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Pompe disease (OMIM #232300), a rare genetic disorder, leads to glycogen buildup in the body due to an enzyme deficiency, particularly harming the heart and muscles. Infantile-onset Pompe disease (IOPD) requires urgent treatment to prevent mortality, but the unavailability of these methods often delays diagnosis. Our study aims to streamline IOPD diagnosis in the UAE using electronic health records (EHRs) for faster, more accurate detection and timely treatment initiation. This study utilized electronic health records from the Abu Dhabi Healthcare Company (SEHA) healthcare network in the UAE to develop an expert rule-based screening approach operationalized through a dashboard. The study encompassed six diagnosed IOPD patients and screened 93,365 subjects. Expert rules were formulated to identify potential high-risk IOPD patients based on their age, particular symptoms, and creatine kinase levels. The proposed approach was evaluated using accuracy, sensitivity, and specificity. The proposed approach accurately identified five true positives, one false negative, and four false positive IOPD cases. The false negative case involved a patient with both Pompe disease and congenital heart disease. The focus on CHD led to the overlooking of Pompe disease, exacerbated by no measurement of creatine kinase. The false positive cases were diagnosed with Mitochondrial DNA depletion syndrome 12-A (SLC25A4 gene), Immunodeficiency-71 (ARPC1B mutation), Niemann-Pick disease type C (NPC1 gene mutation leading to frameshift), and Group B Streptococcus meningitis. The proposed approach of integrating expert rules with a dashboard facilitated efficient data visualization and automated patient screening, which aids in the early detection of Pompe disease. Future studies are encouraged to investigate the application of machine learning methodologies to enhance further the precision and efficiency of identifying patients with IOPD.

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BACKGROUND: Enzyme replacement therapy (ERT) with recombinant human alglucosidase alfa (rhGAA) was approved in Europe in 2006. Nevertheless, data on the long-term outcome of infantile onset Pompe disease (IOPD) patients at school age is still limited. OBJECTIVE: We analyzed in detail cardiac, respiratory, motor, and cognitive function of 15 German-speaking patients aged 7 and older who started ERT at a median age of 5 months. RESULTS: Starting dose was 20 mg/kg biweekly in 12 patients, 20 mg/kg weekly in 2, and 40 mg/kg weekly in one patient. CRIM-status was positive in 13 patients (86.7%) and negative or unknown in one patient each (6.7%). Three patients (20%) received immunomodulation. Median age at last assessment was 9.1 (7.0-19.5) years. At last follow-up 1 patient (6.7%) had mild cardiac hypertrophy, 6 (42.9%) had cardiac arrhythmias, and 7 (46.7%) required assisted ventilation. Seven patients (46.7%) achieved the ability to walk independently and 5 (33.3%) were still ambulatory at last follow-up. Six patients (40%) were able to sit without support, while the remaining 4 (26.7%) were tetraplegic. Eleven patients underwent cognitive testing (Culture Fair Intelligence Test), while 4 were unable to meet the requirements for cognitive testing. Intelligence quotients (IQs) ranged from normal (IQ 117, 102, 96, 94) in 4 patients (36.4%) to mild developmental delay (IQ 81) in one patient (9.1%) to intellectual disability (IQ 69, 63, 61, 3x <55) in 6 patients (54.5%). White matter abnormalities were present in 10 out of 12 cerebral MRIs from 7 patients. CONCLUSION: Substantial motor, cardiac, respiratory, and cognitive deficits are frequent in IOPD long-term survivors who started ERT before 2016. The findings of this study can be valuable as comparative data when evaluating the impact of newer treatment strategies including higher enzyme dosage, immunomodulation, modified enzymes, or early start of treatment following newborn screening.

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BACKGROUND: Studies indicate that doses of alglucosidase alfa (ALGLU) higher than label dose (20 mg/kg every other week) improve clinical outcomes in infantile-onset Pompe disease (IOPD). We investigated data from the Pompe Registry to determine the association between ALGLU dose and survival in IOPD. RESULTS: We included 332 IOPD patients from the Registry as of January 2022 who had cardiomyopathy and were first treated at age < 1 year. We used Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between ALGLU as a time-varying exposure and survival, adjusting for age at first treatment, sex, and cross-reactive immunologic material (CRIM)/immune tolerance induction (ITI) status. Dose was measured as average relative dose received over time (in multiples of label dose, range > 0 to 4 times label dose), current dose, and lagged dose. 81% patients received label dose at treatment initiation. Over time, 52% received a higher dose. Higher ALGLU dose over time was associated with improved survival: adjusted HR 0.40 (95% CI 0.22-0.73, p = 0.003) per 1-unit increase in average relative dose, with similar results for invasive ventilation-free survival (adjusted HR 0.48, 95% CI 0.28-0.84; p = 0.010). The association was consistent in patients first treated before or after 3 months of age and did not vary significantly by CRIM status. Results for current and lagged dose were similar to average dose. CONCLUSIONS: Higher ALGLU doses were associated with significantly improved overall and invasive ventilator-free survival in IOPD. Results were consistent across sensitivity analyses.

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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_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.

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In Infantile Onset Pompe Disease (IOPD), enzyme replacement therapy (ERT) may improve survival, cardiac function, and motor development. However, even with early enzyme replacement therapy, some patients experienced poor response to ERT and abnormal motor milestones that could be due to motor neuron involvement. In this long-term retrospective study, we analyzed concomitant clinical motor outcomes and electroneuromyography (ENMG) findings in patients with IOPD and Juvenile Onset Pompe Disease (JOPD). Twenty-nine pediatric patients were included and 20 surviving were analyzed for neuromotor studies: 12 had IOPD (group 1), 4 had JOPD (group 2) and 4 (group 3) received ERT in the first month of age. Motor nerve conduction studies were mostly normal. Needle EMG performed at diagnosis always indicated the existence of myopathy that responded to ERT. Two IOPD patients (group 1) presenting with mixed motor neuropathy and myopathy displayed a poor outcome and never walked. Two patients became non-walkers (one IOPD patient and one patient of group 3) at respectively 9 and 3 years of age. One JOPD patient is about to lose walking ability. This motor deterioration was associated with the development of a motor neuropathy. Patients older than 10 years of age develop a motor neuropathy. Initial or secondary motor neuron involvement seems to be associated with a poor motor outcome showing that ERT may fail to prevent the accumulation of glycogen in motor neuron. Neurophysiological findings are important to assess severity of motor neuron damage in all Pompe pediatric patients and should be systematically performed.

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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.

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This retrospective observational case series is to evaluate the histopathological findings of drooping eyelids in patients with infantile-onset Pompe disease and assess the feasibility of levator muscle resection combined with conjoint fascial sheath suspension for ptosis correction. It included six patients from a single tertiary referral center with ptosis and infantile-onset Pompe disease between January 1, 2013, and December 31, 2021. They most suffered from recurrent ptosis after initial surgical correction (6/11 eyes, 54.55%). The recurrence rate was high in eyes with levator muscle resection alone (4/6 eyes, 66.67%). No recurrence of ptosis was observed in eyes with levator muscle resection combined with conjoint fascial sheath suspension. The follow-up period was approximately 16-94 months. Histopathological examination revealed that the levator muscle had the most abundant glycogen accumulation-related vacuolar changes, followed by Müller's muscle and extraocular muscles. No vacuolar changes were observed in the conjoint fascial sheath. For patients with infantile-onset Pompe disease-related ptosis, performing levator muscle resection alone is not sufficient, while utilizing conjoint fascial sheath suspension can achieve the desired long-term outcomes with minimal recurrence. These findings may have important implications for the management of ophthalmic complications in patients with infantile-onset Pompe disease.

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Infantile-onset Pompe disease manifests with early signs of cardiomyopathy during the first few days to weeks of life. We present the case of a newborn born via emergency cesarean section with atrial flutter and moderate biventricular hypertrophy who was diagnosed with Pompe disease on New York State newborn screen. Diagnosis was confirmed with repeat leukocyte acid alpha-glucosidase (GAA) enzyme activity, GAA gene sequencing, urine Hex4, and evaluation of Cross-Reactive Immunological Material (CRIM) status. The patient was also found to be persistently neutropenic which to our knowledge has not been previously reported in the literature in association with Pompe disease. This report highlights the impact that newborn screening had on time to diagnosis and initiation of treatment with enzyme replacement therapy. We also discuss how our patient's concurrent neutropenia impacted decision making related to immune tolerance induction prior to starting enzyme replacement therapy.

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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 (r2 = 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.

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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.

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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-1ß) 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.

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Pompe disease (PD) is a progressive neuromuscular disorder caused by a lysosomal acid α-glucosidase (GAA) deficiency. Enzymatic replacement therapy is available, but early diagnosis by newborn screening (NBS) is essential for early treatment and better outcomes, especially with more severe forms. We present results from 7 years of NBS for PD and the management of infantile-onset (IOPD) and late-onset (LOPD) patients, during which we sought candidate predictive parameters of phenotype severity at baseline and during follow-up. We used a tandem mass spectrometry assay for α-glucosidase activity to screen 206,741 newborns and identified 39 positive neonates (0.019%). Eleven had two pathogenic variants of the GAA gene (3 IOPD, 8 LOPD); six carried variants of uncertain significance (VUS). IOPD patients were treated promptly and had good outcomes. LOPD and infants with VUS were followed; all were asymptomatic at the last visit (mean age 3.4 years, range 0.5-5.5). Urinary glucose tetrasaccharide was a useful and biomarker for rapidly differentiating IOPD from LOPD and monitoring response to therapy during follow-up. Our study, the largest reported to date in Europe, presents data from longstanding NBS for PD, revealing an incidence in North East Italy of 1/18,795 (IOPD 1/68,914; LOPD 1/25,843), and the absence of mortality in IOPD treated from birth. In LOPD, rigorous long-term follow-up is needed to evaluate the best time to start therapy. The high pseudodeficiency frequency, ethical issues with early LOPD diagnosis, and difficulty predicting phenotypes based on biochemical parameters and genotypes, especially in LOPD, need further study.

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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 < 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 < 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.

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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.

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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.

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Infantile onset Pompe disease (IOPD) is a rare devastating disease that presents in early infancy with rapidly progressive hypertrophic cardiomyopathy, severe generalized myopathy and death within the first year of life. The emergence of enzyme replacement therapy (ERT) with recombinant human acid alpha glucosidase (rhGAA) has improved the natural course of IOPD with a significant impact on cardiomyopathy but has a more limited effect on the progression of myopathy and consequently the later deterioration of the disease. Possible reasons for reduced ERT efficacy include insufficient enzyme, partial targeting of skeletal muscle and the development of IgG rhGAA antibodies especially in patients who are cross-reactive immunological material (CRIM) negative. We report a CRIM-negative IOPD female patient who started treatment upon diagnosis at 4.5 months with ERT at 20 mg/kg every other week and a course of combined immunomodulation with rituximab, methotrexate and IVIG according to the published Duke protocol and increased ERT within a month to 40 mg/kg/week. Despite initial good clinical response to ERT and immunomodulation, monthly monitoring identified a gradual increase of serum antibody titers to rhGAA necessitating a second course of immunomodulation with bortezomib and maintenance rituximab and methotrexate. A gradual reduction in frequency of immunotherapy was instituted and over a period of 14 months was discontinued. Serum anti-rhGAA antibody titers remained negative for 5 months since cessation of immunomodulation and the patient is now immune tolerant with recovery of CD19. At the age of 30 months the patient is walking independently and has normal cardiac function and anatomy. We recommend initiating ERT at 40 mg/kg/week in CRIM-negative IOPD patients, concomitant with immunomodulation and monthly monitoring of serum anti-rhGAA IgG titers upon confirmation of the diagnosis.

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BACKGROUND: Pompe disease has a broad disease spectrum, including infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD) forms. It is a type of glycogen storage disorder belonging to autosomal recessive genetic disease, for an estimated incidence of 1/40000 among the neonatal population. In severe cases, the natural course is characterized by death due to cardiopulmonary failure in the first year after birth. However, the clinical outcomes have improved since the emergence of enzyme replacement therapy (ERT) was widely used. CASE SUMMARY: The reported female case in China was an atypical IOPD, which demonstrates an unusual presentation of glycogen accumulation syndrome type II without obvious skeletal muscle involvement, and reviewed physical examination, biochemical examinations, chest radiograph, and acid α-glucosidase (GAA) mutation analysis. After 4-mo specific ERT, the case received 12-mo follow-up. Moreover, the patient has obtained a very good prognosis under ERT. CONCLUSION: For the atypical IOPD patients, early diagnosis and treatment may contribute to good prognosis.

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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_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.

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Pompe disease (PD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of acid α-1,4-glucosidase enzyme (GAA). PD has two forms, namely the infantile-onset and the late-onset form. In untreated cases, infantile-onset form usually leads to cardio-respiratory failure and death in the first year of life. Herein, we report a newborn with infantile-onset PD characterized by muscular hypotonia, respiratory distress, hypertrophic cardiomyopathy, hepatomegaly, elevated serum enzyme levels of aspartate aminotransferase of 117 IU/L (three times the normal value), alanine aminotransferase of 66 IU/L (1.8 times the normal value), lactate dehydrogenase of 558 IU/L (1.2 times the normal value), and creatine kinase >5,000 IU/L (16 times the normal value). Dried blood spot testing was performed and revealed decreased GAA enzymatic activity (0.07 nmol/mL/h, normal 0.93-7.33 nmol/mL/h). GAA gene analysis performed for confirming the diagnosis showed homozygous mutation c.896T >C (p.Leu299Pro). Initiation of enzyme replacement therapy (ERT) (ERT; 20 mg/kg, once every week) at 28 days of age resulted in weaning off from respiratory support within 1 week after treatment, normalization of cardiac abnormalities, and normal neuromotor development in the 16th month of age. Early diagnosis and early treatment with ERT, especially in the neonatal period, is of great importance to improve cardiac function and motor development in infantile-onset PD.

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BACKGROUND: Enzyme replacement therapy (ERT) with alglucosidase alfa improves the prospect of patients with infantile-onset Pompe disease (IOPD). However, a progressive decline has been reported. Objective quantification of the response to ERT when assessing newer strategies is warranted. METHODS: This combined retrospective-prospective study assessed the acute and long-term effects of ERT on exercise in IOPD patients. Evaluation included cardiopulmonary exercise testing (CPET), 6-min walking test (6MWT), spirometry, motor function test (GMFM-88) and enzyme blood levels. RESULTS: Thirty-four CPETs (17 pre- and 17 two days-post ERT) over variable follow-up periods were performed in four patients. Two days following ERT, blood enzyme levels increased (median, 1.22 and 10.15 µmol/L/h (p = 0.003)). However, FEV1, FVC and GMFM-88, the median 6MWD and the peak VO2 were unchanged. Long-term evaluations showed stabilization in young patients but progressive deterioration in adolescents. Clinical deterioration was associated with more pronounced deterioration in peak VO2 followed in the decreasing order by 6MWD, FVC and GMFM-88. CONCLUSIONS: The peak VO2 and 6MWD might serve as more sensitive markers to assess clinical deterioration. More studies are needed to clarify the sensitivity of the peak VO2 and 6MWT for quantification of individualized response. This may be important when assessing newer strategies and formulations in IOPD.