D2hydroxyglutaric

D2hydroxyglutaric acid (D2HG) is a naturally occurring organic compound found in small amounts in human tissues and fluids. It belongs to the class of hydroxyglutaric acids, which are derivatives of the amino acid alanine. D2HG is primarily synthesized in the brain and is involved in various metabolic pathways, though its precise physiological role remains largely unclear.

The most significant medical interest in D2HG stems from its association with certain neurological disorders. One of the most well-known conditions linked to elevated levels of D2HG is D2HGase deficiency, an autosomal recessive metabolic disorder. In this condition, the enzyme D2-hydroxyglutarate dehydrogenase (D2HGase) is deficient, leading to an accumulation of D2HG in tissues, particularly the brain. Symptoms of D2HGase deficiency can vary widely but often include developmental delays, intellectual disability, seizures, movement disorders, and hypotonia (low muscle tone). The disorder typically presents in infancy or early childhood.

Another condition associated with D2HG is succinate dehydrogenase (SDH) deficiency, particularly in the context of hereditary paraganglioma-pheochromocytoma syndrome (HPPPS). In these cases, mutations in SDH genes can lead to elevated D2HG levels, contributing to tumor development in the paraganglia and adrenal glands. While D2HG itself is not directly toxic, its accumulation may disrupt normal cellular metabolism and contribute to disease progression.

Diagnosis of elevated D2HG levels often involves metabolic screening, including urine or plasma testing, particularly in individuals with suspected inborn errors of metabolism or neurological symptoms. Treatment remains largely supportive, focusing on managing symptoms such as seizures, movement disorders, and developmental delays. Research into potential therapeutic interventions, including enzyme replacement or gene therapy, is ongoing but not yet widely available.

Understanding the role of D2HG in normal physiology continues to be an area of active study, as its precise biochemical functions and potential implications in other diseases remain subjects of investigation.