Narrative review of glycogen storage disorder type III with a focus on neuromuscular, cardiac and therapeutic aspects

Abstract

Glycogen storage disorder type III (GSDIII) is a rare inborn error of metabolism due to loss of glycogen debranching enzyme activity, causing inability to fully mobilize glycogen stores and its consequent accumulation in various tissues, notably liver, cardiac and skeletal muscle. In the pediatric population, it classically presents as hepatomegaly with or without ketotic hypoglycemia and failure to thrive. In the adult population, it should also be considered in the differential diagnosis of left ventricular hypertrophy or hypertrophic cardiomyopathy, myopathy, exercise intolerance, as well as liver cirrhosis or fibrosis with subsequent liver failure. In this review article, we first present an overview of the biochemical and clinical aspects of GSDIII. We then focus on the recent findings regarding cardiac and neuromuscular impairment associated with the disease. We review new insights into the pathophysiology and clinical picture of this disorder, including symptomatology, imaging and electrophysiology. Finally, we discuss current and upcoming treatment strategies such as gene therapy aimed at the replacement of the malfunctioning enzyme to provide a stable and long‐term therapeutic option for this debilitating disease.

Hipoglicemia, hepatomegalia y déficit pondoestatural: expresión clínica de glucogenosis.

“…Los pacientes con glucogenosis hepática, particularmente el tipo I y III, deben permanecer en seguimiento por equipo multidisciplinario, dado el riesgo de desarrollar alteraciones hepáticas como esteatosis, fibrosis periportal, cirrosis, insuficiencia, adenomas y carcinoma hepatocelular, este último más frecuente en el tipo I (Berling et al, 2021).…”

Suppression of pullulanase-induced cytotoxic T cell response with a dual promoter in GSD IIIa mice

“…Another approach under development is lipid nanoparticle (LNP)-mRNA mediated gene therapy to express human GDE in the liver. However, this mRNA treatment will be effective only in the liver and requires repeated drug administration (29).…”

A functional mini-GDE transgene corrects impairment in models of glycogen storage disease type III

“…Histological analysis of muscle biopsies from patients with GSDIII shows glycogen accumulation in large vacuoles, which disrupts the myofibril architecture ( 5 ). Most adult patients also display left ventricle hypertrophy on echocardiography, but only 15% have overt cardiomyopathy ( 2 , 4 ). Although it was long thought that liver involvement improved with age, recent studies report liver fibrosis from an early age with cirrhosis and liver tumor development in adult patients ( 3 , 6 ).…”