Menkes disease is caused by mutations in the ATP7A gene that regulates the metabolism of copper in the body. The disease primarily affects male infants. Copper accumulates at abnormally low levels in the liver and brain, but at higher-than-normal levels in the kidney and intestinal lining.

Infants may be born prematurely but appear healthy at birth and for six to eight weeks. Then, symptoms begin. These can include:

• Floppy muscle tone
• Seizures
• Failure to thrive (slow physical development)

Menkes disease is also characterized by an unstable body temperature and strikingly tangled hair, which is colorless or steel-colored, sparse, and known to break easily. There is often extensive neurodegeneration in the gray matter of the brain. Arteries in the brain may be twisted with frayed and split inner walls. This can lead to rupture or blockage of the arteries. Weakened bones (osteoporosis) may result in fractures.

Treatment with daily copper injections may improve the outcome in Menkes disease if it begins within days after birth. Other treatment is symptomatic and supportive.

Since newborn screening for this disorder is not available, and early detection is infrequent because the clinical signs of Menkes disease are subtle in the beginning, the disease is rarely treated early enough to make a significant difference. The prognosis for babies with Menkes disease is poor.

Normal Function

The ATP7A gene provides instructions for making a protein that is important for regulating copper levels in the body. Copper is necessary for many cellular functions, but it is toxic when present in excessive amounts. The ATP7A protein is found throughout the body, except in liver cells. In the small intestine, this protein helps control the absorption of copper from food. In other cells, the ATP7A protein has a dual role and shuttles between two cellular locations. The protein normally resides in a cell structure called the Golgi apparatus, which modifies newly produced proteins, including enzymes. In the Golgi apparatus, the ATP7A protein supplies copper to certain enzymes that are critical for the structure and function of bone, skin, hair, blood vessels, and the nervous system. If copper levels in the cell environment are elevated, however, the ATP7A protein moves to the cell membrane and eliminates excess copper from the cell.

Health Conditions Related to Genetic Changes

Cutis laxa

Several mutations in the ATP7A gene are responsible for a condition called occipital horn syndrome or X-linked cutis laxa, which is considered a mild form of Menkes syndrome (described below). Occipital horn syndrome is characterized by loose and sagging skin, wedge-shaped calcium deposits in a bone at the base of the skull (the occipital bone), coarse hair, and loose joints.

Most of the mutations that cause occipital horn syndrome reduce but do not eliminate the production of the ATP7A protein. A shortage of this protein impairs the absorption of copper from food and prevents its normal distribution to cells throughout the body. The decreased supply of copper can reduce the activity of numerous copper-containing enzymes, affecting the structure and function of bone, skin, hair, blood vessels, and the nervous system. The reduced activity of these enzymes underlies the characteristic features of occipital horn syndrome.

Menkes syndrome

Researchers have identified more than 150 mutations in the ATP7A gene that cause Menkes syndrome. Many of these mutations delete part of the gene and likely result in a shortened ATP7A protein. Other mutations insert additional DNA building blocks (nucleotides) into the gene or change single nucleotides. All of these mutations prevent the production of functional ATP7A protein. As a result, the absorption of copper from food is impaired, and copper is not supplied to certain enzymes. The abnormal protein may get stuck in the cell membrane and become unable to shuttle back and forth from the Golgi apparatus.

The disrupted activity of the ATP7A protein causes copper to be poorly distributed to cells in the body. Copper accumulates in some tissues, such as the small intestine and kidneys, while the brain and other tissues have unusually low levels. The decreased supply of copper can reduce the activity of numerous copper-containing enzymes, affecting the structure and function of bone, skin, hair, blood vessels, and the nervous system. The signs and symptoms of Menkes syndrome are caused by the reduced activity of these copper-containing enzymes.

Charcot-Marie-Tooth disease

MedlinePlus Genetics provides information about Charcot-Marie-Tooth disease

Other Names for This Gene

• ATP7A_HUMAN
• ATPase, Cu++ transporting, alpha polypeptide
• ATPase, Cu++ transporting, alpha polypeptide (Menkes syndrome)
• ATPP1
• copper pump 1
• MC1
• MK
• MNK
• OHS

Genomic Location

• Progressive nervous system decline
• Seizures
• Kinky, light colored, easily breakable hair
• Low muscle tone (hypotonia)
• Twisted blood vessels (arterial tortuosities)
• Characteristic facial features
• Bladder sacs or pouches (diverticula)

• Gastrostomy (feeding) tube insertion
• Bladder surgery
• Seizure medication

• Neurologist
• Gastroenterologist
• Developmental specialist
• Urologist
• Genetics professional