A Novel Mutation in <b><i>PIGA</i></b> Associated with Multiple Congenital Anomalies-Hypotonia-Seizure Syndrome 2 (MCAHS2) in a Boy with a Combination of Severe Epilepsy and Gingival Hyperplasia

Abstract

Multiple congenital anomalies-hypotonia-seizures syndrome 2 (MCAHS2) is a rare disease caused by mutations in the X chromosomal <i>PIGA</i> gene. Clinically it is characterized by early-onset epilepsy, hypotonia, dysmorphic features, and variable congenital anomalies. <i>PIGA</i> codes for the phosphatidylinositol glycan-class A protein, which forms a subunit of an enzymatic complex involved in glycophosphatidylinositol (GPI) biosynthesis. We present a new case of MCAHS2 and perform a comprehensive review of the available literature to delineate the phenotypical traits associated with germline <i>PIGA</i> mutations. Furthermore, we provide functional evidence of pathogenicity of the novel missense mutation, c.154C>T; (p.His52Tyr), in the <i>PIGA</i> gene causative of MCAHS2 in our patient. By flow cytometry, we observed reduced expression of GPI-anchored surface proteins in patient granulocytes compared to control samples, proving GPI-biogenesis impairment. The patient's severe epilepsy with several daily attacks was refractory to treatment, but the frequency of seizures reduced temporarily under triple therapy with perampanel, rufinamide and vigabatrin. Our study delineates the known MCAHS2 phenotype and discusses challenges of diagnosis and clinical management in this complex, rare disease. Furthermore, we present a novel mutation with functional evidence of pathogenicity.