Integration of Autopsy Pathology and Genetics in Hunter Syndrome (MPSII).
Laura D Wood, Marc K Halushka, Frederic B Askin, Lorraine C Racusen, Robert A Anders, Berivan Baskin, Peter N Ray, Toin Van Kuppevelt, Ronnie G Wismans, Barbara J Crain, Marvin R Natowicz, G Steven Bova. Johns Hopkins University School of Medicine, Baltimore, MD; The Hospital for Sick Children, Toronto, ON, Canada; Radboud University, Nijmegen Medical Centre, Netherlands; Cleveland Clinic, OH
Background: Hunter syndrome (MPSII), a rare X-linked lysosomal storage disorder caused by germ-line mutations in the iduronate-2-sulfatase (IDS) gene, is a mucopolysaccharidosis characterized by abnormal accumulation of glycosaminoglycans (GAGs) in multiple organs. Although the clinical syndrome of MPSII is well described, systematic anatomic studies of its pathology are limited, and studies integrating gross and microscopic pathology with specific mutations have not been reported. Insights from these natural human mutations affecting GAG degradation could improve our understanding of the role of GAGs in health and disease.
Design: We performed comprehensive gross and microscopic analysis for 2 autopsy subjects with MPSII. Tissues were examined using H&E staining, colloidal iron staining, and a novel antibody specific for dermatan sulfate. We also performed DNA sequencing on all coding exons of the IDS gene in formalin-fixed paraffin-embedded lymphoid tissue from each patient.
Results: DNA sequencing of the IDS gene revealed different pathogenic mutations in each patient: one novel single-base deletion in exon 6 creating an in-frame stop codon (c.817delC, p.Arg273fsX) and one previously reported disease-causing missense mutation in exon 3 (c.253G>A, p.Ala85Thr). Gross examination of tissues at autopsy confirmed previously reported anatomic anomalies and identified novel findings, including coronary artery occlusion (not previously reported in MPSII) and choroid plexus fibrosis (not previously reported in any mucopolysaccharidosis). Microscopic examination revealed that abnormal vacuolated cells containing undegraded GAGs were present in multiple organs, including the heart, blood vessels, lungs, liver, kidney, and brain.
Conclusions: This study is the first to integrate systematic autopsy examination with specific mutations in MPSII, highlighting the power of genotype-phenotype correlation in the understanding of the pathogenesis of genetic disease. Moreover, we extend the current notion of genotype-phenotype analysis beyond clinical syndrome to include correlation of gross and microscopic pathology with specific mutations. Expansion of the methods used in this study to additional cases of MPSII could greatly enhance our understanding of the inherited disorders of GAG metabolism and GAG biology more generally.
Monday, February 28, 2011 2:30 PM
Platform Session: Section G, Monday Afternoon