Occipital horn syndrome (OHS) is a genetic condition that affects the connective tissue, skeleton, and nervous system. Symptoms of OHS usually begin in early childhood. They may include wedge-shaped calcium deposits at the base of the skull (occipital horns), loose skin and joints, and dysfunction of the nerves that regulate nonvoluntary body functions (dysautonomia). Other symptoms may include bladder diverticula, coarse hair, low muscle tone, and mild intellectual disability. This condition is a milder form of Menkes disease, which affects copper levels in the body.

OHS is caused by genetic changes (DNA variants) in the ATP7A gene, and it is inherited in an x-linked recessive pattern. It can be diagnosed based on the symptoms, genetic testing, and other blood tests. Treatment for OHS is based on managing the symptoms.

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

Occipital horn syndrome is inherited in an X-linked recessive pattern. X-linked means that the gene for the condition is located on the X-chromosome, one of the sex chromosomes. In males (who have only one X chromosome), one changed copy of the gene is enough to cause the condition. In females (who have two X chromosomes), a change needs to occur in both copies of the gene to cause the condition.

X-linked recessive conditions affect males much more frequently than females. Females, who have one changed gene, are called carriers. While, most female carriers have no signs or symptoms of the condition, in rare cases, female carriers may experience some mild signs or symptoms.

A female who carries one X-linked gene change has a 50% or 1 in 2 chance of having a son with the condition and a 50% chance of having a daughter who is also a carrier. A male with an X-linked recessive condition cannot pass on the disorder to his sons, but all of his daughters will be carriers.

Sometimes a male child is the first person in a family with the condition. In this case, the gene change may have been inherited from the mother, or the change may have occurred by chance for the first time in the child (de novo).

The following list includes the most common signs and symptoms in people with occipital horn syndrome. These features may be different from person to person. Some people may have more symptoms than others and symptoms can range from mild to severe. This list does not include every symptom or feature that has been described in this condition.

Signs and symptoms may include:

• Wedge shaped calcifications at the base of the skull (occipital horns)
• Loose skin and joints
• Bladder pouches (diverticula)
• Blood vessel abnormalities
• Dysautonomia (chronic diarrhea, orthostatic hypotension)
• Mild cognitive deficits
• Decreased muscle tone (hypotonia)
• Hair abnormalities

The symptoms of occipital horn syndrome usually appear by early childhood. Most people with OHS have normal intelligence or only mild intellectual delay. Because this condition is so rare, there is not much information about how this condition affects people as they get older. There is some evidence that serious gastrointestinal, breathing, or bleeding complications can develop by early adulthood.

• Medical geneticist
• Urologist
• Neurologist
• Nutritionist