Myelin Disorders Program
The Myelin Disorders Program at CNMC is a multidisciplinary clinical and bench research program studying inherited disorders of the cerebral white matter or leukodystrophies. This approaches focuses on the mechanisms of disease in mendelian disorders of glial cell function. The program includes an integrated clinical program with a Myelin Disorders Clinic staffed by neurologists, pediatricians, rehabilitation physicians and genetic counselors. The research program has the following focus:
1). Molecular Mechanisms in Vanishing White Matter disease
Vanishing White Matter (VWM) disease, also known as Childhood Onset Ataxia and Central Nervous System Hypomyelination (CACH) or eIF2B related disorder, is a disorder of glial cell endoplasmic (ER) stress regulation caused by mutations in one of five genes encoding the eIF2B complex. This disorder is characterized clinically by severe white matter loss in the context of fever, falls or fright, and in pathophysiology by an exaggerated ER stress response. It is unclear, however, how mutations in EIF2B result in glial cell dysfunction and myelin loss. This NIH funded research program uses a combination of human and murine cellular culture, proteomic tools and genomic applications to assess the role of ER stress in myelin homeostasis.
2). Molecular Mechanisms and Clinical Phenotype in Aicardi Goutieres Syndrome
Aicardi Goutières syndrome (AGS) is an inherited disorder of innate cellular immunity primarily affecting the central nervous system, and resulting in severe neurologic disability. AGS is caused by mutations in a series of genes encoding known or putative nucleases and is thought to result from the accumulation of endogenous nucleic acids. This disorder is clinically characterized by evidence of central nervous system inflammation, cerebral calcifications and abnormal myelin development. This program encompasses both a clinical and a bench science approach. A Dana Foundation study explores the effect of cytokine elevations known to occur in AGS on glial cell physiology and myelin maintenance. Additionally, an international consortium will study the natural history and phenotype of patients with AGS.
3). Unsolved Leukoencephalopathies
Approximately fifty percent of patients with leukodystrophy remain unsolved, despite extensive evaluation. This represents a significant burden of disease, since patients with no known diagnosis continue to undergo extensive and often invasive testing, and in addition have limited options for therapeutic management, or genetic counseling. In addition, these subjects represent a missed opportunity to better understand causes of glial cell dysfunction, and therefore increase our knowledge of myelin homeostasis. To this end, we have developed a national consortium to identify and diagnose patients with unsolved leukodystrophies via a virtual second opinion program and biorepository (www.myelindisorders.org ). Wherever possible, a known diagnosis will be established by a consortium of experts in the leukodystrophy field, reviewing virtual records and if necessary by direct clinical evaluation in a Center of Excellence in Leukodystrophy and Leukoencephalopathy (CELL). Those patients remaining without a diagnosis are retained for participation in the search for new nosologic entities and genetic causes of leukodystrophy using state of the art genomic and proteomic applications.