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.

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Author Info: Terri A. Knutel MS, CGC, The Gale Group Inc., Gale, Detroit, Gale Encyclopedia of Genetic Disorders Part I, 2002

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