Ketogenic diet as elective treatment in patients with drug-unresponsive hyperinsulinemic hypoglycemia caused by glucokinase mutations

Arianna Maiorana,Paolo Alfieri,Carlo Dionisi-Vici,Raffaella Cusmai,Silvia Maria Bernabei,Carmen Campana,Antonella Mosca,Stefania Caviglia,Benedetta Greco,Francesca Cumbo

doi:10.1186/s13023-021-02045-3

Abstract

BackgroundHyperinsulinemic hypoglycemia (HI) is the most frequent cause of recurrent hypoglycemia in children. Despite diagnostic and therapeutic advances, it remains an important cause of morbidity, leading to neurological complications, such as psychomotor retardation and epilepsy. Patients with diffuse drug-unresponsive HI manifest neurological impairment and neurobehavioral problems, even though surgically treated with a near-total pancreatectomy. Based on the analogies between HI and GLUT1 deficiency, both presenting with neuroglycopenia and lack of alternative cerebral energy sources, we administered a ketogenic diet (KD) in three drug-unresponsive GCK-HI patients with the aim of preserving neurodevelopment and avoiding the need of a near-total pancreatectomy. They presented recurrent symptomatic hypoglycemia, intellectual disability and refractory epilepsy. Patients were treated with classical KD for 79, 27 and 18 months, respectively.ResultsAll patients became asymptomatic in a few days and showed an important improvement of the alert state. Epilepsy disappeared and no appearance of novel hypoglycemic lesions was detected with a brain MRI. Cognitive and adaptive abilities rapidly improved and normalized. IQ rose significantly from 81 to 111 (p = 0.04) in patient 1, from 82 vs 95 (p = 0.04) in patient 2, from 60 to 90 (p = 0.04) in patient 3.ConclusionsWe demonstrated the safety and efficacy of KD in the treatment of drug-unresponsive GCK-HI at a short and long-term. The neuroprotective effects of KD determined the recovery from epilepsy and intellectual disabilities and averted the need of a near-total pancreatectomy. All patients and their families reported an improvement of physical and psychosocial well-being, with a substantial improvement of their quality of life. These results might change the course and the quality of life of these patients and their families, having a relevant impact on human lives. Therefore, KD might be considered the elective treatment in unresponsive forms of GCK-HI.

Highlights

Hyperinsulinemic hypoglycemia (HI) is the most frequent cause of recurrent hypoglycemia in children [1] leading to a large percentage of neurological complications, such as psychomotor retardation and epilepsyMaiorana et al Orphanet J Rare Dis (2021) 16:424[2,3,4,5]
The analysis of a large cohort of hypoglycemic patients comparing glycogen storage disease type 1 (GSD1), fatty acids oxidation defects (FAOD) and HI showed the highest prevalence of sequelae in FAOD and HI patients, in which hypoglycemia occurs without alternative energy sources [7]
Based on the similarities of brain metabolism perturbation shared by Glucose transporter 1 (GLUT1) deficiency and HI, we successfully utilized ketogenic diet (KD) in a patient with severe drug-unresponsive HI with dominant mutation in glucokinase (GCK) gene (GCKHI), presenting recurrent hypoglycemia, refractory epilepsy and mild intellectual disability [11]

Summary

Introduction

Hyperinsulinemic hypoglycemia (HI) is the most frequent cause of recurrent hypoglycemia in children [1] leading to a large percentage of neurological complications, such as psychomotor retardation and epilepsyMaiorana et al Orphanet J Rare Dis (2021) 16:424[2,3,4,5]. In patients with GLUT1 deficiency, the impaired transport of glucose across the blood brain barrier induces neuroglycopenia without generation of other cerebral energy substrates, leading to epilepsy, developmental delay and movement disorders [8, 9] In this rare disease, the ketogenic diet (KD) is the elective treatment, which effectively improves neurological outcomes by providing ketone bodies as an alternative cerebral energy source [8, 10]. Based on the analogies between HI and GLUT1 deficiency, both presenting with neuroglycopenia and lack of alternative cerebral energy sources, we administered a ketogenic diet (KD) in three drug-unresponsive GCK-HI patients with the aim of preserving neurodevelopment and avoiding the need of a near-total pancreatectomy They presented recurrent symptomatic hypoglycemia, intellectual disability and refractory epilepsy. Patients were treated with classical KD for 79, 27 and 18 months, respectively

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Conclusion