The ACOX1 gene holds the instructions for making an enzyme known as peroxisomal straight-chain acyl-CoA oxidase, or simply ACOX1. This enzyme is a specialized biological catalyst involved in the metabolism of certain fats. Its primary function is to help break down and process specific types of fat molecules that the body would otherwise struggle to use or eliminate.
The Function of the ACOX1 Enzyme
The ACOX1 enzyme works inside small cellular structures called peroxisomes. These compartments house enzymes that break down different substances, including particular kinds of fat molecules. The ACOX1 enzyme performs the first step in a process called peroxisomal beta-oxidation. This metabolic pathway is dedicated to processing very-long-chain fatty acids (VLCFAs), which are fat molecules with long carbon backbones.
The ACOX1 enzyme is the rate-limiting enzyme in this pathway, meaning the overall speed of VLCFA breakdown is dictated by this initial step. During this step, the enzyme shortens the long fatty acid chains, removing two carbon atoms at a time. This initial cut allows other enzymes in the peroxisome to continue the process, shortening the fatty acid until it is small enough for transport and energy production.
One can think of VLCFAs as large logs that are too big for a fireplace. The ACOX1 enzyme acts like a saw that makes the first cut, turning a large log into a more manageable piece. Once that cut is made, other tools can easily chop the wood into smaller, usable pieces. In the same way, ACOX1 starts breaking down VLCFAs into smaller units that the cell’s mitochondria can use.
ACOX1 Deficiency Disorder
Mutations in the ACOX1 gene can lead to a rare condition known as ACOX1 deficiency disorder. This is an autosomal recessive disorder, meaning an individual must inherit a non-functional copy of the gene from both parents to be affected. The parents, who each carry one mutated copy, show no signs of the condition themselves. The disorder is exceptionally rare, with only a few dozen cases described in medical literature.
The disorder manifests shortly after birth with serious symptoms. Affected newborns present with severe hypotonia, or very weak muscle tone, and experience seizures. While some infants may reach early developmental milestones like walking and talking, they experience neurological regression between ages one and three. This decline involves the loss of previously acquired motor and verbal skills.
This progressive deterioration is a direct consequence of the non-functional ACOX1 enzyme. Without the enzyme, VLCFAs accumulate to toxic levels within cells and tissues. This buildup triggers inflammation that leads to the destruction of myelin, the protective sheath that insulates nerve fibers. The loss of myelin disrupts communication between nerve cells, and the condition worsens over time, leading to severe epilepsy and the gradual loss of hearing and vision.
Connection to Other Health Conditions
Altered ACOX1 activity is also implicated in more common health conditions, particularly those affecting the liver. This connection is not due to a complete loss of function, but a consequence of the enzyme’s normal biochemical activity under certain metabolic stresses. As part of its function, the ACOX1 enzyme generates hydrogen peroxide, a type of reactive oxygen species (ROS). Excessive production can overwhelm cellular defenses and lead to oxidative stress, which damages cellular components.
In liver health, this process is relevant to non-alcoholic fatty liver disease (NAFLD), a condition characterized by excess fat accumulation in the liver. In conditions of high fat intake, the activity of enzymes like ACOX1 may increase to handle the metabolic load. This leads to greater production of hydrogen peroxide and heightened oxidative stress in liver cells.
This sustained oxidative stress is believed to contribute to the progression of NAFLD to more severe forms like non-alcoholic steatohepatitis (NASH), which involves liver inflammation and damage. Some research suggests that this environment of chronic inflammation and cellular damage may, over time, contribute to the development of hepatocellular carcinoma, a common type of liver cancer.
Diagnosis and Medical Management
Diagnosing ACOX1 deficiency disorder involves biochemical and genetic testing. The primary method is analyzing a blood sample to measure the levels of very-long-chain fatty acids. An accumulation of these fats in the blood points toward a defect in the peroxisomal beta-oxidation pathway. Brain magnetic resonance imaging (MRI) may also be used to show abnormalities in the brain’s white matter.
To confirm the diagnosis and pinpoint the cause, genetic testing is performed. This involves sequencing the ACOX1 gene to identify the specific mutations responsible for the enzyme’s malfunction. Prenatal diagnosis is also possible for families with a known history of the disorder by analyzing amniotic fluid or chorionic villus cells to detect the gene mutations.
Currently, there is no cure for ACOX1 deficiency, so medical management is supportive and focuses on managing symptoms. Treatment strategies include physical and occupational therapy to help with movement and function, as well as medications to control seizures. Supportive care aims to provide comfort and improve the quality of life for the affected individual.