Congenital hyperinsulinism (CHI) is the most frequent cause of hypoglycemia in children [
1,
2]. Mutations that affect insulin secretion regulation by the three main classes of energy substrates, i.e. glucose, aminoacids, and free fatty acids (FFA) [
2,
3], can cause CHI that requires rapid diagnosis and treatment to limit/avoid neuronal damage [
4] and the irreversible neurological sequelae consequent to prolonged, severe hypoglycemia. Neurons in the superficial layers of cerebral cortex and hippocampus are those preferentially affected by lack of glucose, followed by neurons in basal ganglia and thalamus [
5]. However, mild, recurrent hypoglycemia can cause hippocampal synaptic dysfunction even in absence of neuronal damage [
6,
7]. These experimental findings explain why memory, learning, intelligence and attention are the cognitive domains most vulnerable to hypoglycemia in children with type 1 diabetes [
8,
9]. Although glucose is the main energy source for neurons, human brain can also utilize ketone bodies from FFA, lactate, pyruvate, glycerol and some aminoacids, as alternative substrate [
10]. The protective effect of ketone bodies on hypoglycemia-induced neuronal damage has been demonstrated in animal studies [
11,
12] and also in patients with type 1 diabetes, in whom the ingestion of medium-chain triglycerides prevented the cognitive deficit induced by hypoglycemia by elevating blood levels of 3-hydroxybutyrate [
13]. Ketogenic diet (KD), which provides FFA as alternative fuel to carbohydrates for neuronal energy metabolism, has therefore a strong potential neuroprotective effect. The main indication of KD in children is the treatment of refractory epilepsy, but it is also the causal therapy of GLUT1 deficiency, a metabolic disorder characterized by epilepsy, developmental delay and movement disorders [
14,
15]. In GLUT1 deficiency, neuroglycopenia that ensues as consequence of the impaired glucose transport across the blood-brain barrier [
14,
15] is effectively improved by KD that provides ketone bodies as alternative energy source for the brain. In CHI, excessive insulin secretion not only induces severe neuroglycopenia, but also halts, by inhibiting gluconeogenesis, glycogenolysis and lipolysis, the use of other metabolic pathways that provide energetic substrates to the neurons. Other inherited metabolic diseases, such as mitochondrial fatty oxidation defects, share the same neurological risk of hypoglycemia because of lack of ketones [
16]. Therefore, developing brain of patients with CHI is more vulnerable than other forms of hypoglycemia. Based on the similarities of brain metabolism perturbation shared by GLUT1 deficiency and CHI, we attempted to tackle neuroglycopenic symptoms and outcome by administering KD in a patient with severe, drug-resistant form of CHI.