NORD gratefully acknowledges Mario Melika, NORD Editorial Intern from the Massachusetts College of Pharmacy and Health Sciences, and Stephen G. Kaler, MD, CAPT, US Public Health Service (Ret), Professor of Pediatrics and Genetics, The Ohio State University College of Medicine, Center for Gene Therapy; Abigail Wexner Research Institute, Nationwide Children’s Hospital, for assistance eon the preparation of this report.
Menkes disease (MD) is an inherited X-linked recessive disorder that affects many systems in the body. Affected infants are often born prematurely and may have non-specific symptoms such as hypothermia, hypoglycemia, and prolonged jaundice. One obvious and specific physical sign is “steely” or “kinky” hair that usually develops by several months of age. Menkes disease is also associated with seizures, stunted growth, failure to thrive, unstable body temperature, and intellectual disability.
Menkes disease is caused by mutations in the ATP7A gene that is responsible for transport of copper throughout the body. The body uses copper as a cofactor to activate certain enzymes in order to carry out certain functions. When these enzymes are not working normally, serious and fatal effects can ensue over time related to the function of the copper-dependent enzymes that control the development of hair, brain, bones, liver, and arteries. Variants of MD that are caused by mutations in the ATP7A gene but result in less severe symptoms include mild Menkes disease and occipital horn syndrome.
There is no complete cure for Menkes disease at this time, but treatment with parenteral copper histidinate (CuHis) can increase survival and lessen the neurological symptoms if initiated early, within approximately 28 days following birth.
Menkes disease is characterized by dry skin and abnormal hair that is often brittle, tangled, sparse, steely or kinky and is often white, ivory, or grey in color. The affected infant may also appear to have a yellow appearance (jaundice) which is caused by excessive bilirubin in the blood (hyperbilirubinemia). Lower than normal body temperature (hypothermia) also may occur in the neonatal period. The normal, asymptomatic phase of the illness typically lasts for two to three months.
Brain and cognitive abnormalities are central in this disorder. Blood clots (subdural hematomas) and/or rupture or thrombosis of arteries in the brain may occur. Neurodegenerative effects such as seizures, and delayed growth and development may also arise. Reduced bone density (osteoporosis) is common and may result in fractures. The combination of subdural hematoma and bone fractures may lead to an incorrect diagnosis of child abuse. Emphysema, bladder diverticula, neck masses due to internal jugular vein phlebectasia, and cortical blindness have also been described.
Occipital horn syndrome (OHS) is recognized as a milder form of MD with less severe neurological involvement and is usually diagnosed around the age of 5-10 years.
Menkes disease is an X-linked genetic disorder caused by mutations in the ATP7A gene. This gene is responsible for production of the ATPase enzyme that regulates copper levels in the body. Individuals with Menkes disease have an abnormally low level of copper in the brain and liver and excess copper in the intestines and kidneys. Without the copper as a key element in their structure and functioning, the activity of the body’s copper-dependent enzymes is diminished. For example, reduced activity of the cuproenzyme tyrosinase causes reduced pigmentation of the hair and skin. Reduced activity of the cuproenzyme lysine oxidase causes failure of connective tissue to form strong, inner blood vessels walls.
X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest in males. Females that have a non-working gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the non-working gene. However, since males have one X chromosome, inherited from the mother, if a male inherits an X chromosome harboring a non-working gene, he will develop the disease.
Female carriers of an X-linked disorder have a 50% chance to have a son affected with the disease and a 50% chance of an unaffected son. There is a 50% chance with each pregnancy to have asymptomatic “carrier” daughter like themselves, and a 50% chance to have a non-carrier daughter.
If a male with an X-linked disorder is able to reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
Recent studies suggest that the incidence of Menkes disease is about 1 in 35,000 live male births. The majority of diagnosed infants are male; however, MD may still occur in females, related to unusual genetic circumstances.
The diagnosis of MD is suggested by the appearance of brittle, tangled, sparse, steely or kinky hair at several months of age. Blood tests showing low levels of serum copper and ceruloplasmin support the diagnosis. It is important to note that these levels are typically low in otherwise healthy newborns. A new method of diagnosis that can potential identify affected infants before copper deficiency affects the brain involves measurement of plasma catecholamine levels. This may be the basis for Menkes disease newborn screening in the future. Molecular genetic testing for mutations in the ATP7A gene may also prove to be an efficient method of population-based newborn screening.
For infants suspected to be affected on clinical and biochemical grounds, ATP7A mutation testing is available commercially to confirm the diagnosis. Carrier testing and prenatal diagnosis are also available once a specific ATP7A gene variant has been identified in an affected family member.
Early (ideally within 28 days of age of birth, corrected for prematurity) treatment of Menkes disease is essential. Injections of a copper histidinate (CuHis), a new molecular entity prepared as a freeze-dried product, have been shown to increase the concentration of copper in the blood and improve neurodevelopmental outcomes in some patients. The degree of CuHis treatment efficacy in older, symptomatic Menkes disease patients is less clear.
Genetic counseling is recommended for the parents and families of affected children for a proper understanding of recurrence risk.
One-time adeno-associated viral gene therapy in combination with subcutaneous CuHis injections represents a promising treatment approach in development for subjects with Menkes disease.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site:
A Menkes Disease Clinic was established in Fall 2019 at Nationwide Children’s Hospital in Columbus, OH in affiliation with the Ohio State College of Medicine:
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For more information about clinical trials conducted in Europe, contact:
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