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Introduction: The efficacy of enzyme replacement therapy (ERT) with alglucosidase alfa for infantile-onset Pompe disease (IOPD) is limited in some patients due to the development of high and sustained antibody titers (HSAT; ≥12,800)., Methods: We carried out detailed immunophenotyping of IOPD patients (n=40), including analysis of circulating cell populations by flow cytometry and plasma cytokines by multiplex array, to determine whether patients with HSAT have unique immunological characteristics compared to those with low titers (LT; <12,800)., Results: Compared to patients with LT, patients who develop HSAT were skewed toward a type 2 immune profile, with an increased frequency of Th2 cells that was positively correlated with levels of Th2 (IL-4, IL-5, IL-13) and pro-inflammatory (IL-6, TNF-α, MIP-1α, MIP-1β) cytokines. B cells were increased in HSAT patients with a decreased fraction of unswitched memory B cells. Plasma GM-CSF concentrations were lower on average in HSAT patients, while CXCL11 was elevated. Finally, using principal components analysis, we derived an HSAT Signature Score that successfully stratified patients according to their antibody titers., Discussion: The immune profiles revealed in this study not only identify potential biomarkers of patients that developed HSAT but also provide insights into the pathophysiology of HSAT that will ultimately lead to improved immunotherapy strategies., Competing Interests: AD has received grant support from Sanofi Genzyme and the Lysosomal Disease Network. AD has received honoraria from Sanofi Genzyme. PK has received research/grant support from Sanofi Genzyme and Amicus Therapeutics. PK has received consulting fees and honoraria from Sanofi Genzyme, Amicus Therapeutics, Maze Therapeutics, Bayer, and Asklepios Biopharmaceutical, Inc. AskBio. PK is a member of the Pompe and Gaucher Disease Registry Advisory Board for Sanofi Genzyme, Pompe Disease Advisory Board for Amicus Therapeutics, and Advisory Board for Baebies. PK has equity with Maze Therapeutics and has held equity in Asklepios Biopharmaceuticals, and may receive milestone payments related to that equity in the future. AR is on the Medical Advisory Board of Sonoma Biotherapeutics, and the Scientific Advisory Boards of 4DMT and the Alice and YT Chen Genetics and Genomics Center and is a Consultant for EpiVax, Inc. AR is employed by Epivax, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Desai, Smith, Yi, Rosenberg, Burt and Kishnani.)

Background: Classical infantile-onset Pompe disease (IOPD) is the most severe form of Pompe disease. Enzyme replacement therapy (ERT) has significantly increased survival but only a few studies have reported long-term outcomes., Methods: We retrospectively analyzed the outcomes of classical IOPD patients diagnosed in France between 2004 and 2020., Results: Sixty-four patients were identified. At diagnosis (median age 4 months) all patients had cardiomyopathy and most had severe hypotonia (57 of 62 patients, 92%). ERT was initiated in 50 (78%) patients and stopped later due to being ineffective in 10 (21%). Thirty-seven (58%) patients died during follow-up, including all untreated and discontinued ERT patients, and 13 additional patients. Mortality was higher during the first 3 years of life and after the age of 12 years. Persistence of cardiomyopathy during follow-up and/or the presence of heart failure were highly associated with an increased risk of death. In contrast, cross-reactive immunologic material (CRIM)-negative status (n = 16, 26%) was unrelated to increased mortality, presumably because immunomodulation protocols prevent the emergence of high antibody titers to ERT. Besides survival, decreased ERT efficacy appeared after the age of 6 years, with a progressive decline in motor and pulmonary functions for most survivors., Conclusions: This study reports the long-term follow-up of one of the largest cohorts of classical IOPD patients and demonstrates high long-term mortality and morbidity rates with a secondary decline in muscular and respiratory functions. This decreased efficacy seems to be multifactorial, highlighting the importance of developing new therapeutic approaches targeting various aspects of pathogenesis., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Pompe disease is a rare glycogen storage disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA), leading to glycogen deposition in multiple tissues. Infantile-onset Pompe disease (IOPD) patients present within the first year of life with profound hypotonia and hypertrophic cardiomyopathy. Treatment with enzyme replacement therapy (ERT) has significantly improved survival for this otherwise lethal disorder. This study aims to describe the clinical and molecular spectrum of Malaysian IOPD patients, and to analyze their long term treatment outcomes., Methods: Seventeen patients diagnosed with IOPD between 2000 and 2020 were included in this retrospective cohort study. Clinical and biochemical data were collated and analyzed using descriptive statistics. GAA enzyme levels were performed on dried blood spots. Molecular analysis of the GAA gene was performed by polymerase chain reaction and Sanger sequencing. Structural modelling was used to predict the effect of the novel mutations on enzyme structure., Results: Our cohort had a median age of presentation of 3 months and median age of diagnosis of 6 months. Presenting features were hypertrophic cardiomyopathy (100%), respiratory insufficiency (94%), hypotonia (88%), failure to thrive (82%), feeding difficulties (76%), and hepatomegaly (76%). Fourteen different mutations in the GAA gene were identified, with three novel mutations, c.1552-14&#95;1552-1del, exons 2-3 deletion and exons 6-10 deletion. The most common mutation identified was c.1935C > A p.(D645E), with an allele frequency of 33%. Sixteen patients received ERT at the median age of 7 months. Overall survival was 29%. Mean age of death was 17.5 months. Our longest surviving patient has atypical IOPD and is currently 20 years old., Conclusions: This is the first study to analyze the genotype and phenotype of Malaysian IOPD patients, and has identified the c.1935C > A p.(D645E) as the most common mutation. The three novel mutations reported in this study expands the mutation spectrum for IOPD. Our low survival rate underscores the importance of early diagnosis and treatment in achieving better treatment outcomes., (© 2023. Institut National de la Santé et de la Recherche Médicale (INSERM).)

Purpose: Mini-COMET (NCT03019406; Sanofi) is a phase 2, open-label, ascending-dose, 3-cohort study, evaluating avalglucosidase alfa safety, pharmacokinetics, and efficacy in individuals with infantile-onset Pompe disease aged <18 years who previously received alglucosidase alfa and showed clinical decline (cohorts 1 and 2) or suboptimal response (cohort 3)., Methods: During a 25-week primary analysis period, cohorts 1 and 2 received avalglucosidase alfa 20 and 40 mg/kg every other week, respectively, for 6 months, whereas cohort 3 individuals were randomized (1:1) to receive avalglucosidase alfa 40 mg/kg every other week or alglucosidase alfa (current stable dose) for 6 months., Results: In total, 22 individuals were enrolled (cohort 1 [n = 6], cohort 2 [n = 5], cohort 3-avalglucosidase alfa [n = 5], and cohort 3-alglucosidase alfa [n = 6]). Median treatment compliance was 100%. None of the individuals discontinued treatment or died. Percentages of individuals with treatment-emergent adverse events were similar across dose and treatment groups. No serious or severe treatment-related treatment-emergent adverse events occurred. Trends for better motor function from baseline to week 25 were observed for 40 mg/kg every other week avalglucosidase alfa compared with either 20 mg/kg every other week avalglucosidase alfa or alglucosidase alfa up to 40 mg/kg weekly., Conclusion: These data support the positive clinical effect of avalglucosidase alfa in patients with infantile-onset Pompe disease previously declining on alglucosidase alfa., Competing Interests: Conflict of Interest P.S.K. reports advisory board participation for Amicus Therapeutics, Baebies, and Sanofi; receiving consulting fees from Amicus Therapeutics, Asklepios Biopharmaceutical Inc (AskBio), JCR Pharma Co Ltd, Maze Therapeutics, and Sanofi; performing contracted research for Amicus Therapeutics and Sanofi; receiving honoraria from Amicus Therapeutics, AskBio, Maze Therapeutics, and Sanofi; having ownership interest of <5% (stocks, stock options, or other ownership interest excluding diversified mutual funds) in AskBio and Maze Therapeutics; and receiving travel expenses from Amicus Therapeutics and Sanofi. D.K. reports advisory board participation for AskBio and Sanofi; performing contracted research for Sanofi; serving on the Speaker’s bureau for Sanofi; and receiving travel expenses from AskBio and Sanofi. A.Bra. reports advisory board participation for Alexion, Sanofi, and Shire; receiving consulting fees from Alexion; and receiving travel expenses from Alexion, BioMarin, Orphan Europe, Sanofi, and Shire. A.Bro. reports advisory board participation for Sanofi and receiving honoraria from Orchard Therapeutics and Sanofi. J.D. reports advisory board participation for Sanofi, Recordati RRD, and Orchard Therapeutics; receiving consulting fees from bluebird bio Inc; and serving on the Speaker’s bureau for Sanofi, Recordati RRD, and FYMCA Medical Ltd. S.H.H. reports advisory board participation for Alexion Pharmaceutical Inc; performing contracted research for Sanofi; receiving honoraria from Alexion Pharmaceutical Inc; membership of the Seattle Children’s Hospital workforce; serving as temporary CEO of KEY PROTEO, Inc; being an inventor of intellectual property that has been licensed to KEY PROTEO, Inc; being a founder of KEY PROTEO, Inc and having ownership equity interests in the company; and receiving royalties from UpToDate. S.K., F.L., and H.O. declare no conflicts of interest. S.P. reports receiving travel expenses from Sanofi. S.G.P. reports performing contracted research for Sanofi and receiving consulting fees from Sanofi. K.A.H. and her spouse are employees of Sanofi and both have ownership interest of <5% (stocks, stock options, or other ownership interest excluding diversified mutual funds) in Sanofi. B.K. is an employee of Sanofi and has ownership interest of <5% (stocks, stock options, or other ownership interest excluding diversified mutual funds) in Sanofi. X.M. is an employee of TechData Service LLC (contracted to Sanofi). S.S. is an employee of Sanofi and has ownership interest of <5% (stocks, stock options, or other ownership interest excluding diversified mutual funds) in Sanofi. C.W. reports receiving consulting fees from Sanofi and Regenxbio. A.Z. is an employee of Sanofi and has ownership interest of <5% (stocks, stock options, or other ownership interest excluding diversified mutual funds) in Sanofi Canada. Y.-H.C. reports advisory board participation for Amicus Therapeutics and Sanofi; receiving consulting fees from Amicus Therapeutics and Sanofi; performing contracted research for Sanofi; and receiving honoraria from Biogen, Novartis, Sanofi, and Takeda., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The study aimed to describe central nervous system (CNS) progression in patients with infantile-onset Pompe disease (IOPD) and explore the potential clinical impact and predictors., Methods: Patients with IOPD treated with enzyme replacement therapy were longitudinally followed with brain magnetic resonance imaging (MRI) and evaluation for IQ scores from 2004 to 2021. Investigation of CNS involvement focused on white matter (WM) abnormalities and was quantified using a scoring system for metachromatic leukodystrophy. MRI scores were correlated with plasma neurofilament light chain (NfL) concentration and IQ scores., Results: A total of 19 patients who started enzyme replacement therapy at a mean age of 26 days were analyzed; the median age at last examination was 12.1 (range = 1.7-19) years. MRI abnormalities were found in all patients, from supratentorial central WM to U-fibers, then to infratentorial WM, and eventually to gray matter. MRI scores progressed (n = 16) at variable rates (range = 0.8-2.7/y) and were positively correlated with age (n = 16) and negatively correlated with IQ scores (n = 8). Plasma NfL concentration was positively correlated with MRI scores (r 2  = 0.8569; P < .001; n = 13)., Conclusion: Our results suggest that the progression of CNS involvement in IOPD may be associated with neuroaxonal injury and decreased IQ scores. NfL could serve as a biomarker for CNS involvement in IOPD., Competing Interests: Conflict of Interest Y.-H.C. has served on the advisory boards of Amicus Therapeutics, Inc and Sanofi Genzyme, undertaken contracted research for Sanofi Genzyme, and received honoraria and consulting fees from Sanofi Genzyme. W.-L.H. has served on the advisory boards of Audentes Therapeutics and Sanofi Genzyme, undertaken contracted research for Sanofi Genzyme, and received honoraria and consulting fees from Sanofi Genzyme. N.-C.L. has served on the registry advisory boards of Sanofi Genzyme and received honoraria from Sanofi Genzyme. All other authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Infantile-onset Pompe disease (IOPD) is a rare and devastating, autosomal recessive lysosomal storage disorder that manifests immediately after birth. In severe IOPD cases, complete/almost-complete acid alpha-glucosidase enzyme deficiency is observed. Considering the rapid progression of the disease, timely diagnosis and treatment are important; even slight delays can remarkably alter the course of the disease. Enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase is safe and beneficial for IOPD patients. However, there is heterogeneity in the patient response to ERT. The factors influencing treatment effectiveness include the patient's age at the time of treatment initiation, pre-existing muscle damage, and cross-reactive immunologic material (CRIM) status at baseline. Immunomodulation along with ERT is the recently developed therapeutic approach that has been included in the therapeutic armamentarium of IOPD for optimizing clinical benefits, particularly in CRIM-negative IOPD patients. However, there is a dearth of published data on the early diagnosis and clinical position of the immunomodulation protocol along with ERT in the treatment of IOPD in the Gulf region., Methods and Results: Expert panel meetings, involving six experts from the Kingdom of Saudi Arabia, Kuwait, Oman, Qatar, and the United Arab Emirates, were convened to develop consensus-based recommendations addressing current diagnostic and management challenges for patients with IOPD in the Gulf region. Furthermore, this consensus guideline may be implemented in clinical practice for the timely diagnosis and management of patients with IOPD., Conclusion: The expert consensus will help clinicians to make appropriate and timely decisions regarding immunomodulation initiation and ERT treatment in IOPD patients in the Gulf region., (© 2022. The Author(s).)

Pompe disease (PD) is an autosomal recessive disorder by a deficiency of acid α-glucosidase (GAA) with intralysosomal glycogen accumulation in multiple tissues. We present the case of a 5-month-old male with hypertrophic cardiomyopathy, hypotony, feeding difficulties, and oxygen requirement since birth. At 3 months of age, he develops heart failure, respiratory impairment, and neurological deterioration. The echocardiogram revealed concentric hypertrophic cardiomyopathy with left-diastolic dysfunction. We found increased creatine-phosphokinase, lactate dehydrogenase, and urinary glucose tetrasaccharide levels, 50% of PAS-positive vacuolated lymphocytes in the peripheral blood smear, and low GAA activity. Sequencing of coding exons and flanking intronic sequences revealed a novel homozygous 4 bp deletion in exon 15 of the GAA gene (c.2066&#95;2069delAGCC/p.Glu689Glyfs*6). IOPD was diagnosed. At 5 months old, we started enzyme replacement therapy with an alpha-alglucosidase of 20 mg/kg weekly and immunomodulation with intravenous immunoglobulin. He developed two cardiorespiratory arrests with subsequent neurologic deterioration, convulsive crisis, and respiratory failure and died at 9 months old. We found the usual PD hallmarks in the heart, striated muscle, and liver but also we found neuronal lesions characterized by cytoplasm vacuolization with PAS-positive granules in the central nervous system and myenteric plexus. We describe a novel GAA gene pathogenic variant with a particular phenotype characterized by classic IOPD and neurologic histopathological findings. Enhancing the knowledge of lysosomal diseases is critical to improving the diagnosis and treatment of these patients., (© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Background: ADVANCE (NCT01526785) presented an opportunity to obtain a more nuanced understanding of motor function changes in treatment-experienced children with Pompe disease receiving 4000L-production-scale alglucosidase alfa for 52 weeks., Objective: To estimate minimal detectable change (MDC) and effect size on Gross Motor Function Measure-88 (GMFM-88) after 52 weeks of 4000L alglucosidase alfa (complete data N =  90)., Methods: The GMFM-88 mean total % score changes, MDC, and effect size were analyzed post hoc by Pompe Motor Function Level at enrollment, age groups at enrollment, and fraction of life on pre-study 160L-production-scale alglucosidase alfa., Results: Overall, participants aged &lt; 2 years surpassed MDC at Week 52 (change [mean±standard deviation] 21.1±14.1, MDC range 5.7-13.3, effect size 1.1), whereas participants aged≥2 years did not attain this (change -0.9±15.3, MDC range 10.8-25.2, effect size -0.03). In participants aged &lt; 2 years, improvements surpassed the MDC for walkers (change 17.1±13.3, MDC range 3.0-6.9, effect size 1.7), supported standers (change 35.2±18.0, MDC range 5.9-13.7, effect size 1.8) and sitters (change 24.1±12.1, MDC range 2.6-6.2, effect size 2.7). Age-independent MDC ranges were only attained by walkers (change 7.7±12.3, MDC range 6.4-15.0, effect size 0.4) and sitters (change 9.9±17.2, MDC range 3.3-7.7, effect size 0.9)., Conclusions: These first GMFM-88 minimal-detectable-change estimates for alglucosidase alfa-treated Pompe disease offer utility for monitoring motor skills., Trial Registration: ClinicalTrials.gov; NCT01526785; Registered 6 February 2012; https://clinicaltrials.gov/ct2/show/NCT01526785.

Background: Infantile-onset Pompe disease (IOPD) is the most severe phenotype of a lysosomal storage disorder caused by acid alpha-glucosidase (GAA) deficiency. An enzymatic newborn screening (NBS) program started regionally in Japan in 2013 for early enzyme replacement therapy (ERT). We report the ERT responses of the first NBS-identified Japanese IOPD case and of another case diagnosed prior to NBS, to discuss the problems of promptly starting ERT in Japan., Methods: Acid alpha-glucosidase activity was measured by fluorometric assay in both patients. The diagnosis of IOPD was confirmed by next-generation followed by Sanger-method sequencing (patient 1) or direct sequencing of polymerase chain reaction (PCR)-amplified products (patient 2) of the GAA gene., Results: A female infant identified by NBS had a novel out-of-frame (p.F181Dfs*6) variant and a reported pathogenic (p.R600C) variant, along with two pseudodeficiency variants. Enzyme replacement therapy was started at age 58 days when the infant had increased serum levels of creatine kinase and slight myocardial hypertrophy. Clinical and biochemical markers improved promptly. She has been alive and well without delayed development at age 14 months. Patient 2, a Japanese male, received a diagnosis of IOPD at age 5 months before the NBS era. He had a homozygotic variant of GAA (p.R608X), later registered as a cross-reactive immunological material (CRIM)-negative genotype, and developed a high titer of anti-rhGAA antibodies. The patient has survived myocardial hypertrophy with continuous respiratory support for 12 years of ERT., Conclusions: Enzyme replacement therapy should not be delayed over the age of 2 months for reversible cardiac function, although CRIM-negative cases may hamper turnaround time reduction., (© 2022 Japan Pediatric Society.)

The addition of Pompe disease (PD) and other conditions with later-onset forms to newborn screening (NBS) in the United States (US) has been controversial. NBS technology cannot discern infantile-onset PD (IOPD) from later-onset PD (LOPD) without clinical follow-up. This study explores genetic health care practitioners' (HCPs) experiences and challenges providing NBS patient care throughout the US and their resultant opinions on NBS for PD. An online survey was distributed to genetic counselors, geneticists, NBS follow-up care coordinators, and nurse practitioners caring for patients with positive NBS results for PD. Analysis of 78 surveys revealed the majority of participating HCPs support inclusion of PD on NBS. Almost all HCPs (93.3%) feel their state has sufficient resources to provide follow-up medical care for IOPD; however, only three-fourths (74.6%) believed this for LOPD. Common barriers included time lag between NBS and confirmatory results, insurance difficulties for laboratory testing, and family difficulties in seeking medical care. HCPs more frequently encountered barriers providing care for LOPD than IOPD (53.9% LOPD identified ≥3 barriers, 31.1% IOPD). HCPs also believe creation of a population of presymptomatic individuals with LOPD creates a psychological burden on the family (87.3% agree/strongly agree), unnecessary medicalization of the child (63.5% agree/strongly agree), and parental hypervigilance (68.3% agree/strongly agree). Opinions were markedly divided on the use of reproductive benefit as a justification for NBS. Participants believe additional education for pediatricians and other specialists would be beneficial in providing care for patients with both IOPD and LOPD, in addition to the creation of evidence-based official guidelines for care and supportive resources for families with LOPD., Competing Interests: Declaration of competing interest Laura Davids, MMSc, CGC, Yuxian Sun, MPH, Reneé Moore, Ph.D., and Angela Wittenauer, MSN, FNP-C, RN, have no conflicts of interest to report. Emily Lisi, MS, CGC, has received research support from Sanofi Genzyme, Pfizer, and Shire Takeda, as well as lecturers' honoraria from Sanofi Genzyme. These activities were monitored and in compliance with conflict of interest policies at Emory University. William Wilcox, MD, Ph.D, is a consultant to Sanofi-Genzyme and Amicus Therapeutics and has received research support from both companies. These activities were monitored and in compliance with conflict of interest policies at Emory University. Nadia Ali, Ph.D., has received research support from Sanofi Genzyme, Shire Takeda, BioMarin, Amicus, and Pfizer, as well as lecturers' honoraria from Sanofi Genzyme, BioMarin, Amicus, and Vitaflo. These activities are monitored and in compliance with conflict of interest policies at Emory University., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Studies suggest that enzyme-replacement therapy (ERT) is crucial to the survival of patients with infantile-onset Pompe disease (IOPD). Hearing impairment (HI) is one of the clinical sequelae observed in long-term survivors. However, the benefits of early ERT for hearing outcomes have not yet been reported. This study aimed to investigate the impact of early ERT on IOPD patients., Methods: This retrospective longitudinal study recruited IOPD patients who were referred by newborn screening for confirmatory diagnosis based on our rapid diagnostic criteria and received early ERT treatment between January 1, 2010, and January 31, 2018. The hearing test battery included a tympanogram, otoacoustic emission, auditory brainstem evoked response (ABR), pure-tone audiometry or conditioned play audiometry., Results: Nineteen patients with IOPD were identified, 6 of whom had hearing impairment (HI); 1 had conductive HI, 2 had sensorineural HI (one had bilateral mild HI and one had mild HI in a single ear) and 1 had moderate mixed-type HI. Two patients failed the newborn screening test and had mild HI in the ABR. The mean age of the initial time to ERT was 11.05 ± 4.31 days, and the HI rate was 31.6% (6/19)., Conclusion: Our study is the largest cohort to show the characteristic hearing outcomes of IOPD patients after ERT. Early ERT within 2 weeks after birth may contribute to better hearing outcomes. Clinicians should be vigilant in testing for the hearing issues associated with IOPD and should intervene early if any HI is detected., (© 2021. The Author(s).)

Objectives: To evaluate the clinical and molecular spectrum, and factors affecting clinical outcome of patients in India diagnosed with infantile-onset Pompe disease (IOPD)., Study Design: In this multicenter, cross-sectional study, we evaluated the records of 77 patients with IOPD to analyze their clinical course, outcomes, and factors influencing the outcomes., Results: Of the 77 patients with IOPD, phenotype data were available in 59; 46 (78%) had the classic phenotype. Overall, 58 of 77 (75%) and 19 of 77 (25%) patients were symptomatic before and after age 6 months, respectively. Alpha-glucosidase gene variant analysis available for 48 patients (96 alleles) showed missense variants in 49 alleles. Cross-reactive immunologic material (CRIM) status could be determined or predicted in 44 of 48 patients. In total, 32 of 44 patients (72%) were CRIM-positive, and 12 of 44 patients (27%) were CRIM-negative. Thirty-nine cases received enzyme-replacement therapy (ERT), alglucosidase alfa, and 38 patients never received ERT. Median age at initiation of ERT was 6.5 months. Response to ERT was better in babies who had CRIM-positive, non-classic IOPD., Conclusions: This study highlights the clinical spectrum of IOPD in India and provides an insight on various factors, such as undernutrition, feeding difficulties, and recurrent respiratory infection, as possible factors influencing clinical outcomes in these patients. The study also reiterates the importance of raising awareness among clinicians about the need for early diagnosis and timely treatment of IOPD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Enzyme replacement therapy in infantile onset Pompe disease has led to a new phenotype with features not known in the pre-enzyme replacement therapy era. We investigated the origin of a rapidly emerging and severe weakness of the foot dorsiflexors in a 7-year-old boy after 6.5 years of enzyme replacement therapy. Electroneurography yielded normal findings except low compound muscle action potentials of the extensor digitorum brevis muscles after stimulation of the peroneal nerves. Electromyography of the tibial muscle demonstrated a myopathic pattern. Tibial muscle, sural nerve, and skin biopsy showed a myopathy with empty and glycogen containing vacuoles, a mild loss of myelinated and unmyelinated axons, and a moderately reduced intraepidermal nerve fiber density. These findings provide evidence for a severe distal muscle involvement and a mild sensory neuropathy evolving during the course of disease after long-term enzyme replacement therapy, thereby expanding the new emerging phenotype of infantile onset Pompe disease., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Infantile-onset Pompe disease is a lysosomal storage disorder characterised with hypertrophic cardiomyopathy, respiratory insufficiency, and hypotonia. Dilated cardiomyopathy is an extremely rare and curable complication of nutritional hypocalcaemic rickets. A 3-month-old female infant was referred to our paediatric ICU with a 4-day history of fatigue, tachypnoea, tachycardia, hypoxia, and respiratory failure. According to the laboratory, radiology, and echocardiography findings, she was first diagnosed with nutritional hypocalcaemic rickets-related dilated cardiomyopathy, but vitamin D and elementary calcium supplementation unmasked the underlying infantile-onset Pompe disease. Nutritional hypocalcaemic rickets and infantile-onset Pompe disease must always be kept in mind among the causes of concomitant dilated cardiomyopathy and hypertrophic cardiomyopathy.

Introduction: The aim of this study was to evaluate the muscle MRI pattern of 9 patients (median age: 6.5 ± 2.74 years) affected by classic infantile-onset Pompe disease who were treated with enzyme replacement therapy., Methods: We performed and qualitatively scored T1-weighted (T1-w) sequences of the facial, shoulder girdle, paravertebral, and lower limb muscles and short-tau inversion recovery (STIR) sequences of the lower limbs using the Mercuri and Morrow scales, respectively., Results: On T1-w images, mild (grade 1) or moderate (grade 2) involvement was found in the tongue in 6 of 6 patients and in the adductor magnus muscle in 6 of 9. STIR hyperintensity was detected in all areas examined and was categorized as limited to mild in 5 of 8 patients., Conclusions: On T1-w sequences, mild/moderate adipose substitution in the adductor magnus and tongue muscles was documented. STIR edema-like alterations of thigh and calf muscles are novel findings. Correlations with biopsy findings and clinical parameters are needed to fully understand these findings. Muscle Nerve 55: 841-848, 2017., (© 2016 Wiley Periodicals, Inc.)

Background: Patients with infantile-onset Pompe disease (IOPD) can be treated by recombinant human acid alpha glucosidase (rhGAA) replacement beginning at birth with excellent survival rates, but they still commonly present with speech disorders. This study investigated the progress of speech disorders in these early-treated patients and ascertained the relationship with treatments., Methods: Speech disorders, including hypernasal resonance, articulation disorders, and speech intelligibility, were scored by speech-language pathologists using auditory perception in seven early-treated patients over a period of 6 years. Statistical analysis of the first and last evaluations of the patients was performed with the Wilcoxon signed-rank test., Results: A total of 29 speech samples were analyzed. All the patients suffered from hypernasality, articulation disorder, and impairment in speech intelligibility at the age of 3 years. The conditions were stable, and 2 patients developed normal or near normal speech during follow-up. Speech therapy and a high dose of rhGAA appeared to improve articulation in 6 of the 7 patients (86%, p = 0.028) by decreasing the omission of consonants, which consequently increased speech intelligibility (p = 0.041). Severity of hypernasality greatly reduced only in 2 patients (29%, p = 0.131)., Conclusion: Speech disorders were common even in early and successfully treated patients with IOPD; however, aggressive speech therapy and high-dose rhGAA could improve their speech disorders., (Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Most patients with infantile-onset Pompe disease die in early infancy before beginning enzyme replacement therapy, which has made it difficult to evaluate the impact of Pompe disease on cognitive development. Patients with infantile-onset Pompe disease can survive with enzyme replacement therapy, and physicians can evaluate cognitive development in these patients. We established an effective newborn screening program with quick clinical diagnostic criteria. Cognitive and motor development were evaluated using the Bayley Scales of Infant and Toddler Development-Third Edition at 6, 12, and 24 months of age. The patients who were treated very early demonstrate normal cognitive development with no significant change in cognition during this period (P = .18 > .05). The cognitive development was positively correlated with motor development (r = 0.533, P = .011). The results indicated that very early enzyme replacement therapy could protect cognitive development in patients with infantile-onset Pompe disease up to 24 months of age., (© The Author(s) 2016.)

Pompe disease is caused by a deficiency of acid α-glucosidase (GAA; EC, 3.2.1.20), and the infantile-onset form is rapidly fatal if left untreated. However, recombinant human GAA (rhGAA) enzyme replacement therapy (ERT) extends survival for infantile Pompe patients. Although cross-reactive immunologic material (CRIM)-negative patients, who lack detectable endogenous GAA, mount an immune response to rhGAA that renders the therapy ineffective, timely induction of immune tolerance in these patients may improve clinical outcomes. Previously, CRIM status has been determined by Western blot analysis in cultured skin fibroblasts, a process that can take a few weeks. We present a blood-based CRIM assay that can yield results within 48 to 72 h. Results from this assay have been confirmed by GAA Western blot analysis in fibroblasts or by GAA sequencing in a small number of Pompe disease patients. Rapid classification of CRIM status will assist in identifying the most effective treatment course and minimizing treatment delays in patients with infantile-onset Pompe disease., (© 2013.)

The aim of this study was to: (a) analyze the results of a large-scale newborn screening program for Pompe disease, and (b) establish an effective diagnostic protocol to obtain immediate, valid diagnosis of infantile-onset Pompe disease (IOPD) to promote earlier treatment and better outcomes. In this study, 402,281 newborns were screened for Pompe disease from January 1, 2008 to May 1, 2012. Infants with low acid α-glucosidase (GAA) activity were referred to Taipei Veterans General Hospital for diagnostic confirmation. Physical examination, biochemical parameter (creatine kinase [CK], alanine transaminase, aspartate aminotransferase, and lactate dehydrogenase), and echocardiogram assessments were performed immediately to effectively differentiate IOPD from suspected late-onset Pompe disease (LOPD) or false-positive cases with pseudodeficiency mutation. Six infants with IOPD all presented with hypotonia, extremely low GAA enzyme activity (≤0.5 µmol/L/hr) in initial dried blood spot analysis, high CK (≥250 U/L), and high left ventricular mass index (LVMI, ≥80 g/m(2)). By analyzing these parameters, IOPD was distinguished effectively and immediately from suspected LOPD and false-positive cases. Except for the first referred case, five of the infants with IOPD received first-time enzyme replacement therapy (ERT) within 4 hr of admission and exhibited marked improvement. Our findings indicate that certain clinical manifestations (hypotonia, high CK, enlarged LVMI, and extremely low GAA enzyme activity in initial dried blood spot analysis) can help in the rapid and effective differentiation of patients with IOPD from other patient with low GAA activity. Such differentiation allows for the early application of first-time ERT and leads to better outcomes., (© 2013 Wiley Periodicals, Inc.)

PurposeTo characterize clinical characteristics and genotypes of patients in the ADVANCE study of 4000 L-scale alglucosidase alfa (NCT01526785), the largest prospective United States Pompe disease cohort to date.MethodsPatients aged ≥1 year with confirmed Pompe disease previously receiving 160 L alglucosidase alfa were eligible. GAA genotypes were determined before/at enrollment. Baseline assessments included histories/physical exams, Gross Motor Function Measure-88 (GMFM-88), pulmonary function tests, and cardiac assessments.ResultsOf 113 enrollees (60 male/53 female) aged 1-18 years, 87 had infantile-onset Pompe disease (IOPD) and 26 late-onset (LOPD). One hundred eight enrollees with GAA genotypes had 215 pathogenic variants (220 including combinations): 118 missense (4 combinations), 23 splice, 35 nonsense, 34 insertions/deletions, 9 duplications (1 combination), 6 other; c.2560C>T (n = 23), c.-32-13T>G (n = 13), and c.525delT (n = 12) were most common. Four patients had previously unpublished variants, and 14/83 (17%) genotyped IOPD patients were cross-reactive immunological material-negative. All IOPD and 6/26 LOPD patients had cardiac involvement, all without c.-32-13T>G. Thirty-two (26 IOPD, 6 LOPD) were invasively ventilated. GMFM-88 total %scores (mean ± SD, median, range): overall 46.3 ± 33.0% (47.9%, 0.0-100.0%), IOPD 41.6 ± 31.64% (38.9%, 0.0-99.7%), LOPD: 61.8 ± 33.2 (70.9%, 0.0-100.0%).ConclusionADVANCE, a uniformly assessed cohort comprising most US children and adolescents with treated Pompe disease, expands understanding of the phenotype and observed variants in the United States.

White matter (WM) abnormalities and ventricular enlargement in brain MRI are well-known features in infantile-onset Pompe disease (IOPD) in the era of enzyme replacement therapy (ERT). In this multicentric observational retrospective study, we report a small cohort of IOPD subjects under ERT treatment (n = 5, median age at MRI = 7.4 years, median period of treatment = 85 months) that showed the classic features of extensive supratentorial WM abnormalities but also unusual findings such as early infratentorial WM abnormalities and late supratentorial U-fiber involvement. Given the recent implementation of ERT and the rarity of the disease, a complete spectrum of presentation and understanding of progressive pathology in the brain of IOPD subjects in treatment remains underacknowledged. The availability of long-term follow-up of IOPD subjects under ERT treatment allows a better insight into the evolution of brain abnormalities in such disease. [ABSTRACT FROM AUTHOR]

Background: Infantile-onset Pompe disease is a rare genetic and lethal disorder which is caused by the lack of acid alpha-glucosidase activity (GAA). The aim of our study was to identify the demographic and clinical characteristics, and natural history of these patients. Materials and Methods: In this retrospective study, clinical file of 15 patients diagnosed with infantile-onset Pompe disease whose symptoms started before the age of 12 months were studied. Diagnosis was based on clinical history, physical examination and diagnostic parameters in chest X-ray, echocardiogram, electrocardiogram and biochemical tests after rule out the other metabolic and neuromuscular disorders. Results: Sixty percent of the patients were male and 40% were female. The mean age at the onset of symptoms was 78 days (range: 3-150 days). Most frequent clinical and paraclinical symptoms were cardiomegaly, hypotonia, hyporeflexia, macroglossia, failure to thrive, hepatomegaly, and feeding problems, respectively. The mean age at the time of death was 5.96 months (range: 4-8 months), and all patients died before one year of age. Muscle enzymes including AST, ALT, LDH, and CPK were elevated in all patients. Due to the lack of availability, enzyme replacement therapy was not possible for any patient. Conclusion: The study showed that despite the supportive measures and no specific treatment, the clinical course is not significantly different with similar studies and the overall prognosis of this form of disease is very poor and disappointing. [ABSTRACT FROM AUTHOR]

Pompe disease or glycogen storage disease type II is a glycogen storage disorder associated with malfunction of the acid α-glucosidase enzyme ( GAA; EC.3.2.1.3) leading to intracellular aggregations of glycogenin muscles. The infantile-onset type is the most life-threatening form of this disease, in which most of patients suffer from cardiomyopathy and hypotonia in early infancy. In this study, a typical case of Pompe disease was reported in an Iranian patient using molecular analysis of the GAA gene. Our results revealed a new c.1824_1828dupATACG mutation in exon 13 of the GAA gene. In conclusion, with the finding of this novel mutation, the genotypic spectrum of Iranian patients with Pompe disease has been extended, facilitating the definition of disease-related mutations. [ABSTRACT FROM AUTHOR]