ATP7A-related disorders

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What are ATP7A-related Disorders?

ATP7A-related disorders are a group of diseases characterized by the body's inability to control the amount of copper in its organs and tissues. These disorders are caused by harmful genetic changes (mutations) in a gene called ATP7A. The ATP7A gene moves copper across the barriers that separate cells (cell membranes), so that the correct amount of copper is present in different areas of the body. Deficient ATP7A function causes individuals to have abnormal copper levels, which leads to organ damage. These disorders generally occur in males, while females do not usually have symptoms.

Classic Menkes Disease

Menkes disease, the most common ATP7A-related disorder, is associated with low or absent copper levels in the blood. Boys with Menkes disease usually start to show symptoms at a few months of age. Symptoms include delayed development and/or loss of milestones, low muscle tone, poor growth, seizures, and out-pouching of the bladder (diverticula). Differences in an individual's appearance may also be noticeable at a few months of age. These differences include hair with lighter color, a coarse texture, and a flat, twisted shape of the hair shaft (pili torti); and sagging in the face.

Mild Menkes Disease

Boys with mild Menkes disease develop symptoms at an older age than those with the classic form. Many of the symptoms of mild Menkes disease are related to the connective tissues (which connect and protect the organs and other tissue types in the body) and include loose skin, unstable joints, and unique facial features. In addition, boys typically have learning difficulties (mild intellectual disability), issues with balance (ataxia) and speech (dysarthria), and pili torti.

Occipital Horn Syndrome (OHS)

OHS is a milder copper transport disorder, with boys not showing symptoms until they are several years old. Many of the symptoms of OHS are related to the connective tissues. Symptoms of OHS typically include loose skin, unstable joints, pili torti, and wedge-shaped calcium deposits at the base of the skull (occipital horns), which give the condition its name.

Distal Motor Neuropathy

In rare cases, ATP7A mutations can lead to a variable condition that causes weakness in the hands and feet and some absent reflexes. Individuals may also have trouble lifting the front of the foot (foot drop), which can affect walking. It has been reported in early childhood to late adulthood, but most individuals develop symptoms between ages 20 and 40.

Additional considerations for carriers

ATP7A-related disorders are X-linked diseases. This means that the ATP7A gene is on the X chromosome. Males have just one copy of the X chromosome and the ATP7A gene, while females have two copies. Because of this, ATP7A-related disorders primarily affect males. It is possible for some females with a mutation in the ATP7A gene (known as carrier females) to have some symptoms. About half of carrier females have pili torti.

How common are ATP7A-related Disorders?

The incidence of Menkes disease is estimated to be between 1 in 100,000 and 1 in 250,000 births worldwide and is reported to be significantly higher in Australia. The exact incidence of OHS is unknown. At least 34 individuals have been reported with OHS worldwide. The exact incidence of distal motor neuropathy due to an ATP7A mutation is also unknown. Only a few families with this disorder have been reported.

Approximately one out of three males with an ATP7A-related disorder has a brand new ATP7A mutation that was not inherited from his parent (known as a “de novo” mutation).

How are ATP7A-related Disorders treated?

These conditions are treated by providing the body with extra copper by an injection (copper supplementation). Early supplementation (within the first few weeks of life) may improve outcomes and increase life expectancy for some children with Menkes disease, though less is known about the effects for OHS and distal motor neuropathy.

In individuals where symptoms have already developed, treatment is aimed at helping manage those symptoms. For example, a feeding tube may be given to ensure proper nutrition. Early intervention may assist with developmental issues, and physical or occupational therapy and orthopedic aids may improve symptoms caused by connective-tissue problems.

What is the prognosis for an individual with an ATP7A-related Disorder?

Without treatment, children with classic Menkes disease do not typically survive more than three years. Early treatment of Menkes disease with copper supplementation can improve outcomes and increase life expectancy in some cases. Individuals with OHS can live into mid-adulthood. Little is known about the success of copper supplementation in OHS. Life expectancy is thought to be unaffected by distal motor neuropathy, but only a few cases with this condition have been identified, and long-term outcomes are unknown.