Menkes Kids Stories

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Blaine is in this article, although not noted by name...

New Test for Menkes' Disease Allows Early Diagnosis and Treatment

Susan Jeffrey

February 6, 2008 — Researchers at the National Institutes of Health (NIH) have developed a new test that allows early diagnosis of Menkes' disease, a fatal neurodegenerative disorder of copper metabolism. Patients who received copper-replacement therapy on the basis of this test, well before symptoms of the disease began, have shown prolonged survival and, in isolated cases, had normal cognitive and developmental outcomes to date.

Their work is reported in the February 7 issue of the New England Journal of Medicine.

Stephen G. Kaler, MD, clinical director of the National Institute of Child Health and Human Development (NICHD) and first author on the paper, told Medscape Neurology & Neurosurgery that their work shows that Menkes' disease can be detected prospectively in newborn infants who look otherwise normal and that early treatment increases survival "across the board" for these children. The best outcomes were seen in children with mutant alleles that did not completely abrogate copper transport, he noted.

The authors suggest that this diagnostic approach is sufficiently sensitive and specific that it could open the door to newborn screening and early treatment. "Like many genetic disorders, it's not exactly a public health threat, but if your child has this, it doesn't really mean much that it's a rare disorder," he said.

"The study represents an important advance in the diagnosis and treatment of a rare but devastating genetic disorder," Duane Alexander, MD, director of the NICHD, said in a statement from the NIH. "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."

Irreparable Harm

Menkes' disease occurs in about 1 in 100,000 newborns and affects only males, as it is an X-linked disease. It is caused by a defect in the ATP7A gene, which regulates copper transport, resulting in abnormally low levels of copper in the brain and liver and excessive copper in the liver and intestines. Although required only in trace amounts, copper plays a critical role in brain development. Levels of certain neurochemicals are determined by a copper-dependent enzyme, dopamine-beta-hydroxylase, and are abnormal in Menkes'. Copper is also required for the normal production of myelin.

Infants with Menkes' generally appear normal at birth and develop normally for 6 to 8 weeks, the authors note. "Subsequently, hypotonia, seizures, and failure to thrive occur, and death by 3 years of age is typical." Dr. Kaler noted that imaging studies show significant brain atrophy in these infants.

Treatment with daily copper injections might improve outcomes, but to date, there has been no specific diagnostic test for the disease; rather, children come to attention only after they have developed neurologic symptoms and suffered irreparable brain damage.

In this study, the researchers investigated whether measurement of the neurochemicals dopamine, norepinephrine, dihydroxyphenylacetic acid, and dihydroxyphenylglycol in plasma might detect affected infants.

"Because of the decreased activity of dopamine-beta-hydroxylase, the ratio of dihydroxyphenylacetic acid to dihydroxyphenylglycol is distinctively elevated in Menkes' disease," the authors note. "From the known pathways of catecholamine synthesis and metabolism, one would also predict a high ratio of dopamine to norepinephrine."

In this prospective study, the researchers measured these neurochemicals in 81 infants considered at risk for Menkes' disease referred for evaluation between May 1997 and July 2005. Of the 81 infants, 46 were found to have this distinctive, abnormal neurochemical pattern, indicating low dopamine-beta-hydroxylase activity, they note. On the basis of longitudinal follow-up, patients were classified as affected or unaffected by Menkes' disease, and the neurochemical profiles were shown to have high sensitivity and specificity for detecting the disease.

Copper Replacement Trial

Twelve newborns with Menkes' disease who met eligibility criteria (ie, they were 1 month of age or less and had no neurological symptoms) were enrolled in a clinical trial of early copper treatment. The study drug was copper histidine, a drug being investigated under a Food and Drug Administration investigational new drug application held by Dr. Kaler and prepared by the NIH Pharmaceutical Development Service.

Patients received 250 µg by subcutaneous injection twice daily until the age of 1 year and once daily thereafter. "Eight patients received treatment for 3 years; 1 patient, who died during the trial, received treatment for 1.6 years, and 3 patients under 3 years of age are still being treated," the authors write.

Among the 12 patients, survival at a median follow-up of 4.6 years was 92%, compared with 13% at a median of 1.8 years in a group of historical controls of 15 children with a later diagnosis and treatment.

Two of the patients actually had normal neurodevelopment and brain myelination. They were found to have mutations that, while not identical, each allowed some residual copper transport. The researchers speculate that it was the combination of this residual activity along with the copper-replacement treatment that resulted in these especially good clinical outcomes.

In the remaining 9 children with mutations associated with more definitive disruption of copper transport, normal neurodevelopment was not achieved despite early treatment, they note. "However, these patients had better survival and lower incidence of clinical seizures (2 of 9 infants, or 22%) than would be expected among those with untreated Menkes' disease, perhaps as a result of their early diagnosis and treatment," they write.

Dr. Kaler noted that they treated these children only for 3 years, reasoning that the process of myelination is usually complete by 24 months of age. Copper treatment can result in copper overload in the kidneys and other organs, he said, so they also felt that 3 years was a "reasonable" time frame in terms of the medical risk/benefit ratio. "Notably, we didn't find there was any regression in developmental milestones in any of our patients when we stopped treatment after 3 years," he said.

Challenges Remain

Although their findings are good news for some, the majority of children with Menkes' disease will require additional approaches to treatment, Dr. Kaler said. Gene therapy is 1 possibility, and they are currently engaged in gene-therapy trials with a murine model of Menkes' disease, he added.

Nevertheless, "it's a significant advance, I think, and the beginning of an era when the parents of a child born with this might anticipate a better overall outcome," he concluded.

In the NIH press statement on this work, Dr. Kaler encourages couples with a family history of Menkes' disease to contact the NIH if they have any questions about this study.

The study was supported by funding from the intramural research program of the National Institutes of Health. The authors report no potential conflict of interest relevant to this article.

N Engl J Med. 2008;358:605-614.

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This is probably something I should have started 15 years ago but back then who knew about blogging? Its been a good summer so far, exceept of course for the passing of Blaine's "Gramma Girl".  Blaine was the world to her.  Their love was a very, very strong one.  i know she will be keeping an eye on him and guiding him through this recovery from knee surgery.  He'll be running around (again) in no time!!  School starts (10th grade!!!) in 22 days...ughhh...wish I could stay home all year long.  Blaine's looking forward to starting because this is the school year he will get his license...OMG!!