Case report: Two unexpected cases of DGUOK-related mitochondrial DNA depletion syndrome presenting with hyperinsulinemic hypoglycemia.

Timely diagnosis of persistent neonatal hypoglycemia is critical to prevent neurological sequelae, but diagnosis is complicated by the heterogenicity of the causes. We discuss two cases at separate institutions in which clinical management was fundamentally altered by the results of molecular genetic testing. In both patients, critical samples demonstrated hypoketotic hypoglycemia and a partial glycemic response to glucagon stimulation, thereby suggesting hyperinsulinism (HI). However, due to rapid genetic testing, both patients were found to have deoxyguanosine kinase (DGUOK)-related mitochondrial DNA depletion syndrome, an unexpected diagnosis. Patients with this disease typically present with either hepatocerebral disease in the neonatal period or isolated hepatic failure in infancy. The characteristic features involved in the hepatocerebral form of the disease include lactic acidosis, hypoglycemia, cholestasis, progressive liver failure, and increasing neurologic dysfunction. Those with isolated liver involvement experience hepatomegaly, cholestasis, and liver failure. Although liver transplantation is considered, research has demonstrated that for patients with DGUOK-related mitochondrial DNA depletion syndrome and neurologic symptoms, early demise occurs. Our report advocates for the prompt initiation of genetic testing in patients presenting with persistent neonatal hypoglycemia and for the incorporation of mitochondrial DNA depletion syndromes in the differential diagnosis of HI.

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Copyright © 2023 Guzman, Yazdani, Harmon, Chapman, Vitola, Pyle, McKnight, Sigal, Lord, De Leon, Merchant and Ganetzky.

Déclaration de conflit d'intérêts

NM is currently on the advisory board of BioMarin and Pfizer; there is no conflict of interest in relation to this current paper or topic. KC is on the advisor board of Travere Therapeutics and PI for the HERO trial by HemoShear Therapeutics and her institution is reimbursed for her time; there is no conflict of interest in relation to this current paper or topic. BV is a consultant for Mirum Pharmaceuticals; there is no conflict of interest in relation to this current paper or topic. DL has received consulting fees from Eiger Biopharmaceuticals, Crinetics Pharmaceuticals, Hanmi Pharmaceuticals, and Zealand Pharma. She has also received research funding/contracts from Zealand Pharma, Hanmi Pharmaceuticals, Twist Pharma, Crinetics Pharmaceuticals, Rezolute, and Ultragenyx. There is no conflict of interest in relation to this current paper or topic. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.