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NORD is very grateful to John H. Menkes, MD, Professor Emeritus of Neurology and Pediatrics, UCLA School of Medicine, and Director Emeritus of Pediatric Neurology, Cedars-Sinai Medical Center, for assistance in the preparation of this report.
Menkes disease is a genetic disorder of copper metabolism that is detectable before birth (prenatally) and which follows a progressively degenerative path involving several organs of the body but especially the brain. It is characterized by seizures, mental retardation, stunted growth, failure to thrive, unstable body temperature, and very unusual color and texture of hair.
It is the failure of the copper transport systems within the cell and then across the cell membrane that is responsible for the symptoms of the disorder. Because of the failure of this transport system, copper is unavailable to various cells where it is essential for the structure and function of various enzymes that control the development of hair, brain, bones, liver and arteries.
Menkes disease is an X-linked genetic disorder caused by mutations in the ATP7A gene that is responsible for production of the ATPase enzyme that regulates copper levels in the body. Variants of Menkes that are caused by mutations in the ATP7A gene but result in less severe symptoms include mild Menkes disease and occipital horn syndrome.
Menkes disease is characterized by brittle, tangled, sparse, steely or kinky hair that is often white, ivory, or gray in color. Unusual facial features include pudgy cheeks and abnormal eyebrows. Affected infants are often born prematurely. Lower than normal body temperature (hypothermia) and excess bilirubin in the blood (hyperbilirubinemia) may occur causing a yellow appearance (jaundice). Hypothermia may also occur in older infants. In some cases, early symptoms may resolve, and normal or slightly slowed development may proceed for two to three months. Severe developmental delay, loss of early development skills, and convulsions may occur. Brain abnormalities such as a blood clot at the base of the brain (subdural hematoma) and/or rupture or thrombosis of arteries in the brain not infrequently occur. Spastic dementia and seizures may eventually arise. Weakened bones (osteoporosis) are common and can result in fractures. The combination of subdural hematoma and bone fractures may lead to an incorrect diagnosis of child abuse. Emphysema, bladder abnormalities, degeneration of the retina and cysts of the iris have also been described. In rare cases, symptoms are very mild and only a few typical symptoms may appear.
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 body's natural copper-dependent enzymes fail. Experimental evidence is clear that without the copper bound to the amino-acid peptide, the defective enzyme cytochrome-c oxidase is the cause of the hypothermia; the defective enzyme tyrosinase is the cause of the lack of pigment of the hair and skin; the defective enzyme lysyl oxidase is the cause of the failure of the connective tissue to create strong, inner walls of blood vessels; the defective enzyme monoamine oxidase is the cause of the kinky hair; and the defective enzyme ascorbate oxidase is the cause of the substandard bone formation. Variants of Menkes that are caused by mutations in the ATP7A gene but result in less severe symptoms include mild Menkes disease and occipital horn syndrome. Lower activity of ATPase is related to more severe disease.
X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and occur mostly in males. Females that have a disease 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 one is inactivated so that the genes on that chromosome are nonfunctioning. It is usually the X chromosome with the abnormal gene that is inactivated. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease gene he will develop the disease.
Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
Males with X-linked disorders pass the disease gene to all of their 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. Males with Menkes disease have not been reported to live to reproductive age. Fertility of individuals with mild Menkes disease or occipital horn syndrome is not known.
Recent studies suggest that the incidence of Menkes disease ranges from about 1 in 100,000 live births to 1 in 250,000 live births.
Symptoms of the following disorders can be similar to those of Menkes disease. Comparisons may be useful for a differential diagnosis:
Wilson disease is a rare genetic disorder of copper metabolism characterized by excess storage of copper in the body tissues, particularly in the liver, brain and corneas of the eyes. It leads eventually to liver disease, brain dysfunction, and a characteristic rusty-brown colored ring around the cornea of each eye known as a Kayser-Fleischer ring. Symptoms usually do not appear in early infancy and patients do not have the characteristic kinky hair of Menkes disease. (For more information on this disorder, choose "Wilson" as your search term in the Rare Disease Database.)
Primary biliary cirrhosis (PBC), also known as Hanot cirrhosis, is a rare condition occurring mainly in women. Four pathologic stages occur in increasing severity. Gradual deterioration of the small bile ducts inside the liver causes a blockage in the flow of bile (cholestasis) and liver enlargement. In time, retention of chemicals in the liver cause further damage. Bile acids are absorbed abnormally from the liver into the blood and soft tissues, causing itching accompanied by yellow skin discoloration (jaundice). Dietary and bone problems can also result. Copper retention in the liver, also present in Menkes disease, can also occur. (For more information on this disorder, choose "PBC" as your search term in the Rare Disease Database.)
Indian childhood cirrhosis is a familial and probably genetically determined disease. An extremely large amount of copper accumulates in the liver, a phenomenon similar to that of Menkes disease.
Menkes disease is diagnosed by measurement of a decreased amount of copper and ceruloplasmin in blood plasma but these tests are not always reliable in the newborn period. A new method of diagnosis that can potentially identify affected infants before copper deficiency affects the brain involves measurement of catecholamine levels in blood plasma. Molecular genetic testing for mutations in the APT7A gene is available to confirm the diagnosis. Carrier testing and prenatal diagnosis are available if a specific ATP7A mutation in an affected family member.
Prenatal or very early (within weeks) diagnosis of Menkes disease is essential. Injections of a copper histidine compound have been shown to increase the concentration of copper in the blood and thus become available for the development of copper-dependent enzymes and the production of myelin. The effectiveness of histidine-copper treatment depends on whether some activity of the APT7A enzyme has been preserved, and whether copper supplementation has been initiated promptly.
The National Institute of Neurological Disorders and Stroke (NINDS) is sponsoring a Phase II clinical trial of Early Copper Histidine Therapy in Menkes Disease: Relationship of Molecular Defects to Neurodevelopmental Outcomes. NINDS hopes to enroll 52 persons for this study.
Therapeutic strategies for the treatment of Menkes disease must:
1. bypass the block in intestinal absorption of copper;
2. deliver circulating copper to the brain;
3. deliver copper to the enzymes within the cells that require it as a coenzyme
4. identify infants requiring treatment
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.
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FROM THE INTERNET
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Report last updated: 2008/02/11 00:00:00 GMT+0