Menkes Disease: Disorder of Copper Metabolism

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Table of Contents

Introduction
Epidemiology
Pathogenesis
Clinical presentation
Diagnosis
Treatment
Complications
Summary
References

Introduction

This is an inherited disorder of copper metabolism in the body that leads to a deficiency of copper and accompanying signs (de Bie et al, 2007; William et al, 2005). The condition was described first by Menkes, Alter, Steigleder, Weakley and Sung in 1962 (Menkes et al, 1962).

The inheritance of the condition is linked to the x-chromosome; consequently, the incidence is higher in the males than in the female; additionally, the latter requires two defective alleles for the expression of the defective phenotype.

Epidemiology

The condition is very rare; two figures have been advanced from two different regions. A rate of occurrence of one case in every 254,000 was reported in Europe (Tønnesen et al, 1991). In Japan, even a bigger ratio of one case in every 354,143 people was reported (Gu et al, 2005).

Pathogenesis

Menkes syndrome results from a defect in the ATP7A gene resulting in uneven distribution of copper among the cells of the various systems [Voskoboinik and Camakaris, 2002]. The resultant effects are that while some tissues have very high concentrations of copper, for example, the intestinal mucosa and the kidneys, others have very low levels such as the liver and the brain.

Copper plays a crucial part in the proper functions of many metabolic enzymes acting as a co-enzyme. Deficiency of copper results in the reduced function of these enzymes leading to abnormal anatomy and function of the skeletal system, hair, vasculature and nervous system (Kim et al, 2002). The defective genes are transmitted via an x-linked recessive fashion thus making the syndrome primarily a condition of the male infant.

Clinical presentation

Infants carrying this gene are usually born prematurely; however, they look normal and appear to develop normally for six to eight weeks when the condition sets in. Signs that begin to show include poor development of muscle tone and delay in the development of motor skills; the infants face starts to sag. The brain is severely affected resulting in nervous signs such as seizures and mental retardation. In the brain the main lesion is diffuse degeneration of gray matter (Barnes et al, 2005); the blood vessels supplying brain tissue are also severely degenerated; ruptures and blockages are a common feature. A combination of these lesions results in the central nervous signs seen in this syndrome.

A striking feature in this syndrome is the growth of abnormal hair; hair is one of the parts of the body that requires an optimum amount of copper for proper development, and conditions that may lead to an absolute or relative deficiency of copper in the body severely affects the development of hair. In the case of Menkes syndrome, the hair is kinky, has no pigmentation (another function of copper) or is steel-colored, is brittle and breaks easily.

Clinical signs in infants are generally attributed to abnormal intestinal copper absorption coupled with a deficiency of copper in mitochondrial enzymes that require the ions as co-enzymes for activation. Following the period of slowed development, the infant deteriorates rapidly with almost complete cessation of development and deterioration of some of the aspects.

Other accompanying signs include a lower than normal temperature and loss of bone density leading to a softening of bone or osteoporosis resulting in pathological fractures; there is also widening of the metaphyses. There is a less severe variant of Menkes syndrome known as Occipital horn syndrome; the signs of this condition are usually seen in early to middle childhood. There is a characteristic deposition of calcium on the occipital bone thus giving the condition its name. Other accompanying signs include sagging skin, unstable joints, and coarse hair. The condition is also known as X-linked cutis laxa.

Diagnosis

For the proper early attempt of treatment in order to improve the prognosis, early detection is necessary. However, the development of the signs of Menkes syndrome is usually insidious thus most attempts of treatment are usually delayed.

There has been a development of a test to measure the levels of copper in blood for newborns [Kaler, et al, 2008]. Other proposals include the measurement of the ratio of homovallinic acid and vanillylmaldemic acid in urine as a support diagnostic criterion for detection of Menkes syndrome in infants (Matsuo et al, 2005).

Treatment

Following detection, early intervention via subcutaneous injections or intravenous infusions with a copper compound on a daily basis has been shown to improve the rate of survival in infants and result in the normal development of the nervous system (Kaler et al, 2008). This treatment has however to be done within a few days postpartum before the development of irreversible brain degeneration.

Complications

Due to the insidious onset of the condition, many cases are not diagnosed at the moment when a copper supplement can be administered. Therefore, the prognosis of most cases is poor; and most children with Menkes syndrome do not live to see their tenth birthday.

Summary

Menkes syndrome is a hereditary disease caused by a mutation in the ATP7A gene.
The condition is transmitted in an X-linked recessive pattern making it a predominantly male disease
However, females can also suffer from the condition if they have two defective alleles
The mutation results in a poor distribution of copper in the body with some organs having excess amounts such as the intestines and the kidney; and some having very low concentration.
Copper is important as a co-enzyme for many metabolic enzymes, for bone development, and for the growth of hair
Affected infants are born prematurely, develop normally for a short while then develop the condition that halts development.
Signs of the syndrome include characteristically abnormal hair, muscular hypotonia, weak bone, degeneration of the nervous system and neurological signs
Effective treatment via injection of the infant with copper supplements requires very early detection which is not usually possible.
Therefore, cases of Menkes syndrome generally have a poor prognosis
Menkes syndrome is related to the milder X-linked cutis laxa or the Occipital horn syndrome.

References

Barnes N, Tsivkovskii R, Tsivkovskaia N, Lutsenko S (2005). The copper-transporting ATPases, menkes and wilson disease proteins, have distinct roles in adult and developing cerebellum. Journal of Biological Chemistry 280 (10): 9640–5.
de Bie P, Muller P, Wijmenga C, Klomp LW (November 2007). Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes. Journal of Medical Genetics 44 (11): 673–88.
Gu YH, Kodama H, Shiga K, Nakata S, Yanagawa Y, Ozawa H (2005). A survey of Japanese patients with Menkes disease from 1990 to 2003: incidence and early signs before typical symptomatic onset, pointing the way to earlier diagnosis. Journal of Inherited Metabolic Diseases 28 (4): 473–8.
Kaler SG, Holmes CS, Goldstein DS, et al (February 2008): Neonatal diagnosis and treatment of Menkes disease. New England Journal of Medicine 358 (6): 605–14.
Kim BE, Smith K, Meagher CK, Petris MJ (November 2002). A conditional mutation affecting localization of the Menkes disease copper ATPase. Suppression by copper supplementation. J. Biol. Chem. 277 (46): 44079–84.
Matsuo M, Tasaki R, Kodama H, Hamasaki Y (2005). Screening for Menkes disease using the urine HVA/VMA ratio. Journal of Inherited Metabolic Diseases 28 (1): 89–93
Menkes JH, Alter M, Steigleder GK, Weakley DR, Sung JH (1962). A sex-linked recessive disorder with retardation of growth, peculiar hair, and focal cerebral and cerebellar degeneration. Pediatrics 29: 764–79
Tønnesen T, Kleijer WJ, Horn N (February 1991). Incidence of Menkes disease: Human Genetics 86 (4): 408–10
Voskoboinik I, Camakaris J (2002). Menkes copper-translocating P-type ATPase (ATP7A): biochemical and cell biology properties, and role in Menkes disease. J Bioenerg Biomembr 34 (5): 363–71
William James; Berger, Timothy; Elston, Dirk (2005): Andrews’ Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders

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