Cracking Code of Rare Disorder May Aid MS Fight

By Jeffrey Norris A UCSF geneticist recently identified a gene that triggers a rare disorder resembling multiple sclerosis (MS). In the wake of the discovery, Ying-Hui Fu, PhD, and her colleagues expect to learn more about how the fatty nerve-insulating sheath called myelin normally is maintained and how it is lost in both MS and in this much rarer disease, called autosomal dominant leukodystrophy (ADLD). There currently is no treatment to halt the myelin loss that causes the diseases. In both disorders, symptoms - ranging from muscle weakness to bowel and bladder dysfunction - arise as nerve fibers lose their protective myelin coating and the transmission of electrical signals within nerve pathways falters. Fu's team discovered that an abnormally duplicated gene causes ADLD. The disease is similar to the chronic progressive form of MS. ADLD advances gradually, but relentlessly. Those who are afflicted usually die in their 50s or 60s. In contrast, MS normally is not a cause of death, although it may become severely disabling. ADLD has been identified in a small number of families. While it is certainly very rare, it is also likely that ADLD is underdiagnosed, Fu suggests. Doctors may misdiagnose it as MS. Since Fu's lab group published its findings in October, physicians who have searched the medical research literature for clues to help them diagnose patients have been contacting her about the disease.

Ying-Hui Fu, PhD

Fu's lab group already has engineered the ADLD gene into mice. They now can begin learning more about myelin and about how its loss is linked to the fact that the protein encoded by the gene - called lamin B1 - is present in elevated amounts as a result of the duplication. In addition, the UCSF researchers already are hot on the trail of a different gene that causes loss of myelin in another rare human disease. Putting Pieces Together Yields Bigger Picture "I like to study rare disorders that show a clear pattern of genetic inheritance - but that resemble more common diseases in which the genetic contribution is more complex," says Fu. Along with her scientific partner and husband, Howard Hughes Medical Institute investigator Louis Ptáček, MD, she has taken this same approach to successfully tackle a range of rare disorders. "Working with families affected by a disease, we can identify a specific gene mutation that causes it," Fu says. "That can be a starting point for better understanding both the rare disease and the similar, more common one. "Now we have a starting point that I believe will help us begin to understand how myelin is maintained and degraded," Fu says. ADLD is an autosomal dominant disease. That means inheriting a single copy of the genetic defect from either one's father or one's mother is enough to cause the disease. The normal copy of the gene inherited from the other parent does not prevent the disease. MS Is a Complex Disorder Drug options for halting the course of chronic MS have been limited. In part, this is because few biochemical targets have been clearly identified. Drug treatments for MS reduce inflammation and often improve quality of life, but are not curative.
MRI images

White regions in these cross-sectional MRI images of the brain show where nerve-insulating myelin has been lost in a patient with autosomal dominant leukodystrophy (ADLD). In ADLD, loss of myelin occurs in a symmetrical pattern, unlike in multiple sclerosis. Loss of myelin in turn leads to loss of normal nerve function, and in ADLD leads eventually to death.

MS is genetically complex. Many research teams have spent years trying to find genetic mutations or variations that can trigger the disease. Scientists do not expect to identify a single gene that, when mutated, invariably causes MS. And while researchers expect to identify genes that significantly increase MS risk, they also are convinced that MS is in large part an inflammatory disease. Cells of the immune system make antibodies that target the myelin sheath. In a person who is genetically at risk, many researchers suspect that past exposures to viruses or other environmental factors play a role in triggering the autoimmune response that appears to drive myelin destruction in MS. On the other hand, in ADLD the body's immune system does not attack myelin, and there is no evidence that there is an autoimmune component of the disease. Role of Newly Identified Protein in ADLD and MS Lamin B1 is a structural protein inside all living cells. It forms a mesh surrounding the cell's nucleus. Contained within this nuclear envelope are the cell's gene-bearing chromosomes. Normally, lamin B1 production is high after birth. Levels taper off during adolescence, and normally are much lower in older adults. Individuals with ADLD make higher-than-average amounts of lamin B1, as do Fu's lab mice with the ADLD gene defect. Why elevated levels of a protein found in all cells would appear to initially result in damage only to the myelin sheath surrounding nerves is unclear. Lamin B1 is not part of myelin. "It's a mystery," Fu says. Strangely, lamin B1 is found in "plaque" that forms outside brain cells in some MS patients. Fu says there appears to be no plaque in the brains of ADLD patients. Stephen Hauser, MD, professor and chair of neurology at UCSF, and Jorge Oksenberg, PhD, professor of neurology, have been conducting a large study to search for genetic risk factors among hundreds of MS patients and their families. In light of Fu's recent discovery, they also have begun evaluating whether individual variations in the lamin B1 gene affect the course of MS. Related Links: Ying-Hui Fu's & Louis Ptáček's Laboratories of Neurogenetics ADLD Gene Discovery Nature Genetics, September 3, 2006 NINDS Leukodystrophy Information Page National Institute of Neurological Disorders and Stroke (NINDS) UCSF Multiple Sclerosis Genetics Group MS Genetic Risk Annals of Neurology, January 24, 2007 National Multiple Sclerosis Society