Health 2.0 for Neurologists

Background: Alpha-sarcoglycan ([alpha]-SG) deficiency (limb-girdle muscular dystrophy [LGMD] type 2D) is the most common form of sarcoglycan-LGMD. No treatment is currently available. Prior studies suggest that overexpression of [alpha]-SG via adeno-associated virus (AAV)-mediated gene transfer results in poorly sustained gene expression related to transgene toxicity. These findings potentially preclude gene therapy as a treatment approach for LGMD2D.Methods: The human [alpha]-SG gene (h[alpha]-SG) was directly transferred to the tibialis anterior muscle of 4- to 5-week-old [alpha]-SG KO mice using AAV, type 1. The gene was placed under control of either the ubiquitously expressed cytomegalovirus (CMV) promoter or muscle specific promoters that included desmin, muscle creatine kinase (MCK), and its further modification, truncated MCK (tMCK). Low (3 x 109 vg) and high (3 x 1010 vg) doses of AAV1.h[alpha]-SG were administered.Results: Sustained gene expression was observed irrespective of promoters at 6 and 12 weeks post gene transfer. Quantitation of [alpha]-SG gene expression by fiber counts yielded similar levels of myofiber transduction for both MCK promoters (60 to 70%), while 34% of fibers were transduced with the DES promoter. There was a trend toward lower expression at the 12-week time point with the CMV promoter. Western blot analysis revealed [alpha]-SG overexpression using CMV and both the MCK promoters.Conclusion: Our data demonstrate robust and sustained adeno-associated virus type 1 alpha-sarcoglycan gene expression under control of muscle creatine kinase promoters, without evidence of cytotoxicity. These findings support the use of gene therapy as a potential treatment approach for limb-girdle muscular dystrophy type 2D.(C)2008AAN Enterprises, Inc.

Spinal cord syndromes are "unique" clinical presentations that localize lesions to the spinal cord by their pattern of anatomic dysfunction while implying their underlying etiology. Recognizing these patterns and their significance is best accomplished by relearning and appreciating the relevant anatomy and relationships, which are the major focus of this review. This clinical-anatomic background will provide the framework for the clinical topics that follow in this issue.(C) 2008 American Academy of Neurology

Inflammatory and infectious myelopathies are common and often treatable. Infectious causes include viral, bacterial, mycobacterial, fungal, and parasitic agents. Noninfectious inflammatory myelopathies were previously often categorized as idiopathic transverse myelitis, but advances in neuroimaging and the discovery of a serum autoantibody marker, neuromyelitis optica immunoglobulin G (NMO-IgG), have allowed more specific diagnoses, such as multiple sclerosis and neuromyelitis optica, to be made more confidently and at an earlier stage than previously possible. This chapter summarizes an approach to evaluation and management of infectious and inflammatory causes of acute and subacute myelitis and chronic progressive myelopathy.(C) 2008 American Academy of Neurology