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.

Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms

“…The optic nerves are thin and gray, in sharp contrast to the other cranial nerves and spinal nerve roots that have a normal size and are white. Histopathology may vary according to the type of PLP1 mutation [ 122 ]. In classical PMD due to PLP1 gene duplications, microscopic analysis shows paucity of myelin with a classic tigroid distribution due to preservation of myelin islets around blood vessels.…”

Modeling cognitive deficits following neurodegenerative diseases and traumatic brain injuries with deep convolutional neural networks

“…Thus, simulations with convolutional neural networks that incorporate biophysically plausible neural malfunctions may provide a window of opportunity to better diagnose, for instance, confusion in visual image classification. Focal axonal swelling pathologies are present in AD [2,17,53,91] and in other neurodegenerative diseases such as Parkinson's disease [86,60,28], Multiple Sclerosis [26,70,90], and others [36,50,55,56]. In many cases, FAS arise by the agglomeration of specific proteins over time [16,68], and again, the computational modeling of focal axonal swellings and their effects to spike propagation from [63] provide a platform to investigate network dysfunction.…”

Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes

“…[19][20][21][22][23] PLP1's strong cell-type specificity, abundance in myelin, and inter-species conservation all suggest that it fills an indispensable role in oligodendrocyte and myelin biology. However, PLP1's function in oligodendrocytes and myelin has only recently begun to be elucidated [24][25][26][27] and is still very much in question. As a result, there is no current consensus on the pathogenic processes by which PLP1 mutations cause PMD.…”