Isolated glycerol kinase deficiency

Isolated glycerol kinase deficiency (GKD), also known as hyperglycerolemia, is a rare X-linked metabolic disorder caused by mutations in the GK gene located on chromosome Xp21.2. Glycerol kinase is an enzyme that catalyzes the phosphorylation of glycerol to glycerol-3-phosphate, a key step in fat metabolism and gluconeogenesis. When this enzyme is deficient, glycerol accumulates in the blood (hyperglycerolemia) and is excreted in excess in the urine (glyceroluria). The condition primarily affects males, while females are typically carriers who may occasionally show mild symptoms. Isolated GKD presents with a wide clinical spectrum. Three main clinical forms are recognized: an infantile (symptomatic) form, a juvenile form, and a benign (asymptomatic) adult form. The infantile form can present with episodic vomiting, metabolic acidosis, hypoglycemia, altered consciousness, and seizures, often triggered by intercurrent illness or fasting. Some patients may also exhibit adrenal insufficiency-like symptoms, failure to thrive, and developmental delay. The juvenile form may present with growth delay and mild intellectual disability. The adult or benign form is often discovered incidentally when elevated triglyceride levels are found on routine blood testing — this is actually pseudohypertriglyceridemia, as some laboratory assays cannot distinguish glycerol from triglycerides. There is no specific cure for isolated glycerol kinase deficiency. Management is primarily supportive and includes avoidance of prolonged fasting, prompt treatment of metabolic crises with intravenous glucose and fluids, and monitoring for metabolic decompensation during illness. Dietary management with attention to adequate caloric intake may be recommended. Genetic counseling is important for affected families. It is essential to distinguish isolated GKD from the contiguous gene deletion syndrome involving the GK, DAX1 (NR0B1), and DMD genes, which results in a more severe phenotype including congenital adrenal hypoplasia and Duchenne muscular dystrophy.

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