected stop signal (25), and second are PIG-Q mutations, particularly PIG-Q novel variants, which included two missense mutations (p.G17R; p.G449R), a canonical splice site substitution (c.942+1G>A), an in-frame deletion (p.A377_S389del) and three frameshifts (p.Q527Afs*75, p.R538Afs*24 and p.G557Dfs*) (26). Finally, mutational analysis of PIGA identified 124 PIG-A mutations in 92% of paroxymal nocturnal hemoglobinuria (PNH) patients, of which 101 were distinct mutations and 23 were recurrent (27).…”

“…Some studies tested the impact of GPI pathway manipulation on dependent GPI-anchored complement regulatory protein, CD-59, which was found to be under expressed in congenital and neurological disorders, as well as PNH (21)(22)(23)(24)(25)(26)(27). CD-59 was, however, overexpressed in most solid tumors (28).…”

Spectrum of Neurological Symptoms in Glycosylphosphatidylinositol Biosynthesis Defects: Systematic Review

“…One non-motor focal seizure was observed (behavior arrest). Two patients experienced generalized petit mal seizures ( 59 , 60 ). Patients presented with a first epileptic episode in a mean time of 4.78 months.…”

Pyridoxine or pyridoxal‐5‐phosphate treatment for seizures in glycosylphosphatidylinositol deficiency: A cohort study

“…9 Seizure onset is typically within the first year of life 6,7 and includes either focal, generalized, or combined focal and generalized epilepsy types. [6][7][8] Despite the efforts of the International League Against Epilepsy to propose a framework for the classification and definition of epilepsy syndromes with onset in childhood, 10 most individuals with inherited GPI deficiency do not fit into any of these electroclinical syndromes and can at best be classified as suffering with 'developmental and epileptic encephalopathies' or 'developmental encephalopathies with/without epilepsy'. 6,7,10,11 Only few individuals have been successfully allocated to electroclinical syndromes such as epilepsy with migrating focal seizures 7,8,12 or West syndrome [6][7][8] in infancy.…”

“…Individuals with inherited GPI deficiency often have a high seizure burden and poor quality of life. Many different seizure types have been described; a common denominator is that they have an early onset and are difficult to treat 6–8 . The natural history of seizures in inherited GPI deficiency is yet to be fully elucidated but the burden of seizures is often stable over time 7 .…”