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Background and purpose: The Rasch‐Built Pompe‐Specific Activity (R‐PAct) scale is a patient‐reported outcome measure specifically designed to quantify the effects of Pompe disease on daily life activities, developed for use in Dutch‐ and English‐speaking countries. This study aimed to validate the R‐PAct for use in other countries. Methods: Four other language versions (German, French, Italian, and Spanish) of the R‐PAct were created and distributed among Pompe patients (≥16 years old) in Germany, France, Spain, Italy, and Switzerland and pooled with data of newly diagnosed patients from Australia, Belgium, Canada, the Netherlands, New Zealand, the USA, and the UK and the original validation cohort (n = 186). The psychometric properties of the scale were assessed by exploratory factor analysis and Rasch analysis. Results: Data for 520 patients were eligible for analysis. Exploratory factor analysis suggested that the items separated into two domains: Activities of Daily Living and Mobility. Both domains independently displayed adequate Rasch model measurement properties, following the removal of one item ("Are you able to practice a sport?") from the Mobility domain, and can be added together to form a "higher order" factor as well. Differential item functioning (DIF)‐by‐language assessment indicated DIF for several items; however, the impact of accounting for DIF was negligible. We recalibrated the nomogram (raw score interval‐level transformation) for the updated 17‐item R‐PAct scale. The minimal detectable change value was 13.85 for the overall R‐PAct. Conclusions: After removing one item, the modified‐R‐PAct scale is a valid disease‐specific patient‐reported outcome measure for patients with Pompe disease across multiple countries. [ABSTRACT FROM AUTHOR]

Background and purpose: Pompe disease is a rare, inheritable, progressive metabolic myopathy. This study aimed to estimate the minimal clinically important difference (MCID) for an improvement in forced vital capacity in the upright seated position (FVCup) and the 6‐min walk test (6MWT) after a year of treatment with enzyme replacement therapy. Methods: Data were obtained from two prospective follow‐up studies. Between‐group and within‐group MCIDs were estimated using anchor‐based methods. Additionally, a distribution‐based method was used to generate supportive evidence. As anchors, self‐reported change in health and in physical functioning, shortness of breath and a categorization of the Short‐Form 36 Physical Component Summary score were used. Anchor appropriateness was assessed using Spearman correlations (absolute values ≥0.29) and a sufficient number of observations in each category. Results: In all, 102 patients had at least one FVCup or 6MWT measurement during enzyme replacement therapy. Based on the anchors assessed as appropriate, the between‐group MCID for an improvement in FVCup ranged from 2.47% to 4.83% points. For the 6MWT, it ranged from 0.35% to 7.47% points which is equivalent to a distance of 2.18–46.61 m and 1.97–42.13 m for, respectively, a man and a woman of age 50, height 1.75 m and weight 80 kg. The results of the distribution‐based method were within these ranges when applied to change in the outcome values. Conclusion: The MCIDs for FVCup and 6MWT derived in this study can be used to interpret differences between and within groups of patients with Pompe disease in clinical trials and cohort studies. [ABSTRACT FROM AUTHOR]

Pompe disease is a rare, progressive, and metabolic myopathy. Reduced pulmonary function is one of the main problems seen in adult patients with late‐onset Pompe disease (LOPD). We aimed to explore the association between changes over time in pulmonary function and in patient‐reported outcome measures (PROMs), in these patients treated with enzyme replacement therapy (ERT). This is a post hoc analysis of two cohort studies. Pulmonary function was assessed as forced vital capacity in the upright position (FVCup). As PROMs, we assessed the physical component summary score (PCS) of the Medical Outcome Study 36‐item Short‐Form Health Survey (SF‐36) and daily life activities (Rasch‐Built Pompe‐Specific Activity [R‐PACT] scale). We fitted Bayesian multivariate mixed‐effects models. In the models of PROMs, we assumed a linear association with FVCup, and adjusted for time (nonlinear), sex, and age and disease duration at the start of ERT. One hundred and one patients were eligible for analysis. PCS and R‐PAct were positively associated with FVCup, while their relation with time was nonlinear (initial increase then decrease). A 1%‐point increase in FVCup is expected to increase PCS by 0.14 points (95% Credible Interval: [0.09;0.19]) and R‐PACT by 0.41 points [0.33;0.49] at the same time point. In the first year of ERT, we expect a change of PCS and R‐PAct scores by +0.42 and +0.80 points, and in the 5th year of +0.16 and +0.45, respectively. We conclude that the physical domain of quality of life and daily life activities improve when FVCup increases during ERT. [ABSTRACT FROM AUTHOR]

Pompe disease is an inherited metabolic myopathy caused by deficiency of acid alpha‐glucosidase (GAA), resulting in lysosomal glycogen accumulation. Residual GAA enzyme activity affects disease onset and severity, although other factors, including dysregulation of cytoplasmic glycogen metabolism, are suspected to modulate the disease course. In this study, performed in mice and patient biopsies, we found elevated protein levels of enzymes involved in glucose uptake and cytoplasmic glycogen synthesis in skeletal muscle from mice with Pompe disease, including glycogenin (GYG1), glycogen synthase (GYS1), glucose transporter 4 (GLUT4), glycogen branching enzyme 1 (GBE1), and UDP‐glucose pyrophosphorylase (UGP2). Expression levels were elevated before the loss of muscle mass and function. For first time, quantitative mass spectrometry in skeletal muscle biopsies from five adult patients with Pompe disease showed increased expression of GBE1 protein relative to healthy controls at the group level. Paired analysis of individual patients who responded well to treatment with enzyme replacement therapy (ERT) showed reduction of GYS1, GYG1, and GBE1 in all patients after start of ERT compared to baseline. These results indicate that metabolic changes precede muscle wasting in Pompe disease, and imply a positive feedforward loop in Pompe disease, in which lysosomal glycogen accumulation promotes cytoplasmic glycogen synthesis and glucose uptake, resulting in aggravation of the disease phenotype. [ABSTRACT FROM AUTHOR]

Our objective was to investigate brain structure, cerebral vasculature, and cognitive function in a cohort of patients with late‐onset Pompe disease, with particular reference to the differences from those with the classic infantile phenotype, where extensive white‐matter abnormalities (WMA) and impaired cognition on long‐term enzyme treatment are reported in a subset of patients. Brain imaging (T1, T2, T2 fluid‐attenuated inversion recovery, susceptibility‐weighted images, and magnetic resonance angiography–time of flight) was combined with extensive cognitive testing of general intelligence (Wechsler IQ Test, Montreal Cognitive Assessment [MoCA]) and specific neuropsychological domains (verbal fluency, cognitive flexibility, attention, memory, and visuospatial abilities). We included 19 patients with late‐onset Pompe disease (age range 11‐56 years). Two patients showed mild punctate WMA within normal range for age, with a Fazekas score (FS) of 1 to 2. Magnetic resonance angiography revealed a slight vertebrobasilar dolichoectasia in two patients yet did not show any aneurysms or vascular dissections. Most patients had age‐adjusted scores within the normal range for the Wechsler index scores (verbal comprehension, perceptual reasoning, working memory, and processing speed) and combined total intelligence (IQ) score (median 101, interquartile range 91‐111; one patient had a below‐average score for total IQ) as well as for the specific domains verbal fluency, attention, and memory. A subset of patients performed suboptimally on the Rey Complex Figure Test (9/14 patients) or cube‐copying/clock‐drawing test of the MoCA (8/10 patients). We therefore concluded that our study showed no brain abnormalities, other than minor microvascular lesions considered within normal range for age, nor general cognitive impairment in late‐onset Pompe patients. These findings are in sharp contrast with the widespread WMA and cognitive problems found in some classic infantile patients. [ABSTRACT FROM AUTHOR]

Patients with the common c.‐32‐13T > G/null GAA genotype have a broad variation in age at symptom onset, ranging from early childhood to late adulthood. Phenotypic variation for other common GAA genotypes remains largely unexplored. Here, we analyzed variation in age at symptom onset for the most common GAA genotypes using the updated and extended Pompe GAA variant database. Patients with the c.2647‐7G > A/null genotype invariably presented symptoms at adulthood, while the c.‐32‐13T > G/null, c.546G > T/null, c.1076‐22T > G/null, c.2238G > C/null, and c.2173C > T/null genotypes led to presentations from early childhood up to late adulthood. The c.1309C > T/null genotype was associated with onset at early to late childhood. Symptom onset shifted toward higher ages in homozygous patients. These findings indicate that a broad variation in symptom onset occurs for various common GAA genotypes, suggesting the presence of modifying factors. We identified three new compound heterozygous c.‐32‐13T > G/null patients who carried the genetic modifier c.510C > T and who showed symptom onset at childhood. While c.510C > T acted by lowering GAA enzyme activity, other putative genetic modifiers did not at the group level, suggesting that these act in trans on processes downstream of GAA enzyme activity. [ABSTRACT FROM AUTHOR]

Abstract: Background: The mucopolysaccharidoses are multisystem lysosomal storage diseases characterized by extensive skeletal deformities, including skull abnormalities. The objective of this study was to determine the incidence of craniosynostosis in the different mucopolysaccharidosis (MPS) types and its clinical consequences. Methods: In a prospective cohort study spanning 10 years, skull imaging and clinical evaluations were performed in 47 MPS patients (type I, II, VI, and VII). A total of 215 radiographs of the skull were analyzed. The presence and type of craniosynostosis, the sutures involved, progression over time, skull shape, head circumference, fundoscopy, and ventriculoperitoneal shunt (VPS) placement data were evaluated. Results: Craniosynostosis of at least one suture was present in 77% of all 47 MPS patients (≤ 6 years of age in 40% of all patients). In 32% of all MPS patients, premature closure of all sutures was seen (≤ 6 years of age in 13% of all patients). All patients with early closure had a more severe MPS phenotype, both in the neuronopathic (MPS I, II) and non‐neuronopathic (MPS VI) patient groups. Because of symptomatic increased intracranial pressure (ICP), a VPS was placed in six patients, with craniosynostosis as a likely or certain causative factor for the increased pressure in four patients. One patient underwent cranial vault expansion because of severe craniosynostosis. Conclusions: Craniosynostosis occurs in the majority of MPS patients. Since the clinical consequences can be severe and surgical intervention is possible, skull growth and signs and symptoms of increased ICP should be monitored in both neuronopathic and non‐neuronopathic patients with MPS. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Pompe disease is a progressive metabolic myopathy for which enzyme replacement therapy (ERT) was approved in 2006. While various publications have examined the effects of ERT in classic‐infantile patients and in adults, little has been published on ERT in children with non‐classic presentations. Study design: This prospective study was conducted from June 1999 to May 2015. Seventeen patients from various countries participated. Outcome measures comprised muscle function (6‐minute walk test, quick motor‐function test (QMFT)), muscle strength (hand‐held dynamometry; manual muscle testing), and lung function (FVC sitting and supine). For each outcome measure, we used linear mixed‐effects models to calculate the difference at group level between the start of therapy and 7 years of ERT. Patients' individual responses over time were also evaluated. Results: Eleven males and six females started ERT at ages between 1.1 and 16.4 years (median 11.9 years); 82% of them carried the common c.‐32‐13T > G GAA gene variant on one allele. At group level, distance walked increased by 7.4 percentage points (p < 0.001) and QMFT scores increased by 9.2 percentage points (p = 0.006). Muscle strength scores seemed to remain stable. Results on lung function were more variable. Patients' individual data show that the proportion of patients who stabilized or improved during treatment ranged between 56 and 69% for lung function outcomes and between 71 and 93% for muscle strength and muscle function outcomes. Conclusions: We report a positive effect of ERT in patients with childhood Pompe disease at group level. For some patients, new or personalized treatments should be considered. [ABSTRACT FROM AUTHOR]

Background: Mucolipidosis type III α/β or γ (MLIII) are rare autosomal recessive diseases, in which reduced activity of the enzyme UDP-N-acetyl glucosamine-1-phosphotransferase (GlcNAc-PTase) leads to intra-lysosomal accumulation of different substrates. Publications on the natural history of MLIII, especially the milder forms, are scarce. This study provides a detailed description of the disease characteristics and its natural course in adult patients with MLIII.Methods: In this retrospective chart study, the clinical, biochemical and molecular findings in adult patients with a confirmed diagnosis of MLIII from three treatment centres were collected.Results: Thirteen patients with MLIII were included in this study. Four patients (31%) were initially misdiagnosed with a type of mucopolysaccharidosis (MPS). Four patients (31%) had mild cognitive impairment. Six patients (46%) needed help with activities of daily living (ADL) or were wheelchair-dependent. All patients had dysostosis multiplex and progressive secondary osteoarthritis, characterised by cartilage destruction and bone lesions in multiple joints. All patients underwent multiple orthopaedic surgical interventions as early as the second or third decades of life, of which total hip replacement (THR) was the most common procedure (61% of patients). Carpal tunnel syndrome (CTS) was found in 12 patients (92%) and in eight patients (61%), CTS release was performed.Conclusions: Severe skeletal abnormalities, resulting from abnormal bone development and severe progressive osteoarthritis, are the hallmark of MLIII, necessitating surgical orthopaedic interventions early in life. Future therapies for this disease should focus on improving cartilage and bone quality, preventing skeletal complications and improving mobility. [ABSTRACT FROM AUTHOR]

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Summary: Background: Pompe disease is a rare metabolic disorder caused by a deficiency of the lysosomal enzyme acid α‐glucosidase. Glycogen accumulation damages skeletal, cardiac, and smooth muscles, causing a progressive and debilitating muscle weakness and cardiomyopathy. As life expectancy has much improved since the introduction of enzyme replacement therapy an increasing number of patients are referred for surgical procedures. Due to the potential cardiopulmonary complications, these patients form a high‐risk group for the anesthesiologist. Aims: In this study, we investigated the incidence of perioperative complications in children with Pompe disease treated in our hospital since the introduction of enzyme replacement therapy. Methods: Anesthetic and perioperative data of children with Pompe disease treated between 1999 and 2015 in the Erasmus MC—Sophia Children's Hospital, University Medical Centre, Rotterdam, The Netherlands, were collected, retrospectively. Results: Of the 65 children with Pompe disease, 34 patients underwent in total 77, mostly low‐risk, surgical procedures. Twenty‐one children had the classic infantile form and 13 had a nonclassic presentation of Pompe disease. In 13 (16.8%) procedures, 1 or more perioperative complications occurred. Perioperative desaturation was the main complication (12.9%), followed by arrhythmia (3.8%) and heart failure requiring diuretic treatment (2.6%). One child died 2 days postoperatively, but this was considered unrelated to the procedure. Conclusion: Despite the potentially high anesthetic risk for children with Pompe disease under enzyme replacement therapy, the incidence of perioperative complications in our study was relatively low. Our data suggest that with proper precautionary measures and a critical choice of timing of the operation, general anesthesia in children with Pompe disease could be relatively safe nowadays. [ABSTRACT FROM AUTHOR]

Copyright of Developmental Medicine & Child Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Muscle weakness is the main symptom of Pompe disease, a lysosomal storage disorder for which major clinical benefits of enzyme replacement therapy (ERT) have been documented recently. Restoration of skeletal muscle function is a challenging goal. Type 2 muscle fibers of mice with Pompe disease have proven resistant to therapy. To investigate the response in humans, we studied muscle biopsies of a severely affected infant before and after 17 months of therapy. Type 1 and 2a fibers were marked with antibodies, and lysosome-associated membrane protein-1 (Lamp1) was used as the lysosomal membrane marker. Quantitative measurements showed a 2.5-3-fold increase of fiber cross-sectional area of both fiber types during therapy and normalization of the Lamp1 signal in ∼95% of type 1 and ∼75% of type 2a fibers. The response of both type 1 and 2a muscle fibers in the patient studied herein corroborates the beneficial effects of enzyme therapy seen in patients with Pompe disease. Muscle Nerve, 2007 [ABSTRACT FROM AUTHOR]