Information on the following diseases can be found in the Related Disorders section of this report:

• Wilson's Disease
• Primary Biliary Cirrhosis
• Indian Childhood Cirrhosis

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's 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's 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, similar to that of Menkes Disease.

Diagnosis
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.

Treatment
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

For further information please contact:
Patient Recruitment and Liaison Office
National Institute of Neurological Disorders and Stroke (NINDS)
9000 Rockville Pike
Bethesda, MD 20892
Tel: 800-411-1222
e-mail: prpl@mail.cc.nih.gov

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.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Menkes Disease. Entry Number; 309400: Last Edit Date; 2/27/2003.

TEXTBOOKS
Menkes JH. Menkes Disease. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:470.

Beers MH, Berkow R, eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:55-56.

Culotta VC, Gitlin JD. Disorders of Copper Metabolism. In: Scriver CR, Beaudet AL, Sly WS, et al. Eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. McGraw-Hill Companies. New York, NY; 2001:3115-18 .

Menkes JH, Sarnat HB, eds. Textbook of Child Neurology. 6th ed. Williams & Wilkins. Baltimore, MD; 2000:129-31.

REVIEW ARTICLES
Shim H, Harris ZL. Genetic defects in copper metabolism. J Nutr. 2003;133(5 Suppl 1):1527S-31S.

Mercer JF, Llanos RM. Molecular and cellular aspects of copper transport in developing mammals. J Nutr. 2003;133(5 Suppl 1):1481S-84S.

Llanos RM, Mercer JF. The molecular basis of copper homeostasis copper-related disorders. DNA Cell Biol. 2002;21:259-70.

Andrews NC. Metal transporters and disease. Curr Opin Chem Biol. 2002;6:181-86.

Strausak D, Mercer JF, Dieter HH, et al. Copper in disorders with neurological symptoms: Alzheimer’s, Menkes, and Wilson diseases. Brain Res Bull. 2001;55:175-85.

Mercer JF. The molecular basis of copper-transport diseases. Trends Mol Med. 2001;7:64-69.

Harris ED. Cellular copper transport and metabolism. Annu Rev Nutr. 2000;20:291-310.

Menkes JH. Menkes disease and Wilson disease: two sides of the same copper coin. Part II: Wilson disease. Eur J Paediatr Neurol. 1999;3:245-53.

Menkes JH. Menkes disease and Wilson disease: two sides of the same copper coin. Part I: Menkes disease. Eur J Paediatr Neurol. 1999;3:145-58.

Kaler SG. Metabolic and molecular bases of Menkes disease and occipital horn syndrome. Pediatr Dev Pathol. 1998;1:85-98.

Kaler SG. Updated 7/13/05. ATP7A-Related Copper Transport Disorders. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2008. Available at http://www.genetests.org. Accessed 2/08.

Kaler SG, Holmes CS, Goldstein DS, et al. Neonatal diagnosis and treatment of Menkes disease. N Engl J Med. 2008;358:605-14.


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