Menkes Disease

Menkes disease is a genetic disease that affects only boys. If left untreated, it results in mental retardation, seizures, and early death. The disease is also characterized by kinky hair that is colorless and easily broken apart. It is caused by an inability to absorb and use dietary copper—-copper is needed in brain and nerve development. Outcomes are poor because the disease is almost always detected too late to initiate effective treatment.

Other Names

 * Menkes Kinky Hair Disease

Cause
Menkes disease is primarily a deficiency of copper. In the disease, a specific] genetic defect prevents dietary copper from being absorbed into the body through the intestines. An otherwise normal baby can not develop Menkes disease simply by avoiding the element because the body needs only an extremely small amount of copper, and it can be obtained in just about every food.

Genetics
Menkes disease is caused by a defect on the MNK gene, which is located on the X chromosome. Thus, the disease is considered X-linked. The MNK gene encodes a protein that transports copper from the inside of the intestine to the blood.

Because of the X-linkage, the disease is passed from the mother (who is a carrier) to the son (who will get the disease). About half the daughters of mothers who are carriers will inherit the mutated gene. Girls will not get the disease because fathers (who don’t have the disease) contribute an X chromosome that counterbalances a defective gene on the X chromosome inherited from the mother. It is impossible for a father to transmit this gene to a daughter so that the daughter is a carrier, because boys with this disease die at a young age, much before they could have children on their own.

Symptoms
Baby boys born with Menkes disease may be born prematurely, but they appear healthy at birth and develop normally for six to eight weeks. Then, the following symptoms begin during the first few months of life:


 * Floppy muscle tone (hypotonia)
 * Seizures
 * Feeding difficulties and poor growth (failure to thrive)
 * Body temperature that is below normal (hypothermia)
 * Abnormal appearance of the hair
 * Severe mental retardation
 * Degeneration of the eyes (optic atophy)
 * Weakened bones, which may lead to fractures
 * Typical facial features

Hair
Menkes disease is characterized by strikingly peculiar hair:


 * Kinkiness. Kinky hair is caused by:
 * 1) fractures along the hair shaft because of the poor strength of the hair, called trichorrhexis nodosa, and
 * 2) natural twisting of the hair, called pili torti.


 * Colorless. The hair may be clear or have a faint steel color.
 * Easily broken

Mental retardation
The mental retardation is severe. The grey matter of the brain is often extensively degenerated because the brain is unable to develop and organize itself properly during its time in the womb and after birth. Arteries in the brain may also be twisted with frayed and split inner walls. This can lead to further brain damage if the arteries become blocked or rupture.



Typical facial features
Baby boys born with Menkes disease are best recognized by their colorless, kinky hair. However, they also frequently have distinctive chubby or rosy cheeks (see picture below).



Diagnosis
Diagnosis is based on the appearance of the hair, poor growth, and, in some cases, seizures. The diagnosis is confirmed by blood tests that measure copper and Ceruloplasmin. Ceruloplasmin is a protein that is used to bind and transport copper. Both copper and ceruloplasmin levels are low in Menkes disease. Another disease of copper metabolism,Wilson disease, is characterized by high copper level and low ceruloplasmin levels. This disease results from too much copper (due to the inability to transport copper out of the liver).

Genetic test
Diagnosis can also be made by genetic testing. Genetic testing is especially useful in families who have a known family history of Menkes disease, such as a previous child with the disease. Amniocentesis or chorionic villi sampling can be used to obtain samples for genetic testing of baby boys. Genetic testing is useful, since treatment for Menkes disease can be started when the child is still in the womb, and the treatment may avert the most damaging aspects of the disease if started early enough. The outcome of children who receive intrauterine treatment (treatment in the womb) is not known.

The genetic test for Menkes disease is not a routine test. It is not part of the normal newborn screen. It is done mainly in families who have already had one son with Menkes disease.

In some cases, abortion decisions are based on the results of genetic testing. In some families with a history of severe X-linked diseases, parents may decide to abort any fetus that is a boy, so genetic testing for the disease may help the parents decide against abortion if it can be shown that the male child doesn’t carry the gene.

Genetic testing can help even if a diagnosis is made long after permanent brain damage has occurred. At this point, the disease has progressed beyond the window of opportunity for effective treatment. In these cases, testing is helpful from a psychological and social perspective as it can confirm the disease and help guide families and physicians in end-of-life care and decisions to withdraw treatment.

Treatment
Daily injections of copper histidine can improve the outcome in Menkes disease if it begins within days after birth. Copper histidine can reduce mental retardation and prolong life in many cases. Treatment is even more effective if done during the fetal stage. The copper histidine is given daily by subcutaneous injection (under the skin),which is continued throughout the child's life.

Other treatment is symptomatic and supportive. Supportive treatment and end-of-life care is frequently used when diagnosis is late and treatment is ineffective. Unfortunately, this is usually the case for the first child born with the defective gene unless the family has a history of the disease.

Prognosis
The disease is rarely treated early enough to make a significant difference. This is because newborn screening for the disorder is not available, and the clinical signs of Menkes disease are subtle in the beginning, which makes early detection difficult. Therefore, the prognosis for babies with Menkes disease is poor. Most children with the disorder die by 3 years of age if they are left untreated.

Outcomes are more promising with early diagnosis and treatment. One study showed that 92% of children lived for more than four years when treatment with copper was started within 22 days of birth. Other research has shown that less than 15% of children with the disease live more than two years if diagnosis and treatment are late.

Current Research
Recent research sponsored by the National Institute of Neurological Disorders and Stroke (NINDS) developed a blood test that could be given to newborns at risk for Menkes disease (those with a family history or other indications). The test measures 4 different chemicals in the blood and can accurately diagnose the presence of Menkes disease before symptoms appear. Study results showed higher survival rates for children given the earliest copper injection treatment and improved, if not normal, neurodevelopment.

Basic research continues to investigate treatment options. Promising work is being done using DNA as a therapeutic agent. For example, an animal model of Menkes disease has been developed using zebrafish. Using this model, researchers have shown that short strands of DNA (called oligonucleotides) can be used to correct the defective protein of Menkes disease. Researchers have also shown that gene replacement in a mouse model was partially effective in correcting the disease. Studies like these suggest that treatments based on gene replacement may hold promise for correcting the copper malabsorption of Menkes disease.

Prevalence
Menkes disease is extremely rare. The incidence in Denmark, the United Kingdom, France, the Netherlands, and West Germany combined between the years of 1976 to 1987 was 1 in 254,000 live births.