3-hydroxy-3-methylglutaric aciduria (HMG)

HMGCL is a gene that codes for an enzyme (protein) that is involved in two processes. The first process is to break down leucine, which is a building block (amino acid) found in protein. The second process is to create ketones from fat. Ketones are a form of energy that the body uses during stress, illness or periods of fasting and are created from the breakdown of fat stores. The body uses ketones for energy for the brain and other tissues when our blood sugar is low or not abundant.

Mutations or pathogenic gene variants in the HMGCL gene impact the structure or function of the HMG CoA lyase enzyme that the gene encodes. Mutations or pathogenic gene variants in the HMGCL gene are like spelling mistakes in the instruction code for the gene. These spelling mistakes lead to an enzyme that does not work properly within each cell. When an enzyme does not work efficiently or correctly, it can lead to the build-up of certain substances in the cells that can have a toxic effect. The HMG CoA lyase enzyme plays a role in breaking down leucine. When leucine is unable to be broken down efficiently, it can have a toxic effect on the cell and lead to the symptoms of 3-Hydroxy-3-methylglutaric aciduria. Additionally, the enzyme (HMG CoA lyase) assists in creating an energy source from fats during stress, illness or fasting. When this enzyme does not work properly, the body is also unable to create ketones as an energy source during stress, illness, and/or fasting.

Yes. Infants and children diagnosed with HMG lyase deficiency need to avoid fasting. Fasting will lead to the symptoms of HMG lyase deficiency. Therefore, infants and children will need to eat frequently to prevent metabolic crisis from occurring. Infants may need to eat more frequently than young children with the diagnosis. A metabolic specialist will be able to tell you how long a child is able to fast. Fasting may also occur when children are sick or prior to a planned medical procedure. Therefore, special precautions and IV nutrition may be needed when a child is sick or requires prolonged fasting.

Additionally, infants and children will have a strict diet that is low in leucine-rich foods. Therefore, the diet may be rich in carbohydrates. It is recommended that foods that are high in leucine be limited or avoided. Foods that are high in leucine include milk and dairy products, meat and poultry, fish, eggs, dried beans, nuts, peanut butter, butters, margarine and oils.

With appropriate dietary modifications and avoidance of fasting, children with HMG lyase deficiency can eliminate or reduce the medical complications associated with their condition.

Two pathogenic variants or mutations in the HMGCL gene result in 3-Hydroxy-3-methylglutaric aciduria. If there are two pathogenic changes within this gene, the patient will have this syndrome.