A rare genetic disorder discovered by UT Southwestern Medical Center researchers and their colleagues can cause brain damage from dangerously low blood sugar levels and liver damage in infants, along with variable body fat loss (lipodystrophy), fatty tumors, and metabolic complications in youth and adults. The study, published in The Journal of Clinical Investigation, found that the mutation on the ACAA2 gene can be inherited from a parent or occur spontaneously.
Abhimanyu Garg, M.D., Professor of Internal Medicine, Chief of the Section of Nutrition and Metabolic Diseases in the Division of Endocrinology, and the study’s lead investigator, suggested pediatricians treating patients with low blood sugar or hepatitis of unknown origins should consider testing for the genetic variant.
“We’ve found four families with the same genetic defect, and it is likely that clinicians will report more patients in the future. Diagnosis of this disorder during infancy can not only prevent serious hypoglycemia but may also protect patients from hepatic (liver) dysfunction.”
Abhimanyu Garg, M.D., Professor of Internal Medicine, Chief of the Section of Nutrition and Metabolic Diseases in the Division of Endocrinology
The genetic variant causes a new subtype of familial partial lipodystrophy (FPL), a group of disorders that result in loss of body fat from the arms, legs, and hips and excess fat accumulation around the trunk, neck, and labia. Some patients develop fatty tumors called lipomas on their upper backs. Patients with FPL commonly develop metabolic dysregulation resulting in fatty liver disease, diabetes, and high blood fat levels. Dr. Garg has spent 30 years studying the genetic causes of FPL.
Dr. Garg explained that mitochondria, which act as powerhouses of human cells, use dietary fats consisting of chains of carbon molecules to produce energy for cellular functions. Several enzymes – including ACAA2, named after acetyl-coenzyme A acyltransferase 2 – are involved in breaking longer chains of fatty acids into shorter ones in a process called mitochondrial fatty acid oxidation.
In the newly discovered genetic variant, glutamic acid is replaced with another amino acid, lysine, within the ACAA2 enzyme that breaks down mostly medium-chain fatty acids.
Dr. Garg and his collaborators speculate the genetic disorder causes an overactivation of the ACAA2 enzyme. They also discovered a key diagnostic marker for the variant: elevated blood levels of long-chain acylcarnitines, which are derived from fatty acids.
Within the four families who were found to have the variant in the ACAA2 gene, six patients experienced transient hepatitis during infancy. Liver biopsies on two patients exhibited a buildup of fat deposits in liver cells, scarring, and damaged mitochondria.
“In one of the four families with the ACAA2 mutation, we saw low blood sugar levels during infancy,” Dr. Garg said. “One patient had such severe hypoglycemia that it resulted in brain damage.”
The fatty acid oxidation disorders prevent patients from generating ketone bodies, which can be used for energy when glucose is not available to fuel the brain.
With the discovery of the novel genetic variant, Dr. Garg sees the potential to develop disease models and test potential therapeutic interventions. He also questions whether other ACAA2 variants may be related to the development of diabetes, high blood triglycerides, or fatty liver in some patients.
“In the future, we expect dietary changes or novel therapies may emerge to lower long-chain acylcarnitine levels in affected individuals, which may reduce their morbidity,” Dr. Garg said.
Dr. Garg is an internationally recognized expert who provides clinical care and conducts research related to patients with rare lipid disorders and lipodystrophies. UTSW is one of 46 Rare Disease Centers of Excellence in 28 states and Washington, D.C., as recognized by the National Organization for Rare Disorders (NORD).
(Newswise/R)
