ANN ARBOR, MI - Scientists report today that they have found a gene for a rare leg-weakening nerve disease that slowly robs children of their ability to walk - a finding that opens the door to better diagnosis and treatment of the disorder, and to insights into other spinal cord problems.
Led by researchers from the University of Michigan Health System who have focused for years on both the childhood and adult forms of the mysterious group of disorders known as hereditary spastic paraplegia, the team publishes its results in the November issue of Nature Genetics.
"This is a major step forward in our understanding of HSP's causes, and has already allowed us to provide diagnostic testing to a few patients," says U-M neurologist and senior author John K. Fink, M.D. "We've been looking for HSP genes since 1993, and we're happy to have found, at last, the first one for a childhood form of the disease. Now, the search continues for the rest."
Mutations in the gene SPG3A, causing alterations in the newfound protein dubbed "atlastin" that it encodes, may be responsible for as many as 25 percent of childhood HSP cases, says Fink. Together with a test for spastin - a gene for an adult form of HSP found by a French team in 1999 - gene testing may lead to diagnosis for more than 50 percent of HSP.
An estimated 10,000 to 20,000 Americans currently have HSP, though the difficulty in diagnosing the disorders, and the lack of HSP clinics like the one Fink leads at UMHS, may mean there are more "hidden" cases misdiagnosed as familial cerebral palsy, primary lateral sclerosis, multiple sclerosis and even vitamin deficiencies.
The disease is insidious, and may begin as toe-walking in early childhood; or subtle difficulty walking and occasional stumbling. But as nerves within the spinal cord break down, HSP can progress to a complete weakening of the legs, and, in some cases, to more severe problems. It can strike at any age, from infancy to old age, and depending on the mode of inheritance can affect parents and some or all of their children at different stages of life.
Fink and his colleagues also see the new gene as a key to understanding why people with HSP, spinal cord injuries, primary lateral sclerosis and amyotrophic lateral sclerosis (Lou Gehrig's disease) all experience a progressive degeneration of certain nerve fibers in their spinal cords.
Though an application of that knowledge toward treatment could be years away, it is this goal that drives the research, says Fink, an associate professor in the Department of Neurology of the U-M Medical School and a member of the Geriatrics Research, Education and Clinical Center at the Ann Arbor Veterans Affairs Medical Center.
His hope springs from the fact that the atlastin protein's predicted structure - based on SPG3A's genetic sequence - gives clues as to the possible biochemical processes that may underlie this form of hereditary spastic paraplegia. Thus far, investigators believe that atlastin is similar to a group of proteins, known collectively as dynamins, that mediate a variety of known cellular phenomena.
For example, dynamins are crucial to the process by which nerve cells communicate with each other, through the release and recapture of bundles of signal molecules called neurotransmitters. Disturbance in this process could lead to nerve degeneration and symptoms of spastic paraplegia.
If further research can uncover more about whether and how the mutated atlastin alters nerve cell behavior, and about how those alterations might affect spinal cord nerve cells on a large scale, Fink says, the team may be able to piece together clues on how to stop or reverse the process in HSP, spinal cord injury, primary lateral sclerosis and ALS patients.
"Our goal is to understand how mutations in this gene cause nerve degeneration so that we can stop this process and facilitate nerve outgrowth again," Fink explains.
The mutations that Fink and his colleagues found in SPG3A were identified in multiple members of six families in which many relatives were affected by HSP. Specifically, the team looked at families who had the autosomal dominant form of the disease - the kind that can be passed down to a child by one parent even if the other parent is completely normal.
Shirley Rainier, Ph.D., a research investigator working in Fink's laboratory, analyzed one family and narrowed the search to the region on chromosome 14 that contained the disease gene. This important discovery reduced the number of potential genes to be studied. Subsequently, lead author and research investigator Xinping Zhao, Ph.D., and research assistant David Alvarado, B.S., analyzed the DNA sequence of candidate genes from this region in samples from affected and unaffected members of the HSP-prone families and from people with no family history of HSP.
The team sequenced DNA samples from a region of chromosome 14 where SPG3A was already suspected to reside - samples taken from living members of the HSP-prone families, and from people with no family history of HSP. By sequencing the gene, they made a map of the DNA "letters", or nucleotides, in the specific order found in each affected and normal person.
In three families, they found a one-letter "missense" mutation, in a position on the gene unique to that family but possessed by every member of the family who had HSP. In three other families, individuals affected with HSP had the same exact genetic mutation. Comparing atlastin's structure to known proteins, they found it resembled the dynamins, but with obvious flaws caused by disease-specific mutations.
"We didn't know before what caused this form of HSP, and know we have the precise genetic cause and insights into possible biochemical mechanisms responsible," says Fink. Now, armed with the sequence to look for, he and his colleagues have been able to test people with HSP-like symptoms to see if they have the SPG3A mutation. They plan to continue to develop the SPG3A test, and to make it available for use alongside the SPG4 spastin test.
Knowing the genetic type of HSP a patient has could be used to confirm the diagnosis of HSP. In some circumstances, it could also be used for prenatal diagnosis.
But Fink indicates that a test for a mutated SPG3A gene sequence will soon allow HSP specialists and geneticists to provide genetic counseling. Such testing and counseling might be valuable to couples whose family or medical history suggests they might be at risk of passing an autosomal dominant form of HSP on to their children. For example, in autosomal dominant HSP families, there is a 50 percent risk that each child will develop this condition.
Even as the UMHS team continues with its genetic research, including a mouse model of HSP that could be used to test theories on the diseases' mechanisms, Fink and his colleagues are building on a longtime reputation as one of the world's foremost HSP clinical research, treatment and education centers.
An international conference for patients, physicians and researchers was held at UMHS last year, and a walkathon for patients and their families in September brought together participants who walked, and used wheelchairs, canes and crutches to get to the finish lines. Plans are underway to establish a Foundation for HSP, Primary Lateral Sclerosis, and Allied Disorders to raise money for more research and give support to the thousands of families with these related conditions already known to exist in the U.S.
Besides Fink, Rainier, Zhao, and Alvarado, the paper's authors include research associate Rosemary Lemons, B.S.; neurology instructor Peter Hedera, M.D.; neurology consultant Christian H. Weber, Ph.D.; postdoctoral fellow Lei Ming, M.D. and undergraduate student Melanie Bui of the U-M; Turgut Tukel, M.D. and Memnune Apak, M.D. of the University of Istanbul, and Terry Heiman-Patterson, M.D. of the Neurology Department in the Hahneman University School of Medicine.
Full citation: Nature Genetics, vol. 29, November 2001