Menkes disease

Menkes syndrome, also called the Menkes disease is a rare inborn error of metabolism, which is based on a copper metabolism disorder. It was named after its first describer John Hans Menkes ( 1928-2008 ). It is transmitted as an X -linked recessive. Even with an early onset of treatment, the life expectancy is significantly shortened in many cases. If left untreated, most patients die within the first three years of life.

The importance of copper for the human organism

With a combined weight of about 70-150 mg provides copper for iron and zinc, the third most abundant trace element in humans dar. copper occurs in many different organs, including the skeleton, brain, muscles and liver.

Copper has a variety of tasks in the human body and is also part of enzymes (currently 16 known ), such as superoxide dismutase, which protects cell membranes from free radical damage. Thus, in its broadest sense also an antioxidant. In addition, copper is responsible for the electron transport ( energy ). Copper is also involved in the formation of collagen and elastin in connective tissue. Also important is the oxidation of various compounds having oxygen as the oxidant, which is catalyzed by copper enzymes (such as catechol oxidase and tyrosinase ), and about the formation of melanin lead (see also albinism ).

Copper deficiency various diseases can occur, such as the Menkes syndrome, which was discovered by John Hans Menkes for the first time. Another disease associated with copper metabolism is the Wilson's disease.

Cause

The Menkes disease is X - chromosomal recessive trait and is located at position X 13.3., So that it occurs only in young boys, as they have a single X chromosome. In girls, the gene product from the second, healthy X chromosome can be formed in sufficient quantity. There is a mutation in the ATP7A gene. This gene encodes an intracellular copper transport protein. Mutations the copper emission is disturbed in normal copper intake. Subsequently, the absorption of copper from the intestine is insufficient. Moreover, this leads to an incorrect distribution of the trace element with decreased concentrations in liver and brain, however, increased concentrations in intestinal cells, heart, pancreas and kidneys.

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

There are various progressive forms of the syndrome known that come through mutations at different locations about. As mildest variant applies the occipital horn syndrome, in which brain development is unremarkable or only minimally impaired and the mainly Bindegewebsauffälligkeiten shows.

Frequency

Even in 1974 the incidence of the disease on 1:350,000 was given by Australian estimates. Recent estimates show that approximately one affected 100000-150000 male newborns. This would for Germany calculate the number of about three to four cases per year.

Symptoms

After birth, no serious symptoms may appear in the first eight to ten weeks of life. Later, feeding difficulties, failure to thrive and developmental delays set with pronounced weakness of the muscles. The involvement of the brain is expressed additionally in movement disorders and seizures. The connective tissue is involved in the form of a flabby, less elastic skin (cutis laxa ), seborrheic dermatitis and a characteristic change of the hair. The hair is not only typically jagged and turned inwards ( pili torti ) but also brittle ( Trichorrhexis nodosa ), sparse and mostly white to silver-gray. Of these, the eyebrows and the eyelashes are affected. The face is expressionless with hanging cheeks and seemingly large ears. On the skeleton can strike a funnel chest. Often you can find umbilical or inguinal hernias. In the urinary tract, the changes in the form of Blasendivertikeln and enlarged ureters show. Vessels may be involved in so far as they have striking tortuosity. In rare severe disease courses that already be fatal in the neonatal period, there is vascular changes with skin hemorrhages and multiple bone fractures.

Diagnostics

The clinical suspicion of corresponding symptoms can be confirmed by determining the level of copper in urine and serum as well as the copper storage protein ceruloplasmin in serum. However difficult the fact that these concentrations are already in newborns is still very low, so that there may be some overlap of the values ​​of healthy and affected parties, an early diagnosis. The impaired copper transport can be demonstrated in vitro in fibroblasts or lymphoblasts affected Zellkululturen from that release after ingestion of labeled copper ions in these lesser extent again. The quickest and surest way to confirm the diagnosis, thus provides for discovery of the genetic basis of the disease represents the molecular genetic analysis of the ATP7A gene with evidence of relevant mutation

If you do x-rays, you can clearly see that the children have bones shift and have vertebral anomalies. An EEG clear signs of hypsarrhythmia be found. In further studies we discover and focal degeneration of the gray and white matter axonal degeneration. Cell of sunsets in the thalamus and in the cerebellum ( Purkinje cells) are also among the symptoms. Under the electron microscope, changes in the mitochondria are clearly visible.

Therapy

Since the Menkes syndrome, the copper may not be forwarded from the gut into the body, it must be administered on the gastro-intestinal tract by ( parenteral). For this purpose, Kupferhistidinat has not only proved effective, but also as a most tolerable substance. It can be injected into the subcutaneous fat tissue, occurs as a copper transport protein in blood and can cross the blood- cerebrospinal fluid barrier and reach the brain. It is an early start of treatment significantly as possible prior to the occurrence of damage to the nervous system. If there are already neurological symptoms Kupferhistidinat can not stop the progressive course of the disease. However, no favorable course itself by early copper replacement therapy guaranteed. Kaler reported in his work on eleven children, in whom treatment at the age of less than a month was started and of which five still died. Of the eleven children who started therapy later, six died. However, the treatment with Kupferhistidinat only positively affect the neurological development of children. The manifestations of the connective tissues are not improved.

Forecast

The prognosis appears to depend even more than from the time of diagnosis, and thus from the start of therapy on the nature and localization of the causative mutation in the ATP7A gene. Few patients reach adulthood. For all show more or less severe changes in the connective tissue.

History

Already in the 30s of the 20th century, the important role of copper for the development of the nervous system of mammals became clear when Australian vets were able to establish a relationship between copper deficiency and a myelin sheath loss in ataxic lambs. The ewes had grazed on pastures during the low-copper gestation period, the offspring suffered from a loss of the myelin sheath ( demyelination ) and other changes in brain structure. 1962 described John Hans Menkes five male children of a family of Irish descent, who were all affected by a characteristic symptom complex from degradation of the nervous system, peculiar hair, and failure to thrive. At birth, yet unobtrusive, the boy later developed seizures and development setbacks, until she finally died at the age of seven months to three and a half years. In the early seventies of the last century fell to DM Danks that the unusual hair of children was similar to that described by Menkes syndrome of brittle, brittle wool of Australian sheep that grazed on kupferverarmten floors. He determined the copper concentration in the serum of seven patients and found Menkes low values ​​in all cases. Similarly, decreased was the content of the copper transport protein ceruloplasmin. Having already suggesting the pedigree of the first family described by Menkes that the disturbance follows an X-linked recessive mode of inheritance has been identified by various working groups, the Menkes gene in 1993. This groundbreaking discovery finally revealed that it is the gene product to a cation -transporting ATPase, which plays a crucial role in the transport of ions across cellular and intracellular membranes.