Menkes syndrome(MD), alias kinky hair disease, results is abnormal copper metabolism in the body. The leading clinical findings have revealed its symptoms as short, curly, twisted, coarse, whitish, or gray hair, eyelashes, and eyebrows. MD is one among the uncommon neurogenerative maladies caused by the mutations in ATP7A gene. This particular gene is responsible for coding copper-transporting ATPase in cell organelles. Many copper-dependent enzymes go dud resulting in low concentration and accumulation in some tissues.
Individuals affected with MD accumulate excess copper levels in kidneys and intestines while the concentration remains low in brain and liver. It results in malfunctioning of copper-dependent enzymes. Experiments have revealed that defects in cytochrome-c oxidase cause hypothermia, problems in tyrosinase causes lack of pigment in skin and hair, and defects in lysyl oxidase weakens connective tissues in the body that may further fail to build strong inner walls of blood vessels; malfunctioning in enzyme monoamine oxidase results in kinky hair, and the defective ascorbate oxidase causes low-standard bone formation in the body. Lower activities of ATPase have been associated with severe symptoms while mutations in ATP7A genes result in less-severe symptoms.
Epidemiology
A study has calculated the incidence of Menkes disease for West Germany, France, Denmark, The Netherlands, and Denmark. The survey considered MD patients born between 1976-87. The collective frequency for these five nations is 1 Menkes per 2,98,000 live births. Considering the affected numbers of fetus, the incidence comes down to 1 Menkes per 2,54,000 live births. This study highlights the extreme rarity of Menkes Syndrome. However, the incidence varies country to country. MD occurs in 1 per 3,00,000 live births in America. In Australia, it occurs in 1 case per 35,000 population. Death is usually caused by pneumonia when the patient is 2-3 years of age.
Another study suggests that the incidence ranges from 1 case per one lakh live births to 1 case in 2,50,000 births. A recent statistics has revealed that approximately 540-1350 infants with MD take birth worldwide annually. The lifespan of affected children cannot be foretold though most of these kids pass away by they are three years. Some infants die because of the absence of proper medical care, still, Pneumonia is the biggest cause of death because it fails the respiratory system. Symptoms occur within initial days or months of the patient's life. Typical signs include hypotonia and seizures. Hair changes may not appear at the time of birth but appear soon. Hair of scalp and eyebrows are short, sparse, thin, white, silver, or gray.
However, no sound connections have been identified between the occurrence of MD and the race and ethnicity of patients. The genetic theory suggests that around 30 percent MD infants represent new mutations. However, these new mutations occur at an equal frequency among all racial and ethnic groups.
Genetics
Menkes Disorder is an X-linked recessive trait, and it usually affects male infants. Females with an abnormal gene on one of their X-chromosome are the carrier of the disorder. However, carrier females do not reflect symptoms of the disease because they have two X chromosomes and the one with abnormal gene gets inactivated. By contrast, if males inherit the X chromosome with abnormal gene, he will be affected. Female carriers reflect symptoms only in the case of unusual genetic circumstances. Unusual genetic circumstances may include skewed X-inactivation, Turner syndrome with Menkes gene mutation or sex chromosome aneuploidy.
Female transporters have 25 percent chances, with each pregnancy, to have a girl child with the same genetic problem, 25 percent chances of delivering a non-carrier girl child, 25 percent chances of delivering a baby boy affected with gene dysfunction, and 25 percent chances of delivering an unaffected and healthy baby boy. By contrast, males with X-linked disorders pass on the diseased gene to all daughters who, then, will become female carriers. Males cannot pass the diseased gene to their sons because they always pass on Y chromosome, not X, to their male offspring. Males affected with this disease do not usually live up to the age of reproduction.
Treatment and Therapies
Diagnosis of MD is suspected on the basis of facial expression, seizures, and hair and skin pigmentation. The examination and final diagnosis, in the past, was made by cultured skin lymphoblasts and fibroblasts that reflected the impaired copper metabolism. However, this method has been replaced by molecular genetic testing. Abnormalities can also be judged by EEG, and imaging studies as CT, angiography and MRA.
MD is a progressive disorder that leads to the death in early years; however, some of the patients may survive after five years of age. Research has revealed that care is significant in increasing the chances of survival though symptomatic treatment is available in major cases.
The purpose of medical treatment is to provide extra copper to copper-dependent enzymes and tissues. Adequate administration of copper, coupled with extra care and support, and pep up the life span of affected children up to 13 years. The main treatment is copper injection therapy. Copper is given parenterally or subcutaneously as oral administration of copper gets trapped in intestines. Copper histidine is the most effective copper compound. Its positive effect on health depends on the early diagnosis of the problem, timely initiation, and the presence of functional( or partially functional) ATP7A. Nevertheless, research studies have identified that oral treatment with copper does not alter the serum and ceruloplasmin concentrations; hence, there is no notable significance of the copper injection therapy. Still, 50 percent success has been reported in some of the cases where the treatment starts in neonatal life, up to the 2nd month of the patient. Therapies and treatment after two months of age is not of much help. A case reported that the treatment started after 8 days of the birth of an infant. It continued till the boy turned four years. The boy started walking in 14 months and showed normal neurological development.
Various research studies have reviewed the outcome of histidine on patients' health. A study monitored four patients, and all of them exhibited ataxia( mild-to-moderate), near-normal brain development, and mild neurological course without seizures. One patient reflected autonomic failure as postural hypotension and diarrhea though it was overcome by l-DOPS. Copper-histidine treatment, nonetheless, could not ameliorate skeletal abnormalities. Despite some reported cases of its successful outcomes, it cannot be accepted as a complete course for treating MD.
Apart from copper injection therapy, occupational and physical therapies are can help in maximizing the functioning and potential of the child. Physical therapies include exercises and activities to improve body posture, balance, and strength. Occupational therapy helps people in building on their skills, interests, and abilities and assist them in normal day-to-day functioning.
Healthcare providers can also offer some alternative strategies that may lessen the gravity of symptoms. These measures include:
Dietitians can recommend a proper diet for children to prevent failure to thrive.
A Gastroenterologist can offer treatments related to digestion and feeding. Their strategies include inserting a feeding tube or removing blockages that occur as a result of copper buildup.
Urologists can recommend surgeries for removing the blockage in the bladder.
Diagnosis is made by specific tests and clinical examination of hair and skin. However, fool-proof therapy and treatment do not exist. There are various antiepileptic drugs available, but research studies have identified that seizures still exist in most of the cases. Treatment, as such, is not much successful primary because of the late diagnosis that happens in most of the cases. Early neonatal treatment may be successful in 50 percent cases.
The main disturbing factor of MD is that copper is eliminated from the cells, and almost all tissues( except liver and brain) accumulate it to abnormal levels. Still, the levels of copper do not reach to the position of toxicity.
Works Cited
Fister, P., J. Rakus and Rener Primec. "Menkes Kinky Hair Disease: A Case Report." 2006.
Jody, Iosias. Menkes Disease. Cred Press, 2012.
Kaler, Stephen G., et al. "Neonatal Dianosis and Treatmet of Menkes Disease." The New England Journal of Medicine (2008).
Shim, H. and ZL. Harris. "Genetic Defects in Copper Metabolism." Jounal of Nutrition (2003).
Tonnensen, T., WJ Kleijer and Horn N. "Incidence of Menkes Disease." Hum Genet. (1991): 408-10.
Tumer, Zeynep and Lisbeth B. Moller. "Menkes Disease." European Journal of Human Genetics (2009).
