Menkes Syndrome

views updated

Menkes syndrome

Definition

Menkes syndrome is a sex-linked recessive condition characterized by seizures and neurological deterioration, abnormalities of connective tissue, and coarse, kinky hair. Affected males are often diagnosed within the first few months of life and die in early childhood.

Description

Menkes syndrome is also known as Menkes disease and "kinky hair syndrome." It was originally described in 1962 based on a family of English and Irish descent who had five male infants with a distinctive syndrome of progressive neurological degeneration, peculiar hair, and failure to thrive. Each of the boys appeared normal at birth but, by the age of several months, developed seizures and began to regress in their physical skills. Each child died at an early age, with the oldest surviving only until three-and-a-half years. In 1972, Menkes syndrome was linked to an inborn copper deficiency. It is now clear that this lack of copper, an essential element for normal growth and development, inhibits the work of specific enzymes in the body. The clinical signs and symptoms of Menkes syndrome are a direct result of these biochemical abnormalities.

Approximately 90–95% of patients with Menkes syndrome have a severe clinical course. This represents classical Menkes syndrome. Males with milder forms of Menkes syndrome have also been described. The mildest presentation is now known as occipital horn syndrome (OHS), which is allelic to Menkes syndrome: both conditions are due to different mutations in the same gene . Mutations responsible for OHS primarily cause connective tissue abnormalities and have significantly milder effects on intellectual development. Individuals with OHS also live longer than those with classical Menkes syndrome.

Genetic profile

Menkes syndrome is an X-linked recessive condition. The gene, which was identified in 1992, is located on the long arm of the X chromosome at band 13.3 (Xq13.3). It is extremely unusual for a female (with two X chromosomes in her cells) to be affected, although it has been reported. Males, who have only one X chromosome, make up the overwhelming majority of patients.

Approximately one-third of affected males are due to a new mutation in the mother's egg cell. There is usually a negative family history, or no other affected male family members. When the mutation occurs as an isolated, random change, the mother's risk of having another affected son is low.

On the other hand, the remaining two-thirds of affected males are born to carrier mothers. Often, there is a family history of one or more affected male relatives (e.g., uncle, brother, cousin), all of whom are related to one another through the maternal side. Carrier females are normal but face a risk of passing on the gene for Menkes syndrome to their children. A carrier mother has a 25% risk of having an affected son, 25% risk of having an unaffected carrier daughter, 25% risk of having a normal son, and a 25% risk of having a normal, non-carrier daughter. These risks apply to each pregnancy.

The Menkes syndrome gene, also known as MNK or ATP7A, is a large gene known to encode a copper-transporting protein. Individuals with Menkes syndrome have low levels of copper in their blood. Their cells are able to take in copper but the metal is unable to leave the cell and be delivered to crucial enzymes that require copper in order to function normally. As a result, copper accumulates in the body tissues, and clinical abnormalities occur. Most symptoms of Menkes syndrome, such as skeletal changes and abnormal hair, may be explained by the loss of specific enzymes. However, the reasons for the brain degeneration are still not entirely clear.

A variety of mutations that cause Menkes syndrome have been identified in the MNK gene. Unfortunately, almost every family studied has had a unique mutation. This makes genetic testing difficult, particularly if the mutation in the family has not yet been determined. OHS is also due to mutations in the MNK gene.

Demographics

Menkes syndrome is relatively rare, with an estimated incidence of one in 100,000–250,000 male births. To put this into a different perspective, among the 3.5 million infants born annually in the United States, approximately 15–35 males would have Menkes syndrome.

Signs and symptoms

Infants with classical Menkes syndrome appear normal at birth and continue to develop normally for roughly the first eight to ten weeks of life. At approximately two to three months of age, affected infants begin to lose previously attained developmental milestones, such as head control and a social smile. They lose muscle tone and become hypotonic, or floppy, develop seizures, and begin to fail to thrive. Changes in the appearance of their face and hair become more apparent. A diagnosis of Menkes syndrome is often made around this time.

The clinical features of Menkes syndrome include:

Neurologic

Mental deterioration and handicap due to structural and functional brain abnormalities
Seizures
Inability to regulate body temperature (hypothermia)
Feeding and sleeping difficulties
Decreased muscle tone

Connective tissue

Tortuous blood vessels due to abnormal formation of blood vessel walls
Abnormalities of bone formation, as noted by x ray (skull, long bones, and ribs)
Bladder diverticulae
Loose skin, particularly at the nape of neck, under the arms, and on the trunk
Loose joints

Other

Unusual facial features (jowly, pudgy cheeks, large ears)
Abnormal hair, including the eyelashes and eyebrows
Light, even for family, skin and hair coloring (hypopigmentation)
Delayed eruption of teeth
Impaired vision
Normal hearing

The hair of individuals with Menkes syndrome deserves special discussion, particularly since this condition is sometimes also called kinky hair syndrome. Abnormal hair is not typically evident during the first few months of life. However, around the time that the other physical signs of the disorder become more apparent, the hair takes on an unusual appearance and texture. On magnified inspection, it is short, sparse, coarse, and twisted. It has been likened to the texture of a steel wool cleaning pad. It shows an unusual orientation, referred to as pili torti, a 180-degree twist of the hair shaft. It is usually fragile and breaks easily. The hair of all affected individuals shows these characteristic changes; it is likewise present in some women who are known gene carriers.

Death occurs early in males with Menkes syndrome, often by the age of three years in classical disease. However, longer survival is not unusual and is most likely due to more recent improvements in medical care. Severity of disease and its rate of progression are fairly consistent among untreated males in a single family.

Diagnosis

An initial diagnosis of Menkes syndrome is usually suspected based on the combination of physical features. However, as these features are generally subtle in the newborn period, they may be missed, particularly if there is no prior family history of the condition.

A somewhat common prenatal and newborn history has been recognized among affected infants. The histories often include: premature labor and delivery; large bruises on the infant's head after an apparently normal, uncomplicated vaginal birth; hypothermia; low blood sugar (hypoglycemia); and jaundice. Hernias may be present at either the umbilicus or in the groin area. These findings are non-specific and occur in normal pregnancies and unaffected infants. However, their presence may alert a knowledgeable physician that Menkes syndrome should be considered as a possibility, especially when other clinical signs are also present.

A clinical diagnosis is strongly supported by decreased serum levels of copper and ceruloplasmin, a protein in the blood to which the majority of copper is attached. Abnormal results, however, do not confirm the diagnosis since both copper and ceruloplasmin levels may also be low in normal infants during the first few months of life. A definitive diagnosis of Menkes syndrome is possible by either specific biochemical analysis to measure the level of copper accumulation in the cells or by identification of the responsible mutation in the MNK gene. Both types of analysis represent highly specialized testing and are available only through a limited number of laboratories in the world.

Prenatal diagnosis, in the context of a family history of the disorder, is possible. Ideally, a woman's carrier status will have been determined prior to a pregnancy as carrier detection may be difficult and time-consuming. Mutation analysis is the most direct and accurate way to determine carrier status. In order for this to be possible, the MNK mutation in an affected family member must have been previously determined. Linkage analysis is another possibility but requires blood samples from other family members, including the affected relative, to facilitate interpretation of results. If the affected relative is deceased, a stored DNA sample may be used.

Other, non-molecular methods of carrier detection include analysis of hair samples to look for areas of pili torti, increased fragility, or hypopigmentation. Skin cells cultured in the laboratory may be used to measure the accumulation of radioactive copper. However, these approaches are not always reliable, even in known carriers.

If a woman is found to be a non-carrier, prenatal testing for Menkes syndrome is generally not necessary in any of her pregnancies. However, in the event that a woman is a confirmed carrier, prenatal testing such as chorionic villus sampling (CVS) or amniocentesis may be offered. Ultrasound examinations alone will not assist in making a diagnosis. CVS or amniocentesis will determine the fetal sex: if female, additional testing is usually not recommended since carrier daughters would be expected to be normal. Carrier testing on the daughter may be performed after birth, if desired, or postponed until later in life.

Further testing is offered when a fetus is male. If mutation studies cannot be performed because the mutation in the family is unknown, biochemical analysis may be attempted. Biochemical testing has serious drawbacks, and a correct diagnosis may not always be possible. Tissue obtained during CVS normally has a very low copper content and is also very susceptible to contamination by maternal tissue or by outside sources, such as laboratory instruments or containers. As a result, if the copper level exceeds a certain level, an unaffected pregnancy could potentially be falsely identified as affected. Specific handling precautions are necessary to minimize this risk.

Similar concerns exist for a sample obtained by amniocentesis. Ordinarily, the cells obtained from this procedure are cultured and grown in the laboratory. A measurement is taken of the total amount of accumulated copper over a certain period. The timing of amniocentesis in the pregnancy is critical because the amniotic fluid cells do not grow as rapidly after a gestational age of 18 weeks. Problems in cell growth cause significant difficulties in the interpretation of the biochemical results.

Other methods of diagnosis are being investigated. Two that hold some promise are assessment of the concentration of copper in a sample of the placenta (extremely high in affected pregnancies) and the level of catecholamines (low) in a sample of blood from the umbilical cord. Both methods, which are fast, reliable, and performed immediately after delivery, clearly require a high level of suspicion of the disorder. In most cases, this will be based on a history of a previous affected son, abnormal or unclear prenatal testing results, or both. Women who do not have a family history of Menkes syndrome and are therefore not expected to be at-risk, are not offered this testing.

Treatment and management

The underlying, critical problem for patients with Menkes syndrome is an induced copper deficiency. Copper uptake is normal but the gene abnormality prevents the release of copper to the appropriate enzymes in the cells. Copper accumulates in the intestinal system, and patients are unable to meet their most basic nutritional needs. The most serious effects are apparent during the first year of life when growth of the brain and physical development are occurring most rapidly. Copper is required in order for both of these processes to occur normally.

Treatment of Menkes syndrome has focused on providing patients with an extra source of copper to try to deliver it to the enzymes that need it for normal function. Studies at the National Institutes of Health (NIH) have focused on the use of a copper-histidine compound in affected males. Copper-histidine is normally present in human serum and is most likely the form in which copper is absorbed by the liver. Also, in the laboratory, the presence of histidine in serum has been shown to increase the uptake of copper. Daily injections are the most successful form of treatment to date.

Two conclusions have been drawn from this work: (1) Treatment is more successful when started at an early age. Most, but not all, treated boys have achieved more normal developmental milestones and have had milder mental impairment. (2) Treatment is much less effective if started after the age of several months, or when neurologic symptoms have already begun. While milder improvements in the areas of physical development, personality, and sleeping habits have been reported in boys whose treatment started later, the degree of mental handicap has not been significantly altered.

A separate study in 1998 lent further support to these results. This study followed four affected males with classical Menkes syndrome, all of whom were started on copper-histidine treatment soon after birth. Three of the four males were born into families with other affected relatives; the fourth child was diagnosed at the age of three weeks. All four showed significant improvements in their development and clinical course. None were completely normal but their remaining clinical abnormalities were similar to those seen in patients with occipital horn syndrome. The oldest survivor of the group was 20 years old at the time of this publishing.

This information strongly supports the importance of nutritional therapy in the care of patients with Menkes syndrome. Early treatment is best but requires early diagnosis. It should also not be seen as a "cure." It has been shown to lessen the severity of the syndrome but not eliminate it. Thus, prenatal diagnosis, and its possible limitations, should continue to be discussed with prospective parents known to be at risk. Mutation studies should be performed, whenever possible, to increase the accuracy of testing results.

Prognosis

Death often occurs by the age of three years in untreated males with classical Menkes syndrome, although longer-term survivors have been reported. Treatment with supplemental copper has resulted in improved physical development, milder mental handicap, and extended life span in some affected males. However, not all patients have responded to the same extent. Additionally, patients treated after the onset of symptoms have done worse than those treated before symptoms occur. Research is continuing to refine the best dosage of copper-histidine, determine the optimal timing and route of treatment, and develop newer treatment strategies.

Resources

BOOKS

Jones, Kenneth L., ed. Smith's Recognizable Patterns of Human Malformations. 5th ed. Philadelphia: W. B. Saunders Company, 1997.

PERIODICALS

Christodoulou, John, David M. Danks, Bibudhendra Sarkar, Kurt E. Baerlocher, Robin Casey, Nina Horn, Zeynup Tumer, and Joe T.R. Clarke. "Early treatment of Menkes disease with parenteral copper-histidine: Long-term follow-up of four treated patients." American Journal of Medical Genetics 76, no. 2 (March 5, 1998): 154–64.

Kaler, Stephen G. "Diagnosis and therapy of Menkes syndrome, a genetic form of copper deficiency." American Journal of Clinical Nutrition 67 supplement(1998): 1029S–34S.

Kaler, Stephen G. and Zeynup Tumer. "Prenatal diagnosis of Menkes disease." Prenatal Diagnosis 18 (1998): 287–89.

Tumer, Zeynup and Nina Horn. "Menkes disease: Underlying genetic defect and new diagnostic possibilities." Journal of Inherited Metabolic Disease 21, no. 5 (August 1998): 604–12.