Fatal Dilated Cardiomyopathy and Monogenic Diabetes Mellitus as SMPD4 ‐Related Disorder

Abstract

ABSTRACT Sphingomyelin phosphodiesterase 4 (SMPD4)‐related disorder is a rare neurodevelopmental disorder caused by biallelic loss‐of‐function variants in SMPD4, characterized primarily by severe neurological manifestations. A subset of long‐term survivors develops diabetes mellitus (DM); however, the progression of systemic complications, including cardiomyopathy, remains poorly understood. In this report, we describe serial clinical observations over 5 years in a previously described child with SMPD4‐related disorder. At 6 years of age, following an infectious episode, the boy was diagnosed with autoantibody‐negative DM and dilated cardiomyopathy (DCM). DM was characterized by progressively increasing insulin requirements due to impaired insulin secretion, leading to the diagnosis of monogenic diabetes associated with SMPD4 deficiency. Serial echocardiographic findings revealed consistent DCM progression, characterized by left ventricular dilatation, myocardial wall thinning, and reduced fractional shortening, accompanied by recurrent infection‐triggered exacerbations that ultimately resulted in advanced DCM. This case suggests that SMPD4‐related disorder can manifest as progressive DM/DCM post‐infancy. This report is the first longitudinal DCM description, underscoring multisystem involvement and the need for lifelong metabolic and cardiac monitoring, particularly during periods of infection‐triggered exacerbations.