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 (variants) in the ATP7A gene. The ATP7A is important to ensure 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. ATP7A-related disorders are inherited in an X-linked manner. This means the condition is typically more severe in individuals assigned male at birth (XY). Individuals assigned female at birth (XX) usually do not have symptoms of the condition. Classic Menkes Disease Menkes disease, the most common ATP7A-related disorder, is associated with low or absent copper levels in the blood. Affected individuals 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 Affected individuals 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, individuals 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 most affected individuals 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 Most XX individuals (who are typically assigned female at birth) are carriers of ATP7A-related disorders and do not have symptoms. However, some carriers may exhibit symptoms, and roughly half of carriers will 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 XY individuals with an ATP7A-related disorder has a new harmful genetic change in ATP7A that was not inherited from their parent (known as a “de novo” change). 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. Other names forATP7A-related disorders ATP7A-related copper transport disorders ATP7A-related distal motor neuropathy Ehlers–Danlos syndrome type IX Menkes disease Menkes kinky hair syndrome Occipital horn syndrome (OHS) X-linked cutis laxa X-linked distal spinal muscular atrophy 3 References Beyens et al., 2019, Genes (Basel), 10(7):528, PMID: 31336972 Kaler, 2011, Nat Rev Neurol, 7(1):15-29, PMID: 21221114 Kaler, 2016, http://www.ncbi.nlm.nih.gov/books/NBK1413/ Ojha and Prasad, 2016, J Multidiscip Healthc, 17(9):371-85, PMID 27574440 Smpokou et al., 2014, Am J Med Genet A, 167A(2):417-20, PMID: 25428120 Tønnesen et al., 1991, Hum Genet, 86(4):408-10, PMID: 1999344 Tümer et al., 2010, Eur J Hum Genet, 18(5):511-18, PMID: 19888294 Vairo et al., 2019, Mol Genet Metab, 126(1):6-13, PMID: 30594472