Transcriptional response to GAA deficiency (Pompe disease) in infantile-onset patients

Palermo, Amelia; Palmer, Rachel; So, KF; Oba-Shinjo, Sueli Mieko; Zhang, M.; Richards, Brandon J.; Madhiwalla, S.T.; Finn, Patrick F.; Hasegawa, Alexandre Pinheiro; Ciociola, Kristina M.; Pescatori, Mario; McVie‐Wylie, Alison; Mattaliano, Robert J.; Madden, Stephen L.; Marie, Suely Kazue Nagahashi; Klinger, Katherine W.; Pomponio, Robert J.

doi:10.1016/j.ymgme.2012.05.004

Cited by 22 publications

(14 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4M). These results may reflect the proinflammatory state associated with the disease1929, which was previously described in infantile Pompe patients30. Alternatively, the reactivity detected against rhGAA in both treated and untreated LOPD patients may reflect an underlying immune response resulting from the expression of the endogenous mutant GAA protein.…”

Section: Resultsmentioning

confidence: 52%

Long-term exposure to Myozyme results in a decrease of anti-drug antibodies in late-onset Pompe disease patients

Masat

Pascal

Antonio

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Immunogenicity of recombinant human acid-alpha glucosidase (rhGAA) in enzyme replacement therapy (ERT) is a safety and efficacy concern in the management of late-onset Pompe disease (LOPD). However, long-term effects of ERT on humoral and cellular responses to rhGAA are still poorly understood. To better understand the impact of immunogenicity of rhGAA on the efficacy of ERT, clinical data and blood samples from LOPD patients undergoing ERT for >4 years (n = 28) or untreated (n = 10) were collected and analyzed. In treated LOPD patients, anti-rhGAA antibodies peaked within the first 1000 days of ERT, while long-term exposure to rhGAA resulted in clearance of antibodies with residual production of non-neutralizing IgG. Analysis of T cell responses to rhGAA showed detectable T cell reactivity only after in vitro restimulation. Upregulation of several cytokines and chemokines was detectable in both treated and untreated LOPD subjects, while IL2 secretion was detectable only in subjects who received ERT. These results indicate that long-term ERT in LOPD patients results in a decrease in antibody titers and residual production of non-inhibitory IgGs. Immune responses to GAA following long-term ERT do not seem to affect efficacy of ERT and are consistent with an immunomodulatory effect possibly mediated by regulatory T cells.

show abstract

Section: Resultsmentioning

confidence: 52%

Long-term exposure to Myozyme results in a decrease of anti-drug antibodies in late-onset Pompe disease patients

Masat

Pascal

Antonio

et al. 2016

Sci Rep

View full text Add to dashboard Cite

show abstract

“…A genome-wide mRNA expression study indicated elevated cTnT expression in skeletal muscle biopsies taken from untreated classic infantile patients with Pompe disease, who have LVH. 39 cTnT expression in skeletal muscle from adult, childhood onset, and treated classic infantile patients with Pompe disease, who lack a cardiac phenotype, has not been reported to date. Accumulating evidence indicates that cTnT expression in skeletal muscle is a general phenomenon in several neuromuscular diseases.…”

Section: Discussionmentioning

confidence: 99%

Elevated Plasma Cardiac Troponin T Levels Caused by Skeletal Muscle Damage in Pompe Disease

Wens

Schaaf

Michels

et al. 2016

Circ Cardiovasc Genet

View full text Add to dashboard Cite

Background— Elevated plasma cardiac troponin T (cTnT) levels in patients with neuromuscular disorders may erroneously lead to the diagnosis of acute myocardial infarction or myocardial injury. Methods and Results— In 122 patients with Pompe disease, the relationship between cTnT, cardiac troponin I, creatine kinase (CK), CK-myocardial band levels, and skeletal muscle damage was assessed. ECG and echocardiography were used to evaluate possible cardiac disease. Patients were divided into classic infantile, childhood-onset, and adult-onset patients. cTnT levels were elevated in 82% of patients (median 27 ng/L, normal values <14 ng/L). Cardiac troponin I levels were normal in all patients, whereas CK-myocardial band levels were increased in 59% of patients. cTnT levels correlated with CK levels in all 3 subgroups ( P <0.001). None of the abnormal ECGs recorded in 21 patients were indicative of acute myocardial infarction, and there were no differences in cTnT levels between patients with and without (n=90) abnormalities on ECG (median 28 ng/L in both groups). The median left ventricular mass index measured with echocardiography was normal in all the 3 subgroups. cTnT mRNA expression in skeletal muscle was not detectable in controls but was strongly induced in patients with Pompe disease. cTnT protein was identified by mass spectrometry in patient-derived skeletal muscle tissue. Conclusions— Elevated plasma cTnT levels in patients with Pompe disease are associated with skeletal muscle damage, rather than acute myocardial injury. Increased cTnT levels in Pompe disease and likely other neuromuscular disorders should be interpreted with caution to avoid unnecessary cardiac interventions.

show abstract

“…One previous report has also detected inflammatory cells in skeletal muscle of an adult Pompe patient [ 36 ], but the cells have not been further characterized. At the molecular level, microarray analysis of genome wide mRNA expression patterns indicate elevated expression levels of several genes involved in immune regulation in skeletal muscle biopsies from classic infantile patients [ 37 ]. In the current study, infiltration of skeletal muscle with CD68-positive cells was observed in severely affected Pompe patients and suggested the presence of macrophages involved in phagocytosis of degenerating muscle fibers.…”

Section: Discussionmentioning

confidence: 99%

Lack of robust satellite cell activation and muscle regeneration during the progression of Pompe disease

Schaaf

Gestel

Brusse

et al. 2015

acta neuropathol commun

View full text Add to dashboard Cite

IntroductionMuscle stem cells termed satellite cells are essential for muscle regeneration. A central question in many neuromuscular disorders is why satellite cells are unable to prevent progressive muscle wasting. We have analyzed muscle fiber pathology and the satellite cell response in Pompe disease, a metabolic myopathy caused by acid alpha-glucosidase deficiency and lysosomal glycogen accumulation. Pathology included muscle fiber vacuolization, loss of cross striation, and immune cell infiltration.ResultsThe total number of Pax7-positive satellite cells in muscle biopsies from infantile, childhood onset and adult patients (with different ages and disease severities) were indistinguishable from controls, indicating that the satellite cell pool is not exhausted in Pompe disease. Pax7/Ki67 double stainings showed low levels of satellite cell proliferation similar to controls, while MyoD and Myogenin stainings showed undetectable satellite cell differentiation. Muscle regenerative activity monitored with expression of embryonic Myosin Heavy Chain was weak in the rapidly progressing classic infantile form and undetectable in the more slowly progressive childhood and adult onset disease including in severely affected patients.ConclusionsThese results imply that ongoing muscle wasting in Pompe disease may be explained by insufficient satellite cell activation and muscle regeneration. The preservation of the satellite cell pool may offer a venue for the development of novel treatment strategies directed towards the activation of endogenous satellite cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0243-x) contains supplementary material, which is available to authorized users.

show abstract

Transcriptional response to GAA deficiency (Pompe disease) in infantile-onset patients

Cited by 22 publications

References 61 publications

Long-term exposure to Myozyme results in a decrease of anti-drug antibodies in late-onset Pompe disease patients

Long-term exposure to Myozyme results in a decrease of anti-drug antibodies in late-onset Pompe disease patients

Elevated Plasma Cardiac Troponin T Levels Caused by Skeletal Muscle Damage in Pompe Disease

Lack of robust satellite cell activation and muscle regeneration during the progression of Pompe disease

Contact Info

Product

Resources

About