Variability in Phelan-McDermid syndrome: The impact of the PNPLA3 p.I148M polymorphism.

The PNPLA3 gene maps in the 22q13 region and can have modifying effects on the phenotype of patients with Phelan-McDermid syndrome (PMS). The PNPLA3 p.I148M variant was detected in two PMS patients presenting with refractory seizures, gastrointestinal issues, and liver dysfunction. The p.I148M variant leads to macrovescicular steaosis and predisposes to liver disorders from steatohepatitis to fibrosis. Accumulation of lipid macrovescicles in the hepatocytes affects several pathways, including the metabolismof anti-epileptics, possibly leading to the lack of response to anti-epileptic treatments reported in the two cases. Screening for the p.I148M variant can identify PMS patients at higher risk for liver dyfunction and help designing personalized therapeutic protocols.