Defects of the Glycosyl-Phosphatidylinositol (GPI) biosynthesis pathway constitute an emerging group of inherited disorders of heterogenous phenotype. A mutation in the PIGM promoter has been identified as the cause of portal vein thrombosis (PVT) and absence seizures in three patients known to date. We report of two additional patients, with further clinical, pathological and molecular delineation of this unique entity.
Two siblings (male and female), born to consanguineous parents of Arab-Muslim descent, were admitted due to macrocephaly, PVT and persistent absence seizures. The brother had suffered from esophageal varices and massive GI bleedings secondary to his PVT, with subsequent cirrhosis and several surgical procedures including a meso-caval shunt, and died at the age of eight awaiting liver transplantation. The sister presented with macrocephaly, GI bleedings due to PVT and multiple daily absence seizures. In contrary to the previous three reported cases, our two patients showed evidence of brain atrophy and/or cerebral infarcts on brain MRI.
While Whole Exome Sequencing (WES) failed to reveal causative mutations, focused sequencing of the PIGM gene found the patients to be homozygous for the previously-described -270c>g transversion, establishing the diagnosis of inherited GPI deficiency.
Following the molecular diagnosis, the sister begun treatment with Sodium Phenylbutirate and showed an increase in the expression of CD59, accompanied by clinical improvement of both frequency and severity of her seizures. Finally, as the patients' mother reported of a new pregnancy, genotyping of the fetus was performed, and a first prenatal diagnosis of the disease was unfortunately made. As this clinical entity is both extremely rare and treatable, and can be missed on WES, a high index of suspicion is required.
