Menkes syndrome

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Classification according to ICD-10
E83.0 Disorders of the copper metabolism
Menkes syndrome
ICD-10 online (WHO version 2019)

The Menkes disease , the Menkes disease called, is a rare congenital metabolic disorder that is based on a copper metabolism disorder. It was named after the person who first described it, John Hans Menkes (1928–2008). It is an X-linked - recessive inherited . Even with early treatment, life expectancy is in many cases significantly reduced. If left untreated, most patients die within the first three years of life.

The importance of copper for the human organism

With a total content of around 70–150 mg, copper is the third most abundant trace element in humans after iron and zinc . Copper occurs in many different organs, including the skeleton , the brain , the muscles and the liver .

Copper has a variety of tasks in the human body and is also part of enzymes (16 known so far), such as superoxide dismutase , which protects cell membranes from damage by free radicals. Thus, in the broadest sense, it is also an antioxidant . In addition, copper is responsible for transporting electrons (energy generation). Copper is also involved in the formation of collagen and elastin in connective tissue . Also important is the oxidation of various compounds with oxygen as an oxidizing agent, which is catalyzed by copper enzymes (such as tyrosinase and catechol oxidase ) and leads to the formation of melanins (see also albinism ).

With a copper deficiency various diseases can occur, such as Menkes syndrome, which was first discovered by John Hans Menkes. Another disease related to copper metabolism is Wilson's disease .

root cause

Menkes disease is inherited as a recessive X chromosomal and is located at X 13.3., So that it only occurs in young boys because they have a single X chromosome. In girls, the gene product can be formed in sufficient quantities from the second, healthy X chromosome. There is a mutation in the ATP7A gene. This gene codes for an intracellular copper transport protein. In the case of mutations, the copper release is disturbed with normal copper uptake. As a result, the absorption of copper from the intestine is insufficient. In addition, this leads to an incorrect distribution of the trace element with reduced concentrations in the liver and brain, but increased concentrations in intestinal cells, heart, pancreas and kidneys.

The reduction in the activity of various copper-dependent enzymes ( cytochome C oxidase , which is involved in the energy metabolism in the mitochondria; lysyl oxidase , which is responsible for the formation of connective tissue; superoxide dismutase , which binds free radicals; dopamine beta-hydroxlase is responsible for the formation of important neurotransmitters ; ascorbic acid oxidase is involved in skeletal structure and pigmentation) leads to the characteristic symptoms of progressive damage to the brain and connective tissue disease.

Various forms of the syndrome are known, which come about through mutations in different places. The mildest variant is the occipital horn syndrome , in which brain development is inconspicuous or only minimally impaired and which mainly shows abnormalities in connective tissue.


In 1974, according to Australian estimates, the frequency of the disease was given at 1: 350,000. Recent estimates suggest that about 1 in 100,000 to 150,000 newborn males is affected. From this the number of around three to four illnesses per year would be calculated for Germany.


After birth, no serious symptoms can be recognized in the first eight to ten weeks of life . Later on there are feeding difficulties, failure to thrive and development delays with pronounced weakness of the muscles. The involvement of the brain is also expressed in movement disorders and epileptic seizures . The connective tissue is involved in the form of sagging, less elastic skin (cutis laxa), seborrheic dermatitis and a characteristic change in the hair. The hair is not only jagged and twisted in the typical way (Pili torti), but also brittle (Trichorrhexis nodosa), sparse and usually white to silver-gray. The eyebrows and eyelashes are also affected. The face is expressionless with drooping cheeks and apparently large ears. A funnel breast can be noticed on the skeleton. Umbilical or inguinal hernias are often found . In the urinary tract, the changes show up in the form of bladder diverticula and dilated ureters. Vessels can be involved insofar as they have conspicuous tortuosity. In rare, most severe forms, which end fatally in the neonatal period, there are vascular changes with skin bleeding and multiple bone fractures.


The clinical suspicion of such symptoms can be confirmed by determining the copper level in the urine and serum as well as the copper storage protein ceruloplasmin in the serum. However, the fact that these concentrations are still very low in newborns, so that the values ​​of healthy and affected persons can overlap, makes it difficult to make an early diagnosis. The disturbed copper transport can also be detected in vitro on cell cultures from affected fibroblasts or lymphoblasts , which after absorption of labeled copper ions release them to a reduced extent. Since the genetic basis of the disease was discovered, the fastest and safest diagnosis option has been the molecular genetic examination of the ATP7A gene with detection of a corresponding mutation.

X-rays of affected children show switching bones and vertebral anomalies. In the EEG there are clear signs of let hypsarrhythmia find. Histopathologically , one also discovers focal degeneration of the gray matter and axonal degeneration of the white matter . Cell loss in the thalamus and cerebellum (Purkinje cells) are also among the symptoms. Changes in the mitochondria can be seen under the electron microscope .


Since in Menkes syndrome the copper cannot be passed on from the intestine into the body, it has to be administered via the gastrointestinal tract (parenterally). For this purpose, copper histidinate has not only proven to be the most effective, but also the most compatible substance. It can be injected into the subcutaneous fatty tissue, occurs as a copper transport protein in the blood and can also reach the brain via the blood-liquor barrier. It is crucial to start treatment as early as possible before the damage to the nervous system occurs. If neurological symptoms already exist, copper histidinate can no longer stop the progression of the disease. However, even early copper replacement therapy does not guarantee a favorable course. In his work, Kaler reports on eleven children in whom treatment was started at the age of less than one month and of whom five died. Six of the eleven children who started therapy later died. However, therapy with copper histidinate can only have a positive effect on the neurological development of children. It does not improve the manifestations on the connective tissues.


The prognosis obviously depends more on the type and location of the causative mutation in the ATP7A gene than on the time of diagnosis and thus the start of therapy. Few patients reach adulthood. All of them show more or less severe changes in the connective tissue.


The important role of copper in the development of the mammalian nervous system became apparent as early as the 1930s, when Australian veterinarians were able to establish a connection between a copper deficiency and a medullary sheath loss in atactic lambs. The dams had grazed on low-copper pastures during the gestation period, the offspring suffered from a loss of myelin sheaths (demyelination) and other changes in the brain structure. In 1962, John Hans Menkes described five male children of a family of Irish descent who were all affected by a characteristic complex of symptoms of breakdown of the nervous system, peculiar hair and failure to thrive. Still normal at birth, the boys later developed epileptic seizures and developmental regressions until they finally died between the ages of seven months and three and a half years. In the early 1970s, DM Danks noticed that the unusual hair of children with the syndrome described by Menkes resembled the brittle, fragile wool of Australian sheep that grazed on copper-deprived soil. He determined the copper concentration in the serum of seven Menkes patients and found low values ​​in all cases. The content of the copper transport protein ceruloplasmin was also reduced . After the pedigree of the first family described by Menkes suggested that the disorder followed an x-linked recessive inheritance, the Menkes gene was identified in 1993 by various working groups. This groundbreaking discovery eventually revealed that the gene product is a cation- transporting ATPase , which has a critical role in the transport of ions across cellular and intracellular membranes .

See also

Web links

Commons : Menkes Syndrome  - Collection of pictures, videos, and audio files

Individual evidence

  1. a b J. H. Menkes, M. Aalter u. a .: A sex-linked recessive disorder with retardation of growth, peculiar hair, and focal cerebral and cerebellar degeneration. In: Pediatrics. Volume 29, May 1962, pp. 764-779, ISSN  0031-4005 . PMID 14472668 .
  2. a b c d Korenke et al: Menkes syndrome. In: Monthly Pediatrics. 2005, 153, pp. 864-870.
  3. T. Tønnesen, WJ Kleijer, N. Horn: Incidence of Menkes disease. In: Hum Genet. 1991; 86 (4), pp. 408-410, PMID 1999344 .
  4. a b c d e G. S. Kaler: Diagnosis and therapy of Menkes syndrome, a genetic form of copper deficiency. In: Am J Clin Nutr. 1998; 67 (5 Suppl), pp. 1002S-1034S, PMID 9587146 .