title: Novel pathologic findings in patients with Pelizaeus-Merzbacher disease.
abstract: Pelizaeus-Merzbacher disease (PMD) is an X-linked inherited hypomyelinating disorder caused by mutations in the gene encoding proteolipid protein (PLP), the major structural protein in central nervous system (CNS) myelin. Prior to our study, whether hypomyelination in PMD was caused by demyelination, abnormally thin sheaths or failure to form myelin was unknown. In this study, we compared the microscopic pathology of myelin from brain tissue of 3 PMD patients with PLP1 duplications to that of a patient with a complete PLP1 deletion. Autopsy tissue procured from PMD patients was embedded in paraffin for immunocytochemistry and plastic for electron microscopy to obtain highresolution fiber pathology of cerebrum and corpus callosum. Through histological stains, immunocytochemistry and electron microscopy, our study illustrates unique pathologic findings between the two different types of mutations. Characteristic of the patient with a PLP1 deletion, myelin sheaths showed splitting and decompaction of myelin, confirming for the first time that myelin in PLP1 deletion patients is similar to that of rodent models with gene deletions. Myelin thickness and g-ratios of some fibers, in relation to axon diameter was abnormally thin, suggesting that oligodendrocytes remain metabolically functional and/or are attempting to make myelin. Many fibers showed swollen, progressive degenerative changes to axons in addition to the dissolution of myelin. All three duplication cases shared remarkable fiber pathology including swellings, constriction and/or transection and involution of myelin. Characteristic of PLP1 duplication patients, many axons showed segmental demyelination along their length. Still other axons had abnormally thick myelin sheaths, suggestive of continued myelination. Thus, each type of mutation exhibited unique pathology even though commonality to both mutations included involution of myelin, myelin balls and degeneration of axons. This pathology study describes findings unique to each mutation that suggests the mechanism causing fiber pathology is likewise heterogeneous.
authors.affiliation: Department of Neuroscience, University of Toledo, College of Medicine and Life Science, Toledo, OH 43614, United States; Department of Neurology, University of Toledo, College of Medicine and Life Science, Toledo, OH 43614, United States. Electronic address: Jeremy.laukka@utoledo.edu.
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Laukka
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, School of Medicine, Detroit, MI 48201, United States; Department of Neurology, University of Iowa, Carver College of Medicine, Iowa City, IA 52242, United States.
authors.forename: John
authors.initials: J
authors.lastname: Kamholz
authors.affiliation: Department of Anatomy and Cell Biology, Wayne State University, School of Medicine, Detroit, MI 48201, United States.
authors.forename: Denise
authors.initials: D
authors.lastname: Bessert
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, School of Medicine, Detroit, MI 48201, United States; Department of Anatomy and Cell Biology, Wayne State University, School of Medicine, Detroit, MI 48201, United States.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Skoff
mesh_terms: D001369:Axons / Q000473:pathology / Q000648:ultrastructure; D054022:Cerebrum / Q000473:pathology* / Q000648:ultrastructure; D003337:Corpus Callosum / Q000473:pathology* / Q000648:ultrastructure; D017353:Gene Deletion; D020440:Gene Duplication; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018991:Myelin Proteolipid Protein / Q000235:genetics*; D009186:Myelin Sheath / Q000473:pathology* / Q000648:ultrastructure; D020371:Pelizaeus-Merzbacher Disease / Q000235:genetics / Q000473:pathology*
chemical_list: D018991:Myelin Proteolipid Protein; C472930:PLP1 protein, human
keywords: Electron microscopy; Hypomyelination; Immunocytochemistry; Myelin and axon pathology; Pelizaeus-Merzbacher disease; Proteolipid protein