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Characterization of pre- and post-treatment pathology after enzyme replacement therapy for Pompe disease.
Lab Invest 2006; 86(12):1208-20LI

Abstract

In Pompe disease, a genetic deficiency of lysosomal acid alpha-glucosidase, glycogen accumulates abnormally in the lysosomes of skeletal, cardiac and smooth muscle, and contributes to clinically progressive and debilitating muscle weakness. The present study involved 8 infantile-onset Pompe patients, treated weekly with 10 mg/kg of recombinant human acid alpha-glucosidase (rhGAA). Muscle biopsies were obtained at baseline, 12 and 52 weeks post-treatment to establish an indicator of efficacy. Several histologic strategies were employed to characterize changes in pre- and post-treatment samples, including high-resolution light microscopy and digital histomorphometry, electron microscopy, capillary density and fiber type analysis, and confocal microscopy for satellite cell activation analysis. Histomorphometric analysis was performed on muscle samples to assess glycogen depletion in response to enzyme replacement therapy (ERT). The extent of glycogen clearance varied widely among these patient samples, and correlated well with clinical outcome. Low glycogen levels, mild ultrastructural damage, a high proportion of type I fibers, and young age at baseline were all features associated with good histologic response. There was no correlation between capillary density and glycogen clearance, and activated satellite cell levels were shown to be higher in post-treatment biopsies with poor histologic responses. This histopathologic study of infantile Pompe disease provides detailed insight into the cellular progression of the disease and its response to therapy while highlighting a number of methodologies which may be employed to assess regression or progression of the associated pathology. As enzyme replacement therapy becomes more prevalent for the treatment of lysosomal storage diseases, such evaluation of post-treatment pathology will likely become a more common occurrence in the daily practice of pathologists.

Authors+Show Affiliations

Department of Pathology, Genzyme Corporation, Framingham, MA 01701-9322, USA. beth.thurberg@genzyme.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17075580

Citation

Thurberg, Beth L., et al. "Characterization of Pre- and Post-treatment Pathology After Enzyme Replacement Therapy for Pompe Disease." Laboratory Investigation; a Journal of Technical Methods and Pathology, vol. 86, no. 12, 2006, pp. 1208-20.
Thurberg BL, Lynch Maloney C, Vaccaro C, et al. Characterization of pre- and post-treatment pathology after enzyme replacement therapy for Pompe disease. Lab Invest. 2006;86(12):1208-20.
Thurberg, B. L., Lynch Maloney, C., Vaccaro, C., Afonso, K., Tsai, A. C., Bossen, E., ... O'Callaghan, M. (2006). Characterization of pre- and post-treatment pathology after enzyme replacement therapy for Pompe disease. Laboratory Investigation; a Journal of Technical Methods and Pathology, 86(12), pp. 1208-20.
Thurberg BL, et al. Characterization of Pre- and Post-treatment Pathology After Enzyme Replacement Therapy for Pompe Disease. Lab Invest. 2006;86(12):1208-20. PubMed PMID: 17075580.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Characterization of pre- and post-treatment pathology after enzyme replacement therapy for Pompe disease. AU - Thurberg,Beth L, AU - Lynch Maloney,Colleen, AU - Vaccaro,Charles, AU - Afonso,Kendra, AU - Tsai,Anne Chun-Hui, AU - Bossen,Edward, AU - Kishnani,Priya S, AU - O'Callaghan,Michael, Y1 - 2006/10/30/ PY - 2006/11/1/pubmed PY - 2007/2/21/medline PY - 2006/11/1/entrez SP - 1208 EP - 20 JF - Laboratory investigation; a journal of technical methods and pathology JO - Lab. Invest. VL - 86 IS - 12 N2 - In Pompe disease, a genetic deficiency of lysosomal acid alpha-glucosidase, glycogen accumulates abnormally in the lysosomes of skeletal, cardiac and smooth muscle, and contributes to clinically progressive and debilitating muscle weakness. The present study involved 8 infantile-onset Pompe patients, treated weekly with 10 mg/kg of recombinant human acid alpha-glucosidase (rhGAA). Muscle biopsies were obtained at baseline, 12 and 52 weeks post-treatment to establish an indicator of efficacy. Several histologic strategies were employed to characterize changes in pre- and post-treatment samples, including high-resolution light microscopy and digital histomorphometry, electron microscopy, capillary density and fiber type analysis, and confocal microscopy for satellite cell activation analysis. Histomorphometric analysis was performed on muscle samples to assess glycogen depletion in response to enzyme replacement therapy (ERT). The extent of glycogen clearance varied widely among these patient samples, and correlated well with clinical outcome. Low glycogen levels, mild ultrastructural damage, a high proportion of type I fibers, and young age at baseline were all features associated with good histologic response. There was no correlation between capillary density and glycogen clearance, and activated satellite cell levels were shown to be higher in post-treatment biopsies with poor histologic responses. This histopathologic study of infantile Pompe disease provides detailed insight into the cellular progression of the disease and its response to therapy while highlighting a number of methodologies which may be employed to assess regression or progression of the associated pathology. As enzyme replacement therapy becomes more prevalent for the treatment of lysosomal storage diseases, such evaluation of post-treatment pathology will likely become a more common occurrence in the daily practice of pathologists. SN - 0023-6837 UR - https://www.unboundmedicine.com/medline/citation/17075580/Characterization_of_pre__and_post_treatment_pathology_after_enzyme_replacement_therapy_for_Pompe_disease_ L2 - http://dx.doi.org/10.1038/labinvest.3700484 DB - PRIME DP - Unbound Medicine ER -