title: CNS, lung, and lymph node involvement in Gaucher disease type 3 after 11 years of therapy: clinical, histopathologic, and biochemical findings.
abstract: A Caucasian male with Gaucher disease type 3, treated with continuous enzyme therapy (ET) for 11 years, experienced progressive mesenteric and retroperitoneal lymphadenopathy, lung disease, and neurological involvement leading to death at an age of 12.5 years. Autopsy showed significant pathology of the brain, lymph nodes, and lungs. Liver and spleen glucosylceramide (GluCer) and glucosylsphingosine (GluS) levels were nearly normal and storage cells were cleared. Clusters of macrophages and very elevated GluCer and GluS levels were in the lungs, and brain parenchymal and perivascular regions. Compared to normal brain GluCer (GC 18:0), GluCer species with long fatty acid acyl chains were increased in the patient's brain. This profile was similar to that in the patient's lungs, suggesting that these lipids were present in brain perivascular macrophages. In the patient's brain, generalized astrogliosis, and enhanced LC3, ubiquitin, and Tau signals were identified in the regions surrounding macrophage clusters, indicating proinflammation, altered autophagy, and neurodegeneration. These findings highlight the altered phenotypes resulting from increased longevity due to ET, as well as those in poorly accessible compartments of brain and lung, which manifested progressive disease involvement despite ET.
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati Ohio.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Ohio.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Burrow
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati Ohio.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Ohio.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati Ohio.|Centro de Medicina Genómica y Metabolismo, Fundación Cardiovascular de Colombia, Colombia.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Prada
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati Ohio.
authors.forename: Laurie
authors.initials: L
authors.lastname: Bailey
authors.affiliation: Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Wujuan
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Amanda
authors.initials: A
authors.lastname: Brewer
authors.affiliation: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Ohio.|Division of Pediatric Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Steve W
authors.initials: SW
authors.lastname: Wu
authors.affiliation: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Ohio.|Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Kenneth D R
authors.initials: KDR
authors.lastname: Setchell
authors.affiliation: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Ohio.|Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: David
authors.initials: D
authors.lastname: Witte
authors.affiliation: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Ohio.|Division of Pediatric Gastroenterology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Mitchell B
authors.initials: MB
authors.lastname: Cohen
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati Ohio.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Ohio.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Grabowski
mesh_terms: D000293:Adolescent; D001921:Brain / Q000473:pathology*; D018450:Disease Progression; D056947:Enzyme Replacement Therapy; D005500:Follow-Up Studies; D005776:Gaucher Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D005963:Glucosylceramides / Q000032:analysis; D006028:Glycosphingolipids / Q000032:analysis; D006801:Humans; D008055:Lipids / Q000032:analysis / Q000134:cerebrospinal fluid; D008099:Liver / Q000737:chemistry / Q000473:pathology; D008136:Longevity; D008168:Lung / Q000737:chemistry / Q000473:pathology*; D008198:Lymph Nodes / Q000473:pathology*; D008264:Macrophages / Q000737:chemistry; D008297:Male; D010641:Phenotype; D011609:Psychosine / Q000031:analogs & derivatives / Q000032:analysis; D013154:Spleen / Q000737:chemistry / Q000473:pathology
chemical_list: D005963:Glucosylceramides; D006028:Glycosphingolipids; D008055:Lipids; D011609:Psychosine; C035742:sphingosyl beta-glucoside
keywords: Enzyme replacement therapy; Gaucher disease; Lymphadenopathy; Lysosomal storage disease; Pathology