+1 Recommend
0 collections
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Effects of immunomodulation in classic infantile Pompe patients with high antibody titers

      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.



          To evaluate whether immunomodulation can eliminate high sustained antibody levels, and thereby improve clinical outcome in classic infantile Pompe patients receiving enzyme replacement therapy (ERT) with recombinant human alpha-glucosidase (rhGAA).


          Three patients (two cross-reactive immunologic material (CRIM) negative) with high sustained antibodies received a three-week treatment protocol with Rituximab and Bortezomib, followed by daily Rapamycin and monthly IVIG. Patients received 40 mg/kg/week rhGAA. Antibody titers were measured using ELISA. Neutralizing effects on cellular uptake were determined. Clinical efficacy was measured in terms of (ventilator-free) survival, reduction in left ventricular mass index (LVMI) and improvement in motor function.


          Before immunomodulation anti-rhGAA antibody titers ranged from 1:156,250 to 1:781,250 and at last assessment from 1:31,250 to 1:156,250. Neutralizing effects of anti-rhGAA antibody titers (observed in two patients) disappeared. Infusion-associated reactions were no longer present. Immunomodulation resulted in substantial increases of aspartate transaminase, alanine transaminase, and creatine kinase levels. The two CRIM-negative patients who could walk at start of immunomodulation maintained their ability to walk; the patient who had lost this ability did not regain it.


          To some extent, the immunomodulation protocol used in our study reduced antibody titers, but it did not eliminate them. Overall, there have been few reports on secondary immunomodulation, and various protocols have been applied. Future research should seek to identify the most successful immunomodulation protocol in patients with high sustained titers.

          Electronic supplementary material

          The online version of this article (10.1186/s13023-019-1039-z) contains supplementary material, which is available to authorized users.

          Related collections

          Most cited references 19

          • Record: found
          • Abstract: found
          • Article: not found

          Recombinant human alpha-glucosidase from rabbit milk in Pompe patients.

          Pompe's disease is a fatal muscular disorder caused by lysosomal alpha-glucosidase deficiency. In an open-label study, four babies with characteristic cardiomyopathy were treated with recombinant human alpha-glucosidase (rhGAA) from rabbit milk at starting doses of 15 mg/kg or 20 mg/kg, and later 40 mg/kg. The enzyme was generally well tolerated. Activity of alpha-glucosidase normalised in muscle. Tissue morphology and motor and cardiac function improved. The left-ventricular-mass index decreased significantly. We recommend early treatment. Long-term effects are being studied.
            • Record: found
            • Abstract: found
            • Article: not found

            Long-term intravenous treatment of Pompe disease with recombinant human alpha-glucosidase from milk.

            Recent reports warn that the worldwide cell culture capacity is insufficient to fulfill the increasing demand for human protein drugs. Production in milk of transgenic animals is an attractive alternative. Kilogram quantities of product per year can be obtained at relatively low costs, even in small animals such as rabbits. We tested the long-term safety and efficacy of recombinant human -glucosidase (rhAGLU) from rabbit milk for the treatment of the lysosomal storage disorder Pompe disease. The disease occurs with an estimated frequency of 1 in 40,000 and is designated as orphan disease. The classic infantile form leads to death at a median age of 6 to 8 months and is diagnosed by absence of alpha-glucosidase activity and presence of fully deleterious mutations in the alpha-glucosidase gene. Cardiac hypertrophy is characteristically present. Loss of muscle strength prevents infants from achieving developmental milestones such as sitting, standing, and walking. Milder forms of the disease are associated with less severe mutations and partial deficiency of alpha-glucosidase. In the beginning of 1999, 4 critically ill patients with infantile Pompe disease (2.5-8 months of age) were enrolled in a single-center open-label study and treated intravenously with rhAGLU in a dose of 15 to 40 mg/kg/week. Genotypes of patients were consistent with the most severe form of Pompe disease. Additional molecular analysis failed to detect processed forms of alpha-glucosidase (95, 76, and 70 kDa) in 3 of the 4 patients and revealed only a trace amount of the 95-kDa biosynthetic intermediate form in the fourth (patient 1). With the more sensitive detection method, 35S-methionine incorporation, we could detect low-level synthesis of -glucosidase in 3 of the 4 patients (patients 1, 2, and 4) with some posttranslation modification from 110 kDa to 95 kDa in 1 of them (patient 1). One patient (patient 3) remained totally deficient with both detection methods (negative for cross-reactive immunologic material [CRIM negative]). The alpha-glucosidase activity in skeletal muscle and fibroblasts of all 4 patients was below the lower limit of detection ( 3 years of treatment. Anti-rhAGLU immunoglobulin G titers initially increased during the first 20 to 48 weeks of therapy but declined thereafter. There was no consistent difference in antibody formation comparing CRIM-negative with CRIM-positive patients. Muscle alpha-glucosidase activity increased from 42 degrees C, unstable blood pressure, and coma. The respiratory course of patient 1 remained uneventful. The 2 older patients, who both were hypercapnic (partial pressure of carbon dioxide: 10.6 and 9.8 kPa; normal range: 4.5-6.8 kPa) at start of treatment, became ventilator dependent before the first infusion (patient 2) and after 10 weeks of therapy (patient 4). Patient 4 was gradually weaned from the ventilator after 1 year of high-dose treatment and was eventually completely ventilator-free for 5 days, but this situation could not be maintained. Currently, both patients are completely ventilator dependent. The most remarkable progress in motor function was seen in the younger patients (patients 1 and 3). They achieved motor milestones that are unmet in infantile Pompe disease. Patient 1 learned to crawl (12 months), walk (16 months), squat (18 months), and climb stairs (22 months), and patient 3 learned to sit unsupported. The Alberta Infant Motor Scale score for patients 2, 3, and 4 remained far below p5. Patient 1 followed the p5 of normal. Our study shows that a safe and effective medicine can be produced in the milk of mammals and encourages additional development of enzyme replacement therapy for the several forms of Pompe disease. Restoration of skeletal muscle function and prevention of pulmonary insufficiency require dosing in the range of 20 to 40 mg/kg/week. The effect depends on residual muscle function at the start of treatment. Early start of treatment is required.
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              Reference values for the 6-minute walk test in healthy children and adolescents in Switzerland

              Background The six-minute walk test (6MWT) is a simple, low tech, safe and well established, self-paced assessment tool to quantify functional exercise capacity in adults. The definition of normal 6MWT in children is especially demanding since not only parameters like height, weight and ethnical background influence the measurement, but may be as crucial as age and the developmental stage. The aim of this study is establishing reference values for the 6MWT in healthy children and adolescents in Switzerland and to investigate the influence of age, anthropometrics, heart rate, blood pressure and physical activity on the distance walked. Methods Children and adolescents between 5–17 years performed a 6MWT. Short questionnaire assessments about their health state and physical activities. anthropometrics and vitals were measured before and after a 6-minute walk test and were previously defined as secondary outcomes. Results Age, height, weight and the heart rate after the 6MWT all predicted the distance walked according to different regression models: age was the best single predictor and mostly influenced walk distance in younger age, anthropometrics were more important in adolescents and females. Heart rate after the 6MWT was an important distance predictor in addition to age and outreached anthropometrics in the majority of subgroups assessed. Conclusions The 6MWT in children and adolescents is feasible and practical. The 6MWT distance depends mainly on age; however, heart rate after the 6MWT, height and weight significantly add information and should be taken into account mainly in adolescents. Reference equations allow predicting 6-minute walk test distance and may help to better assess and compare outcomes in young patients with cardiovascular and respiratory diseases and are highly warranted for different populations.

                Author and article information

                +31 10 704 4840 , a.vanderploeg@erasmusmc.nl
                Orphanet J Rare Dis
                Orphanet J Rare Dis
                Orphanet Journal of Rare Diseases
                BioMed Central (London )
                22 March 2019
                22 March 2019
                : 14
                [1 ]ISNI 000000040459992X, GRID grid.5645.2, Center for Lysosomal and Metabolic Diseases, , Erasmus MC University Medical Center, ; P.O. BOX 2060, 3000 CB Rotterdam, The Netherlands
                [2 ]ISNI 0000000089452978, GRID grid.10419.3d, Department of Pediatrics, , Leiden Medical University Center, ; Leiden, The Netherlands
                [3 ]GRID grid.414786.8, Department of Pediatrics, , Juliana Children’s Hospital, ; The Hague, The Netherlands
                [4 ]ISNI 000000040459992X, GRID grid.5645.2, Department of Pediatric Rheumatology, , Erasmus MC University Medical Center, ; Rotterdam, The Netherlands
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funded by: FundRef http://dx.doi.org/10.13039/501100004243, Prinses Beatrix Spierfonds;
                Award ID: project number W.OR13-21, W.OR15-10, W.OR16-07
                Funded by: FundRef http://dx.doi.org/10.13039/501100003195, Ministerie van Economische Zaken;
                Award ID: no number available
                Funded by: FundRef http://dx.doi.org/10.13039/501100009480, Stichting Vrienden van het Sophia;
                Award ID: project number S17-32
                Funded by: Metakids
                Award ID: project number 2016-063
                Funded by: FundRef http://dx.doi.org/10.13039/501100003593, Conselho Nacional de Desenvolvimento Científico e Tecnológico;
                Award ID: no number available
                Funded by: Colciencias
                Award ID: no number available
                Funded by: FundRef http://dx.doi.org/10.13039/100004329, Genzyme;
                Award ID: no number available
                Custom metadata
                © The Author(s) 2019


                Comment on this article