|NIH Scientists Detect Fatal Copper Disorder
Early Treatment Extends Survival
A test developed by NIH scientists could greatly extend the survival
of infants with Menkes disease, a rare, otherwise fatal disorder
of copper metabolism. The scientists devised a test to diagnose
the condition early, when the chances for successful treatment
are greatest. A study appearing in the February 7 New England
Journal of Medicine describes how the scientists devised the
test to diagnose the condition early, when the chances for successful
treatment are greatest.
Untreated, Menkes disease results in irreparable harm to the brain
and nervous system. Treatment consists of injections with a copper-containing
drug. Children with Menkes disease typically die during the first
decade of life. Previously, there was no blood test for early detection
of Menkes disease.
"The study represents an important advance in the diagnosis
and treatment of a rare but devastating genetic disorder," said
Duane Alexander, M.D., Director of NIH's National Institute of
Child Health and Human Development (NICHD), the lead NIH institute
that conducted the study. "The laboratory techniques the researchers
used to detect Menkes disease eventually may provide the basis
for a newborn screening test to identify children with Menkes at
birth, so they have the greatest chance to benefit from treatment."
The study was a collaboration between researchers in the NICHD,
the National Institute of Neurological Disorders and Stroke (NINDS),
and the NIH Clinical Center. The NINDS researchers contributed
expertise in testing for nervous system chemicals known as catecholamines.
Catecholamine levels are determined by a copper-dependent enzyme
and for this reason are abnormal in Menkes disease infants.
Menkes disease occurs in about one in 100,000 newborns and is
caused by a defect in a gene that regulates copper levels in the
body, explained Stephen G. Kaler, M.D., Clinical Director of the
NICHD and lead author of the study. This defect, in the gene designated
ATP7A, causes abnormally low levels of copper in the brain and
liver as well as excessive amounts of copper in the kidneys and
intestines. Copper, although only needed in trace amounts, is an
essential nutrient that plays a critical role in brain development,
Infants with Menkes disease usually appear normal at birth but
start to show developmental delays at 6 to 8 weeks. Affected children
may experience seizures and below normal body temperature. Children
with Menkes disease also develop distinctive kinky hair, which
is steel-colored or colorless and is easily rubbed off the skull.
Dr. Kaler explained that copper is needed for the production of
myelin, an insulating material that surrounds certain types of
brain and nerve cells. The deposition of myelin around brain and
nerve cells is nearly completed by age 2, so the disorder can potentially
be treated if copper replacement therapy is started soon after
birth. Symptoms of Menkes disease do not usually develop until
2 to 3 months of age, but by that time, the copper deficiency has
already caused significant brain damage which treatment seems unable
to reverse, Dr. Kaler said.
The defective gene in Menkes disease is located on the X chromosome.
Because males have only one X chromosome, they have only one copy
of the ATP7A gene and so are severely affected by the disorder.
Females have two X chromosomes. If they have a defective ATP7A
gene, they are not severely affected, because their remaining X
chromosome usually has a functioning ATP7A gene.
In their research, Dr. Kaler and his co-workers evaluated male
infants who were considered to be at risk for Menkes disease.
Based on catecholamine levels, the researchers predicted 12 male
newborns would develop Menkes disease and administered the copper-containing
drug, beginning at a very early age. DNA studies of the ATP7A gene
confirmed the diagnosis in each case. The infants were given the
copper injections for three years, receiving two shots daily for
the first year and one shot a day during the second and third years.
Because long-term exposure to copper can damage the kidneys, the
copper injections were stopped after 3 years. The researchers followed
the infants throughout childhood to track their survival rates
and mental development. Those who received injections soon after
birth had a much greater survival rate when compared with a previously
documented group of Menkes disease infants who had not received
early copper injections.
Of the 12 males in the study, 92 percent were still alive an average
of 4.6 years later. Only 13 percent of the males in the earlier
group of late-diagnosed patients were alive an average of 1.8 years
Dr. Kaler said that the study participants did not show any decline
in health after stopping the copper replacement.
The boys varied in their response to the copper treatment. Two
developed relatively normally, whereas the remainder had varying
degrees of developmental impairment. When Dr. Kaler and his coworkers
examined the nature of the defect in the boys' ATP7A gene, they
found that boys with particular alterations in the gene responded
better to the copper injections than did boys with other defects
in the gene. They demonstrated that the ATP7A genes of the boys
who had the best clinical responses to the copper injections retained
some rudimentary capacity to regulate copper.
Dr. Kaler and his colleagues are now working to develop from their
research a test that health care providers could use to routinely
screen newborn males for Menkes disease.
"I think our findings may be especially meaningful to parents
who have suffered due to this condition and lost children to it,"
Dr. Kaler said. "Menkes disease and other rare disorders
of childhood convey a burden to families that is unfair and underappreciated.
That a disorder occurs rarely is meaningless if one's child, grandchild,
or sibling is affected."
Dr. Kaler added that while additional treatment approaches are
still needed for many Menkes patients, the present work signals
the beginning of an era when the parents of any infant born with
this disease can anticipate better clinical outcomes. He encouraged
couples with a family history of Menkes disease to contact the
NIH if they have questions about this research study. He can be
reached at 301-496-8368.
Additional information about Menkes disease is available from
the NINDS at http://www.ninds.nih.gov/disorders/menkes/menkes.htm.
The NICHD sponsors research on development, before and after birth;
maternal, child, and family health; reproductive biology and population
issues; and medical rehabilitation. For more information, visit
the Institute's Web site at http://www.nichd.nih.gov/.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.