Genes provide the instructions for building proteins, which perform a vast array of tasks within our cells. The ATP7A gene holds the instructions for a protein that regulates the mineral copper. Copper is a nutrient absorbed from food and is used for cellular processes that support the nervous system, blood vessels, skin, hair, and bones.
The ATP7A protein ensures the correct amount of copper is available to cells. It is found in most tissues, with the exception of the liver. The protein plays a significant role in the small intestine, where it manages the absorption of copper from the diet into the bloodstream. This regulation is important, as copper can be toxic if levels become too high.
The Role of the ATP7A Gene
The protein created by the ATP7A gene functions as a pump, moving copper ions across cell membranes. This transport process is powered by a molecule called ATP, which provides the energy for the protein to function. This mechanism delivers copper where it is needed, preventing both deficiency and toxic buildup.
A primary role of the ATP7A protein is to facilitate the absorption of copper from food. Within the cells of the small intestine, the protein moves copper into the bloodstream for its journey throughout the body. The circulatory system then carries copper to various tissues, where it is used for biological processes.
Inside other cells, the ATP7A protein has a dual function that depends on the cell’s copper levels. It resides in a part of the cell called the trans-Golgi network, a sorting station for proteins. Here, it supplies copper to specific enzymes that require the mineral to become active. These copper-dependent enzymes are involved in producing neurotransmitters and building strong connective tissue.
If copper levels inside a cell become too high, the ATP7A protein moves from the Golgi network to the outer cell membrane. From this position, it pumps the excess copper out of the cell, protecting it from toxicity. This dynamic relocation acts as a cellular safety valve to maintain copper balance.
Menkes Disease
Mutations in the ATP7A gene can lead to Menkes disease, a disorder resulting from a malfunctioning protein that cannot properly transport copper. The primary issue is that copper becomes trapped in the cells of the small intestine and cannot be absorbed into the bloodstream. Consequently, while copper accumulates in the intestines and kidneys, the brain and other tissues suffer from a profound deficiency.
The signs of Menkes disease appear within the first few months of life. One of the most distinctive characteristics is sparse, kinky, and steel-colored hair, a direct result of a faulty copper-dependent enzyme. Infants may also exhibit feeding difficulties, poor growth, and weak muscle tone (hypotonia). The skin may appear pale and loose.
Neurological symptoms are a severe feature of the disease. The lack of copper in the brain impairs the function of many enzymes, leading to progressive neurodegeneration. This can cause developmental delays, intellectual disability, and seizures that are difficult to control. The deterioration of blood vessels in the brain, also due to impaired enzyme function, can lead to bleeding and damage.
Menkes disease is an X-linked recessive disorder. The ATP7A gene is located on the X chromosome, one of the two sex chromosomes. Because males have one X and one Y chromosome, a single mutated copy of the gene on their X chromosome is sufficient to cause the disease. Females have two X chromosomes, so a functional gene on one can compensate for a mutated gene on the other, making them carriers who do not show symptoms.
Related Genetic Conditions
Milder mutations in the ATP7A gene can result in related but less debilitating conditions than Menkes disease. One such disorder is Occipital Horn Syndrome (OHS). Individuals with OHS experience symptoms in late childhood or adolescence that primarily affect connective tissues.
Hallmarks of OHS include lax and sagging skin (cutis laxa), hypermobile joints, and coarse hair. The name comes from wedge-shaped calcium deposits that form at the base of the skull, known as occipital horns. Neurological involvement is much milder than in Menkes disease, but some individuals may experience learning or coordination difficulties. The cause is a partially functional ATP7A protein that allows for insufficient copper transport.
A different ATP7A mutation can cause ATP7A-related distal motor neuropathy (DMN). This disorder presents in adulthood and is characterized by muscle weakness and atrophy that starts in the hands and feet and slowly progresses. Unlike Menkes disease and OHS, this condition does not involve the systemic signs of copper deficiency or neurological issues beyond the peripheral nerves.
Diagnosis and Management
Diagnosing an ATP7A-related disorder begins with observing clinical symptoms. For infants suspected of having Menkes disease, features like kinky hair, hypotonia, and seizures prompt investigation. To confirm a diagnosis, blood tests measure the levels of copper and a protein called ceruloplasmin, which are very low in individuals with Menkes disease and OHS.
While blood tests are suggestive, a definitive diagnosis requires genetic testing. This involves sequencing the ATP7A gene to identify the specific mutation. Genetic testing is also for family planning, as it can identify female carriers who may risk passing the condition to their children. Early diagnosis is a main factor in treatment effectiveness.
The primary treatment for Menkes disease and OHS involves bypassing faulty copper absorption in the intestine. This is achieved through daily injections of a copper compound, most commonly copper histidine, which delivers copper directly into the bloodstream. The success of this therapy is highly dependent on how early it is initiated, ideally before significant neurological symptoms appear.
Management also includes supportive care tailored to the individual’s symptoms. Physical and occupational therapy can help address muscle weakness and improve motor skills. Medications are prescribed to manage seizures, a common complication of Menkes disease. A multidisciplinary team of specialists is involved to manage the patient’s complex health needs.