Early-Onset Epileptic Encephalopathy Related to Germline PIGA Mutations: A Series of Four Patients

Objectives: Phosphatidyl inositol glycan class A (PIG-A) is involved in the synthesis of glycosylphosphatidylinositol (GPI). PIGA protein is present in many organs, including brain, kidney, liver, erythrocytes. PIGA gene is located on X-chromosome (Xp22.2). Its size is 162 kB. Somatic mutations in PIGA create paroxysmal nocturnal hemoglobinuria (PNH), while germline mutations are linked to epileptic encephalopathies with a wide range of phenotypes including numerous severe forms.

Methods: We report a series of four patients exhibiting germline mutations in the PIGA gene. All patients were boys. They were all born with normal birth parameters. They exhibited early epileptic encephalopathy, with infantile spasms or partial seizures beginning between 4 months and 1 year of age. Only one child (patient no. 4) exhibited mild dysmorphic signs. No pattern of suppression burst was present on EEG but atypical hysparrythmia was noted in patient no. 2 and patient no. 1 exhibited multifocal slow spike-waves that were initially suggestive of migrant epilepsy. No typical magnetic resonance imaging (MRI) features were noted at first evaluation, with one boy exhibiting a thin corpus callosum. One patient experienced a progressive cerebellar atrophy. White matter abnormalities and cerebral atrophy were present in all patients during follow-up. Alkaline phosphatases were elevated in two patients. Patients no. 1 and 2 exhibited renal cysts. Half of the patients were bearing a mutation inherited from their asymptomatic mothers. A ketogenic diet was tried in three cases but to no effect. All cases exhibited severe mental retardation with developmental delay and severe epilepsy. Patients no. 1 and 3 died at age 8 and 14 years, respectively.

Conclusion: Germline PIGA mutations are a X-linked disorder leading to severe encephalopathy. To date a few cases are reported (Johnston 2012, Van der Crabben 2014, Belet 2014, Swoboda 2014, Kato 2014, Lin 2018). The dysmorphic signs reported until now may be absent and MRI is poorly informative. Epilepsy is severe with no specific treatment to date. However, renal cysts and elevated Alkaline Phosphatases are important clues that should prompt PIGA sequencing in a boy experiencing early encephalopathy.