Menkes disease (also known as Menkes syndrome, Copper Transport Disease, Steely Hair Disease, Kinky Hair Disease, Menkes Kinky Hair Syndrome) is a genetic X-linked recessive disorder that causes copper deficiency due to mutations in ATP7A protein gene and leads to neurodegeneration.
Description of Menkes disease
Menkes disease is more common for males. Disease occurs in 1 child in 100,000 to 250,000 live births. It was reported that one-third of all the cases are caused by the spontaneous genetic mutations. The first signs of the disorder arise during infancy. The most common symptoms are hypotonia, thin scalp hair, seizures, retention of intellectual and psychomotor development, skeleton abnormalities and joints’ hyperflexibility. Usually children with Copper Transport Disease die by the age of 3. The disorder was described in 1962 by John Hans Menkes.
Menkes disease is an X-linked recessive disorder. This means that the gene causing the disorder is located on the X chromosome. Females have two X chromosomes and men have one X chromosome and one Y chromosome. That’s why men are more likely to suffer from an X-linked recessive disease, while a woman who has one affected chromosome is healthy although she’s a carrier of the mutant gene. For a woman to develop the X-linked recessive disease two X-chromosomes should carry a mutant gene.
Mutations in the ATP7A gene are located on chromosome Xq21.1. ATP7A is a transmembrane protein that binds copper and transports it through the cells’ membranes. This protein can be found in all of the tissues of the human body except the liver. ATP7A helps to absorb the copper from the food in the intestines. In the cells this protein locates in Golgi apparatus where it provides copper to different enzymes such as cytochrome C oxidase, superoxide dismutase, lysyl oxidase, tyrosinase, ascorbic acid oxidase, ceruloplasmin, and many others.
The impairment of transport of dietary copper from intestines leads to the low serum copper levels. Abnormal copper accumulation occurs in duodenal cells, kidney, pancreas, skeletal muscle, and placenta. At the same time other organs (especially brain and central nervous system) suffer from copper deficiency. The decreased supply of copper reduce the activity of copper-containing enzymes that are vital for the structure and function of bone, skin, hair, blood vessels and the nervous system and leads to the development of the main symptoms of the disease. Decreased cytochrome C oxidase (CCO) activity is thought to cause most of the neurologic symptoms, deficient lysyl oxidase (LO) activity accounts for the connective-tissue fragility and vascular abnormalities. Tyrosinase deficiency and failure of melanin biosynthesis leads to the hypopigmentation of the hair and skin present in Menkes disease. Purkinje cell loss is found because of the deficiency of supportive cells called Bergmann glia cells.
As long as the Menkes disease is a genetic disorder anyone with a family history of the disease is at risk. This means that the main method to prevent the disease is a genetic counseling that should be provided for the couples whose families are positive for the condition, if previously children with birth defect or abnormalities were born, or in case of infertility and miscarriages. Testing enables women and couples to prepare for pregnancy, find out the reasons of infertility or miscarriages, to make a decision as to whether or not to continue with their pregnancy, and helps provide information about the genetic diseases and raising an affected child, treatment and future pregnancies.
Affected infants are sometimes born prematurely. Newborns suffer from hypothermia (lower body temperature than normal) and prolonged jaundice caused by hyperbilirubinemia (excessive bilirybin level in blood), hypoglycemia and feeding difficulties although these symptoms are common for prematurely born infants. During labor spontaneous fractures or cephalogematomas may occur. Some children have inguinal or umbilical hernia.
The first symptoms develop during infancy, usually at the age 2-3 months. At this time the skin is pale, frontal or occipital bone is bossing, micrognathia (undersized jaw) may be noted, cheeks are pudgy, and the face is rather expressionless. At the age of 6-10 weeks children develop hypotonia (floppy baby syndrome –a state of low muscle tone), seizures (resistant to medications), hair is thin and lusterless, depigmented or hypopigmented (especially scalp hair), a gradual loss of developed skills occur, mental and motor development is delayed although during the first months of life infant seems to develop normally. At the age of 5-6 months the developmental regression becomes obvious. Later hypotonia is replaced with muscle weakness and spasticity, this leads to the limitation of spontaneous movements and apathy. Other symptoms of the disease include diarrhea, vomiting, refusal to eat and failure to thrive.
Patients have also other abnormalities of the skeleton, urogenital and circulatory systems. The most spread are skeletal changes such as pectus excavatum (a caved-in or sunken appearance of the chest) or pectus carrinatum (keel-shaped deformity of the chest). Bones are affected with osteoporosis that causes spontaneous fractures. The joints are hyperextensive and loose. Blindness and subdural hematomas may occur.
Infection, respiratory failure, vascular complications (cerebral hemorrhage) and neurodegeneration are the main reasons of the death of ill children by the age of 3 years.
Milder variant of Menkes disease is called occipital horn syndrome (X-linked cutis laxa or Ehlers-Danlos type 9). The onset of this variant of the disease takes place in early or middle childhood and is characterized by the calcium deposits in occipital bone, coarse hair, loose joints and skin.
Diagnostic assessment include genetic testing, microscopic examination of hair, EEG, skeleton X-ray and MRI.
The disease is incurable, although appropriate and careful medical care along with copper medications may extend life span up to 13 years or even more. Early copper administration is recommended. This therapy prevents and slows down neurodegeneration. Oral application of copper-containing drugs is not effective, because the chemical element could not be absorbed in the intestines. Copper compounds should be supplemented parenterally or subcutaneously. Copper histidine (350-500 µg/d or qod1) is considered the most effective. Such therapy increases the serum copper level to the normal range after 6 weeks. The effectiveness of histidine-copper treatment depends on the initial activity of the APT7A enzyme and child’s age. Early diagnosis and application of the needed medications assure better results of the treatment.
Anti-seizure and pain therapy is used in case of need.
Treatment of fetuses in utero with copper histidine can avoid the development neurologic symptoms. But unfortunately the damage to the nervous system once it is done is irreversible.