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Subject: HEREDITARY CONDITION CAUSING LIMB WEAKNESS TRACED TO GENE FOR RARE
DISORDER

U.S. Department of Health and Human Services 
NATIONAL INSTITUTES OF HEALTH NIH News 
Eunice Kennedy Shriver National Institute of Child Health and Human
Development (NICHD) <http://www.nichd.nih.gov/>
For Immediate Release: Tuesday, Thursday, March 11, 2010

CONTACT: Robert Bock or Marianne Glass Miller, 301-496-5133, <e-mail: 
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HEREDITARY CONDITION CAUSING LIMB WEAKNESS TRACED TO GENE FOR RARE DISORDER
 
A gene that causes a fatal childhood brain disorder can also cause adults to
develop peripheral neuropathy, a condition resulting in weakness and
decreased sensation in the hands and limbs, according to a study by
researchers at the National Institutes of Health and other institutions.
The study is the first to show that different mutations in the same gene
cause the two seemingly unrelated disorders.   

Inherited peripheral neuropathies are a diverse group of disorders that
cause loss of muscle tissue in the hands, feet, and lower legs of affected
patients, usually starting in adulthood. Various genetic causes have been
identified for Charcot-Marie-Tooth disease (CMT)
<http://www.nature.com/ejhg/journal/v17/n6/pdf/ejhg200931a.pdf.>, the broad
category of inherited peripheral neuropathy that affects approximately
125,000 people in the United States.  The peripheral nervous system consists
of nerves that reside or extend outside of the brain and spinal cord. 

In the current study, the researchers determined that persons with a
CMT-like neuropathy have a mutation in the same gene that causes Menkes
disease, a severe brain disorder that begins in infancy and is fatal if not
treated. This gene, called ATP7A, codes for a protein needed to move the
trace metal copper between different compartments within the body's cells,
or out of cells altogether. 

"The findings provide insight into how peripheral nerves function and may
ultimately lead to new treatments for some peripheral neuropathies," said
Alan E. Guttmacher, M.D., acting director of the Eunice Kennedy Shriver
National Institute of Child Health and Human Development (NICHD), the NIH
Institute that collaborated in the study.   

The findings appear in the March 12 American Journal of Human Genetics. The
study's first author was Marina L. Kennerson, Ph.D. of the ANZAC Research
Institute, University of Sydney, Australia.  Another senior author was
Stephen G. Kaler, M.D., head of the Unit on Human Copper Metabolism at the
NICHD's Molecular Metabolism Program.  The NICHD provided funding for the
NIH-based portion of the research.

Drs. Kennerson, Kaler, and their colleagues discovered the mutated gene's
role in distal motor neuropathy by studying the DNA of two large, unrelated
families with multiple affected members.  Changes in the DNA of the family
members who had the disorder did not appear in the DNA of those who did not
have the disorder.  Dr. Kaler's Unit at the NICHD helped to identify the
location of the ATP7A protein inside human skin cells from patients and
characterized the nature of the mutations in the gene. The mutations causing
distal motor neuropathy appeared to have much lesser effects than did the
mutations found in the infants with Menkes disease. 
 
Menkes disease arises from other mutations in the same gene, which make the
resulting protein unable to fulfill its usual function-transporting copper.
As a result, children with Menkes disease have abnormal levels of copper:
low levels in the blood, the brain and liver, as well as excess amounts in
the kidneys and intestines.

But people with distal motor neuropathy do not have abnormal copper levels,
Dr. Kaler and his colleagues found. The mutations that cause distal motor
neuropathy do not eliminate the protein's function completely-the protein
maintains about 70 percent of its normal ability to move copper. Still, the
researchers found subtle abnormalities in how the protein itself moves
within a cell. The abnormalities apparently affect people's motor neurons,
the nerve cells in the spine that control muscles.

"The ATP7A protein has at least two distinct roles in the nervous system,"
Dr. Kaler said. "We knew it was critical for central nervous system
development. But, before now, there had been no evidence that it played an
important role in the function of motor neurons in the peripheral nervous
system."

Dr. Kaler and colleagues intend to study the mechanism of how the newly
discovered mutations cause the disorder, in hopes of eventually developing
treatments.

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>.
  
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<http://www.nih.gov/news/health/mar2010/nichd-11.htm>.

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