GPI‐anchoring disorders and the heart: Is cardiomyopathy an overlooked feature?

Abstract

Glycosylphosphatidylinositol anchoring disorders (GPI‐ADs) are a subgroup of congenital disorders of glycosylation. GPI biosynthesis requires proteins encoded by over 30 genes of which 24 genes are linked to neurodevelopmental disorders. Patients, especially those with PIGA‐encephalopathy, have a high risk of premature mortality which sometimes is attributed to cardiomyopathy. We aimed to explore the occurrence of cardiomyopathy among patients with GPI‐ADs and to raise awareness about this potentially lethal feature. Unpublished patients with genetically proven GPI‐ADs and cardiomyopathy were identified through an international collaboration and recruited through the respective clinicians. We also reviewed the literature for published patients with cardiomyopathy and GPI‐AD and contacted the corresponding authors for additional information. We identified four novel and unrelated patients with GPI‐AD and cardiomyopathy. Cardiomyopathy was diagnosed before adulthood and was the cause of early demise in two patients. Only one patients underwent cardiac workup after being diagnosed with a GPI‐AD. All were diagnosed with PIGA‐encephalopathy and three had a disease‐causing variant at the same residue. The literature reports five additional children with GPI‐AD related cardiomyopathy, three of which died before adulthood. We have shown that patients with GPI‐ADs are at risk of developing cardiomyopathy and that regular cardiac workup with echocardiography is necessary.

The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders

“… 74 Similarly, though a recent review suggested that IGD-related cardiomyopathy is under-reported, no individuals in our cohort had cardiomyopathy, including individuals with complex, often PIGA -IGD-related, structural cardiac disease. 75 Importantly, the significantly lower prevalence of DD/ID in our cohort expands the milder phenotypic spectrum of the IGDs: not only providing further evidence that children with IGDs can develop into adolescence with normal cognition and mild motor impairment, but also identifying novel and previously reported recurrent variants predictive of this milder phenotype with better long-term outcomes. 76 …”