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White Matter Disease
Disorders of white matter development are very important disorders leading to mental retardation and developmental disabilities. Among these diseases, cerebral palsy is the most common and prevalent. The pathophysiological processes responsible for disorders of white matter development are poorly understood. Recently, intrauterine infection and inflammation have been implicated as important factors in both term and preterm infants who develop cerebral palsy and other disorders of brain development. In particular, it appears that intrauterine inflammation may play a role in the development of autism spectrum disorders. In addition to cerebral palsy, other acquired demyelinating disorders such as multiple sclerosis (MS) and acute demyelinating encephalomyelitis (ADEM) occur within the white matter and are linked to inflammation. Multiple sclerosis is common disease in young adults and is increasingly recognized in children of younger ages (estimates of up to 20,000 undiagnosed childhood cases have been reported). In these disorders, episodes of neurological dysfunction secondary to inflammatory demyelination of white matter pathways are the pathognomonic intracerebral lesion. The root cause(s) remains unknown, but it is believed to be an autoimmune disease influenced by both environmental factors (viral infections, sunlight) as well as genetics.
This growing program aims to improve diagnosis in leukodystrophies and develop novel diagnostic tools. Utilizing the resources of both the genomics and proteomics cores, projects include gene sequencing in rare leukodystrophies, study genotype phenotype correlations, develop animal and cell culture models for the testing of possible therapies, and develop novel methodologies for the rapid diagnosis of unidentified leukodystrophies.
Adeline L. Vanderver, MD, a child neurologist with a special interest in heritable white matter disease, is testing a rapid diagnostic tool in Vanishing White Matter disease with the collaboration of Yetrib Hathout, PhD (proteomics core). She is also developing a cell culture model to test possible therapies in Vanishing White Matter with Michelle Mintz, MD. In 2006, Dr. Vanderver will begin a study to evaluate patients for causes of hypomyelinating leukodystrophy, in collaboration with the NIH and the Vrije University Medical Center of Amsterdam. Rafael Gorospe, J. MD, PhD, a pediatric geneticist with special expertise in heritable white matter disease, is developing an animal model to test possible therapies in Vanishing White Matter disease. Together, Drs. Gorospe and Dr. Vanderver have a study in the genetic causes of leukodystrophy, and offer testing for Alexander disease, Megalencephalic Leukoencephalopathy with subcortical cysts and Vanishing White Matter disease.
Laboratories within the Center are actively exploring the pathological mechanisms responsible for these disorders. In the laboratory run by Michael Bell, MD, a rat and mouse model of inflammation has been developed to mimic intrauterine inflammation in humans. In these studies, Dr. Bell has found that the white matter is damaged, clinically-relevant cytokines are increased in both the placenta and fetal brain and cell death occurs via cytokine-mediated receptor cell death. Ongoing studies include continued characterization of changes in gene expression in vulnerable oligodendrocytes, development of in vitro injury models to more firmly establish the mechanisms of cell death and the assessment of behavior and memory after inflammatory stimuli.
Li-Jin Chew, PhD, studies the cellular and molecular changes within developing oligodendrocyte precursor cells (OPC) that result from the elevation of cytokine levels to mimic the inflammatory response thought to be critical in MS and ADEM. These OPCs are cells that are capable of regeneration of damaged myelin in patients with MS and ADEM but fail to perform this function for unclear reasons. Chronic treatment of cultured OPCs with interferon-gamma revealed a dose-dependent effect on cell survival. Interferon at a non-toxic dose was found to inhibit cell maturation while allowing the growth of immature precursors. This was accompanied by the loss of vital transcription factors necessary for myelin gene expression. Research plans include elucidating the relationship between cell proliferation and maturation, and the identification of novel transcription factors which may be involved in both processes.
Vanishing White Matter Disease
Vanishing white matter disease is generally a slowly progressive childhood disorder of the white matter of the CNS. Patients initially develop normally then show gradual neurological deterioration beginning in late infancy or early childhood. Clinical signs include progressive cerebellar ataxia, spasticity and relatively preserved cognitive abilities. Episodes of clinical deterioration following febrile infections or minor head trauma are common.
Testing is offered for asialotransferrin levels in cerebrospinal fluid. This rapid diagnostic test is being validated as a biomarker for Vanishing White matter disease. Results are available within two weeks. Results are confirmed with gene sequencing of eIF2B (click here for information and consents).
Unclassified White Matter disease:
A great number of patients with white matter disease remain undiagnosed using routine biochemical and genetic tests. New molecular genetic techniques can diagnosis known leukodystrophies and identify novel disorders. This study aims to provide diagnosis for a known leukodystrophies for which commercial testing may not be commonplace or available. MRI’s and clinical history are reviewed. Genetic testing is performed for Alexander disease, Vanishing White Matter disease and Megalencephalic Leukoencephalopathy with subcortical cysts.
Hypomyelinating Leukodystrophies (open soon for enrollement):
As other leukodystrophies are identified, hypomyelinating leukodystrophies, those where there is a near complete absence of myelin deposition in the central nervous system, are emerging as the largest undiagnosed group of white matter disorders in children. Few diagnoses are currently available (Pelizaeus Merzbacher disease and sialic acid transport disorders for example). This study provides a comprehensive evaluation of patients with hypomyelinating leukodystrophies, with the aim to identify known leukodystrophies and delineate novel disorders. MRI’s and clinical history are reviewed. Genetic testing is performed for known causes of hypomyelinating leukodystrophies. Undiagnosed patients are studied to delineate novel disorders (click here for information, forms and consents).
For information on enrollment for the above studies, please contact Erynn Gordon, genetic counselor, at 202-476-6065 or egordon@cnmcresearch.org.
Related Links
Medline
www.ncbi.nlm.nih.gov
Contact Information:
Vittorio Gallo, PhD
Children’s Research Institute
Center for Neuroscience Research
Children's National Medical Center
111 Michigan Avenue, NW
Washington, DC 20010
202-476-4996
vgallo@cnmc.org
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