TY - JOUR
T1 - Characterization of pre- and post-treatment pathology after enzyme replacement therapy for Pompe disease
AU - Thurberg, Beth L.
AU - Maloney, Colleen Lynch
AU - Vaccaro, Charles
AU - Afonso, Kendra
AU - Tsai, Anne Chun Hui
AU - Bossen, Edward H.
AU - Kishnani, Priya S.
AU - O'Callaghan, Michael
N1 - Funding Information:
We thank members of Genzyme’s Department of Pathology who helped support this work, and Trent Richardson, our Medical Illustrator. We also thank the following clinical investigators and their patients who participated in this trial: A Amalfitano, YT Chen (DUMC, Durham); T Voit (University Hospital, Essen, Germany); M Nicolino (Pediatrique Hôpital Debrousse, Lyon, France); G Herman (Children’s Hospital of Columbus); J Waterson (Children’s Hospital of Oakland) RC Rogers (Greenwood Genetics Center); J Levine (Children’s Hospital, Boston, MA). This work was funded by Genzyme Corporation. BLT, CL-M, CV, KA and MO’C are employees of Genzyme. PSK has received research/grant support and honoraria from Genzyme Corporation.
PY - 2006/12/2
Y1 - 2006/12/2
N2 - In Pompe disease, a genetic deficiency of lysosomal acid α-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 α-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.
AB - In Pompe disease, a genetic deficiency of lysosomal acid α-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 α-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.
KW - Acid α-glucosidase
KW - Enzyme replacement therapy (ERT)
KW - Glycogen storage disease type II
KW - Lysosomal storage disease
KW - Pompe disease
UR - http://www.scopus.com/inward/record.url?scp=33751211826&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33751211826&partnerID=8YFLogxK
U2 - 10.1038/labinvest.3700484
DO - 10.1038/labinvest.3700484
M3 - Article
C2 - 17075580
AN - SCOPUS:33751211826
SN - 0023-6837
VL - 86
SP - 1208
EP - 1220
JO - Laboratory Investigation
JF - Laboratory Investigation
IS - 12
ER -