Gene therapy is currently considered as the optimal treatment for inborn errors of metabolism (IEMs), as it aims to permanently compensate for the primary genetic defect. However, emerging gene editing approaches such as CRISPR‐Cas9, in which the DNA of the host organism is edited at a precise location, may have outperforming therapeutic potential. Gene editing strategies aim to correct the actual genetic mutation, while circumventing issues associated with conventional compensation gene therapy. Such strategies can also be repurposed to normalize gene expression changes that occur secondary to the genetic defect. Moreover, besides the genetic causes of IEMs, it is increasingly recognized that their clinical phenotypes are associated with epigenetic changes. Because epigenetic alterations are principally reversible, this may offer new opportunities for treatment of IEM patients. Here, we present an overview of the promises of epigenetics in eventually treating IEMs. We discuss the concepts of gene and epigenetic editing, and the advantages and disadvantages of current and upcoming gene‐based therapies for treatment of IEMs.

Hypoglycemia results from an imbalance between glucose entering the blood compartment and glucose demand, caused by a defect in the mechanisms regulating postprandial glucose homeostasis. Hypoglycemia represents one of the most common metabolic emergencies in childhood, potentially leading to serious neurologic sequelae, including death. Therefore, appropriate investigation of its specific etiology is paramount to provide adequate diagnosis, specific therapy and prevent its recurrence. In the absence of critical samples for biochemical studies, etiological assessment of children with hypoglycemia may include dynamic methods, such as in vivo functional tests, and continuous glucose monitoring. By providing detailed information on actual glucose fluxes in vivo, proof-of-concept studies have illustrated the potential (clinical) application of dynamic stable isotope techniques to define biochemical and clinical phenotypes of inherited metabolic diseases associated with hypoglycemia. According to the textbooks, individuals with glycogen storage disease type I (GSD I) display the most severe hypoglycemia/fasting intolerance. In this review, three dynamic methods are discussed which may be considered during both diagnostic work-up and monitoring of children with hypoglycemia: 1) functional in vivo tests; 2) in vivo metabolic profiling by continuous glucose monitoring (CGM); 3) stable isotope techniques. Future applications and benefits of dynamic methods in children with hypoglycemia are also discussed.

BaCKgRoUND aND aIMS: Patients with glycogen storage disease type 1a (GSD-1a) primarily present with lifethreatening hypoglycemia and display severe liver disease characterized by hepatomegaly. Despite strict dietary management, long-term complications still occur, such as liver tumor development. Variations in residual glucose-6-phosphatase (G6PC1) activity likely contribute to phenotypic heterogeneity in biochemical symptoms and complications between patients. However, lack of insight into the relationship between G6PC1 activity and symptoms/complications and poor understanding of the underlying disease mechanisms pose major challenges to provide optimal health care and quality of life for GSD-1a patients. Currently available GSD-1a animal models are not suitable to systematically investigate the relationship between hepatic G6PC activity and phenotypic heterogeneity or the contribution of gene-gene interactions (GGIs) in the liver.appRoaCH aND ReSUltS: To meet these needs, we generated and characterized a hepatocyte-specific GSD-1a mouse model using somatic CRISPR/CRISPR-associated protein 9 (Cas9)-mediated gene editing. Hepatic G6pc editing reduced hepatic G6PC activity up to 98% and resulted in failure to thrive, fasting hypoglycemia, hypertriglyceridemia, hepatomegaly, hepatic steatosis (HS), and increased liver tumor incidence. This approach was furthermore successful in simultaneously modulating hepatic G6PC and carbohydrate response element-binding protein, a transcription factor that is activated in GSD-1a and protects against HS under these conditions. Importantly, it also allowed for the modeling of a spectrum of GSD-1a phenotypes in terms of hepatic G6PC activity, fasting hypoglycemia, hypertriglyceridemia, hepatomegaly and HS. CoNClUSIoNS:In conclusion, we show that somatic CRISPR/Cas9-mediated gene editing allows for the modeling of a spectrum of hepatocyte-borne GSD-1a disease symptoms in mice and to efficiently study GGIs in the liver. This approach opens perspectives for translational research and will likely contribute to personalized treatments for GSD-1a and other genetic liver diseases.