As little information is available on children with non-classic presentations of Pompe disease, we wished to gain knowledge of specific clinical characteristics and genotypes. We included all ...patients younger than 18 years, who had been evaluated at the Pompe Center in Rotterdam, the Netherlands, between 1975 and 2012, excluding those with the classic-infantile form. None were treated with enzyme replacement therapy at the time of evaluation. We collected information on first symptoms, diagnosis, use of a wheelchair and/or respirator, and enzyme and mutation analysis and assessed muscle strength, pulmonary function, and cardiac parameters.
Thirty-one patients participated. Median age at symptom onset was 2.6 years (range 0.5-13y) and at diagnosis 4.0 years. Most first problems were delayed motor development and problems related to limb-girdle weakness. Fatigue, persistent diarrhea and problems in raising the head in supine position were other first complaints. Ten patients were asymptomatic at time of diagnosis. Five of them developed symptoms before inclusion in this study. Over 50 % of all patients had low or absent reflexes, a myopathic face, and scoliosis; 29 % were underweight. Muscle strength of the neck flexors, hip extensors, hip flexors, and shoulder abductors were most frequently reduced. Pulmonary function was decreased in over 48 % of the patients; 2 patients had cardiac hypertrophy. Patients with mutations other than the c.-32-13T > G were overall more severely affected, while 18 out of the 21 patients (86 %) with the c.-32-13T > G/'null' genotype were male.
Our study shows that Pompe disease can present with severe mobility and respiratory problems during childhood. Pompe disease should be considered in the differential diagnosis of children with less familiar signs such as disproportional weakness of the neck flexors, unexplained fatigue, persistent diarrhea and unexplained high CK/ASAT/ALAT. Disease presentation appears to be different from adult patients. The majority of affected children with GAA genotype c.-32-13T > G/'null' appeared to be male.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Kidney transplantation is associated with harmful processes affecting the viability of the graft. One of these processes is associated with the phenomenon of ischaemia–reperfusion injury. Anaesthetic ...conditioning is a widely described strategy to attenuate ischaemia–reperfusion injury. We therefore conducted the Volatile Anaesthetic Protection of Renal Transplants-1 trial, a pilot project evaluating the influence of two anaesthetic regimens, propofol- vs sevoflurane-based anaesthesia, on biochemical and clinical outcomes in living donor kidney transplantation.
Sixty couples were randomly assigned to the following three groups: PROP (donor and recipient propofol), SEVO (donor and recipient sevoflurane), and PROSE (donor propofol and recipient sevoflurane). The primary outcome was renal injury reflected by urinary biomarkers. The follow-up period was 2 yr.
Three couples were excluded, leaving 57 couples for analysis. Concentrations of kidney injury molecule-1 (KIM-1), N-acetyl-β-d-glucosaminidase (NAG), and heart-type fatty acid binding protein (H-FABP) in the first urine upon reperfusion showed no differences. On day 2, KIM-1 concentrations were higher in SEVO 952.8 (interquartile range 311.8–1893.0) pg mmol−1 compared with PROP 301.2 (202.0–504.7) pg mmol−1. This was the same for NAG: SEVO, 1.835 (1.162–2.457) IU mmol−1vs PROP, 1.078 (0.819–1.713) IU mmol−1. Concentrations of H-FABP showed no differences. Measured glomerular filtration rate at 3, 6, and 12 months showed no difference. After 2 yr, there was a difference in the acute rejection rate (P=0.039). Post hoc testing revealed a difference between PROP (35%) and PROSE (5%; P=0.020). The difference between PROP and SEVO (11%) was not significant (P=0.110).
The SEVO group showed higher urinary KIM-1 and NAG concentrations in living donor kidney transplantation on the second day after transplantation. This was not reflected in inferior graft outcome.
NCT01248871.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The aim of this study was to compare the long‐term outcome of classic infantile Pompe patients treated with 20 mg/kg alglucosidase alfa every other week (eow) to those treated with 40 mg/kg/week, and ...to study the additional effect of immunomodulation. Six patients received 20 mg/kg eow and twelve 40 mg/kg/week. Five patients were cross‐reactive immunologic material (CRIM)‐negative, two in the 20 mg, three in the 40 mg group. We compared (ventilator‐free) survival, motor outcome, infusion associated reactions (IARs), and antibody formation. From 2012 on patients >2 months in the 40 mg group also received immunomodulation with rituximab, methotrexate, and intravenous immunoglobulin (IVIG) in an enzyme replacement therapy (ERT)‐naïve setting. Survival was 66% in the 20 mg group and 92% in the 40 mg group. Ventilator‐free survival was 50% and 92%. Both CRIM‐negative patients in the 20 mg group died, whereas all three are alive in the 40 mg group. In the 20 mg group, 67% learned to walk compared with 92% in the 40 mg group. At the age of 3 years, 33% and 92% were able to walk. Peak antibody titers ranged from 1:1250 to 1:31 250 in the 20 mg group and from 1:250 to 1:800 000 in the 40 mg group. Five patients of the 40 mg group of whom two CRIM‐negative also received immunomodulation. B‐cell recovery was observed between 5.7 and 7.9 months after the last dose of rituximab. After B‐cell recovery titers of patients with and without immunomodulation were similar (ranges 1:6 250‐1:800 000 and 1:250‐1:781 250). This study shows that classic infantile patients treated with 40 mg/kg/week from the start to end have a better (ventilator‐free) survival and motor outcome. Immunomodulation did not prevent antibody formation in our study.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background
Though enzyme-replacement therapy (ERT) with alglucosidase alfa has significantly improved the prospects for patients with classic infantile Pompe disease, some 50 % of treated infants do ...not survive ventilator-free beyond the age of 3 years. We investigated whether higher and more frequent dosing of alglucosidase alfa improves outcome.
Methods
Eight cross-reactive immunological material (CRIM) positive patients were included in the study. All had fully deleterious mutations in both
GAA
alleles. Four received a dose of 20 mg/kg every other week (eow) and four received 40 mg/kg/week. Survival, ventilator-free survival, left-ventricular mass index (LVMI), motor outcome, infusion-associated reactions (IARs), and antibody formation were evaluated.
Results
All eight patients were alive at study end, seven of them remained ventilator-free. The patient who became ventilator dependent was treated with 20 mg/kg eow. Three of the four patients receiving 20 mg/kg eow learned to walk; two of them maintained this ability at study end. All four patients receiving 40 mg/kg/week acquired and maintained the ability to walk at study end (ages of 3.3–5.6 years), even though their baseline motor functioning was poorer. There were no apparent differences between the two dose groups with respect to the effect of ERT on LVMI, the number of IARs and antibody formation.
Conclusions
Our data may suggest that a dose of 40 mg/kg/week improves outcome of CRIM positive patients over that brought by the currently recommended dose of 20 mg/kg eow. Larger studies are needed to draw definite conclusions.
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FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UL, UM, UPUK, VKSCE, ZAGLJ
Pompe's disease is a neuromuscular disorder caused by deficiency of lysosomal acid alpha-glucosidase. Recombinant human alpha- glucosidase is under evaluation as therapeutic drug. In light of this ...development we studied the natural course of cases not fitting the definition of classic infantile Pompe's disease. Our review of 109 reports including 225 cases shows a continuous spectrum of phenotypes. The onset of symptoms ranged from 0 to 71 years. Based on the available literature, no criteria to delineate clinical sub-types could be established.A common denominator of these cases is that first symptoms were related to or caused by muscle weakness. In general, patients with a later onset of symptoms seemed to have a better prognosis. Respiratory failure was the most frequent cause of death. CK, LDH, ASAT, ALAT and muscle glycogen levels were frequently but not always elevated. In most cases a muscle biopsy revealed lysosomal pathology, but normal muscle morphology does not exclude Pompe's disease. In 10% of the cases in which the enzyme assay on leukocytes was used, a normal alpha-glucosidase activity was reported. Data on skeletal muscle strength and function, pulmonary function, disability, handicap and quality of life were insufficiently reported in the literature. Studies of non-classic Pompe's disease should focus on these aspects, before enzyme replacement therapy becomes generally available.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Enzyme replacement therapy (ERT; alglucosidase alfa) has improved the prospects for patients with classic infantile Pompe disease considerably. However, over time we noticed that many of these ...children exhibit distal muscle weakness at an early age, which is in contrast to the primarily proximal and axial muscle weakness in patients with late-onset Pompe disease. This was reason to study the prevalence and severity of distal muscle weakness, and the sequence of muscle involvement over time in patients that had learned to walk under ERT.
In this prospective, single-center cohort study, we studied 16 classic infantile patients. We used video recordings that were made during regular standardized assessments to investigate distal muscle function (active dorsiflexion of the feet during walking; ability to use a pincer grasp/actively extend the fingers) and proximal muscle function (standing up from a supine position; raising the arms above the head).
Median age at start of ERT was 3.2 months (0.1-5.8 months), median age at study end was 5.6 years (2.9-18.2 years). Six patients (6/16, 38%) initially had no evident signs of distal muscle weakness and developed a gait with active dorsiflexion of the feet. The other 10 patients never exhibited active dorsiflexion of the feet during walking. At study-end two patients showed no loss of distal muscle function. A subset of five patients (5/16, 31%) developed also weakness of the hands, particularly of the extensors of the 3rd and 4th digit.
We found that the majority (14/16, 88%) of patients who had learned to walk exhibited distal muscle weakness of the lower extremities, while a subset (5/16, 31%) also developed weakness of the hands. The distal muscle weakness was often more serious than, and preceded the development of, the proximal muscle weakness.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Late-onset Pompe's disease (acid maltase deficiency, glycogen storage disease type II) is a slowly progressive myopathy caused by deficiency of acid α-glucosidase. Current developments in enzyme ...replacement therapy require detailed knowledge of the kind and severity of symptoms and the natural course of the disease in the patient population. A detailed questionnaire covering the patients' medical history and current situation was developed and information was gathered from 54 Dutch patients. The mean age of the participants was 48.6 ± 15.6 years. The first complaints started at a mean age of 28.1 ± 14.3 years and were mostly related to mobility problems and limb-girdle weakness. Fifty-eight percent of the adult patients indicated the presence of mild muscular symptoms during childhood. Twenty-eight percent of the patients waited >5 years for the final diagnosis after the first visit to a physician for disease-related complaints. At the time of questionnaire completion, 48% of the study population used a wheelchair and 37% used artificial ventilation. Movements such as rising from an armchair, taking stairs or getting upright after bending over were difficult or impossible for more than two-thirds of the respondents. The age at onset, the rate of disease progression and the sequence of respiratory and skeletal muscle involvement varied substantially between patients. Seventy-six percent of the participants indicated being troubled by fatigue and 46% by pain. This survey has mapped the age at onset, presenting symptoms, heterogeneity in progression and range of disease severity in a large group ofDutch patients. We conclude that early manifestations in childhood require proper attention to prevent unnecessary delay of the diagnosis. The follow-up of patients with late-onset Pompe's disease should focus on respiratory and limb-girdle muscle function, the capacity to perform daily activities, and the presentation of fatigue and pain.
Pompe's disease van der Ploeg, Ans T, Dr; Reuser, Arnold JJ, PhD
The Lancet (British edition),
2008-Oct-11, Volume:
372, Issue:
9646
Journal Article
Peer reviewed
Summary Pompe's disease, glycogen-storage disease type II, and acid maltase deficiency are alternative names for the same metabolic disorder. It is a pan-ethnic autosomal recessive trait ...characterised by acid α-glucosidase deficiency leading to lysosomal glycogen storage. Pompe's disease is also regarded as a muscular disorder, but the generalised storage of glycogen causes more than mobility and respiratory problems. The clinical spectrum is continuous and broad. First symptoms can present in infants, children, and adults. Cardiac hypertrophy is a key feature of classic infantile Pompe's disease. For a long time, there was no means to stop disease progression, but the approval of enzyme replacement therapy has substantially changed the prospects for patients. With this new development, the disease is now among the small but increasing number of lysosomal storage disorders, for which treatment has become a reality. This review is meant to raise general awareness, to present and discuss the latest insights in disease pathophysiology, and to draw attention to new developments about diagnosis and care. We also discuss the developments that led to the approval of enzyme replacement therapy with recombinant human α-glucosidase from Chinese hamster ovary cells (alglucosidase alfa) by the US Food and Drug Administration and European Medicines Agency in 2006, and review clinical practice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The interaction between epithelial cancer cells and cancer-associated fibroblasts (CAFs) has a major role in cancer progression and eventually in metastasis. In colorectal cancer (CRC), CAFs are ...present in high abundance, but their origin and functional interaction with epithelial tumor cells has not been elucidated. In this study we observed strong activation of the transforming growth factor-β (TGF-β)/Smad signaling pathway in CRC CAFs, accompanied by decreased signaling in epithelial tumor cells. We evaluated the TGF-β1 response and the expression of target genes including matrix metalloproteinases (MMPs) and plasminogen activator inhibitor (PAI)-1 of various epithelial CRC cell lines and primary CAFs in vitro. TGF-β1 stimulation caused high upregulation of MMPs, PAI-1 and TGF-β1 itself. Next we showed that incubation of CAFs with conditioned medium (CM) from epithelial cancer cells led to hyperactivation of the TGF-β signaling pathway, enhanced expression of target genes like PAI-1, and the expression of α-smooth muscle actin (α-SMA). We propose that the interaction of tumor cells with resident fibroblasts results in hyperactivated TGF-β1 signaling and subsequent transdifferentiation of the fibroblasts into α-SMA-positive CAFs. In turn this leads to cumulative production of TGF-β and proteinases within the tumor microenvironment, creating a cancer-promoting feedback loop.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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