title: The leukoencephalopathy of infantile GM1 gangliosidosis: oligodendrocytic loss and axonal dysfunction.
abstract: A myelin deficit in the cerebral white matter in infantile GM1 gangliosidosis is well established. Some have proposed this deficit to be secondary to axonal loss, while others argue for delayed or arrested myelination. We compared the frontal white and gray matter of two infants with GM1 gangliosidosis with four age-matched controls, using light microscopy with a quantitative analysis, immunohistochemistry, terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL), and electron microscopy (EM). In the GM1 cases, we found a marked decrease in the number of oligodendrocytes (85% in case 1 and 50% in case 2) and myelin sheaths (80% and 40%), with a mild decrease in axons (20% and 10%). Ultrastructurally, some naked axons and dilated cisterns of rough endoplasmic reticulum (RER) in oligodendrocytes were observed. There was no appreciable storage in remaining oligodendrocytes, nor obvious neocortical neuronal loss. An immunohistochemical decrease in proteolipid protein (PLP) and a more profound deficiency of myelin basic protein (MBP) indicate that this lesion is not simply the result of a delay or arrest in myelination and suggests a "dying-back" oligopathy. TUNEL-positive oligodendrocytes correlated with activated caspase-3 immunoreactivity. Amyloid precursor protein (APP)-immunoreactive aggregates were observed in proximal axons and meganeurites as well as in white matter axons. These data suggest that the myelin deficit results from a loss of oligodendrocytes and abnormal axoplasmic transport, perhaps consequent to massive neuronal storage of GM1.
authors.affiliation: Department of Pathology, Vrije Universiteit Medical Center, DeBoelelaan 1117, 1007 MB, Amsterdam, The Netherlands. jp.vandervoorn@vumc.nl
authors.forename: J Patrick
authors.initials: JP
authors.lastname: van der Voorn
authors.forename: Wout
authors.initials: W
authors.lastname: Kamphorst
authors.forename: Marjo S
authors.initials: MS
authors.lastname: van der Knaap
authors.forename: James M
authors.initials: JM
authors.lastname: Powers
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D001369:Axons / Q000473:pathology* / Q000648:ultrastructure; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D002256:Carbonic Anhydrases / Q000378:metabolism; D016022:Case-Control Studies; D002452:Cell Count / Q000379:methods; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D016537:Gangliosidosis, GM1 / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D007223:Infant; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008854:Microscopy, Electron / Q000379:methods; D004676:Myelin Basic Protein / Q000378:metabolism; D009836:Oligodendroglia / Q000473:pathology* / Q000648:ultrastructure; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D013344:Subacute Sclerosing Panencephalitis / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D014157:Transcription Factors / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D016564:Amyloid beta-Protein Precursor; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002256:Carbonic Anhydrases; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D019394:Ki-67 Antigen; D004676:Myelin Basic Protein; D017479:Receptors, Platelet-Derived Growth Factor; D014157:Transcription Factors; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C078341:MYT1 protein, human