Intracranial vasculopathy: an important organ damage in young adult patients with late-onset Pompe disease.

BACKGROUND: Late-onset Pompe disease (LOPD) is mainly characterized by progressive limb-girdle muscle weakness and respiratory impairment, whereas stroke and cerebrovascular abnormalities have been insufficiently studied in LOPD. This study aimed to evaluate the frequency and pattern of intracranial artery and brain parenchyma abnormalities in LOPD patients. RESULTS: Neuroimaging data from 30 Chinese adult LOPD patients were collected from our center. Seven patients (7/30) had acute cerebral infarction or hemorrhage. Brain magnetic resonance angiography (MRA) or computed tomography angiography (CTA) revealed artery abnormalities in 23 patients (23/30). Dilative arteriopathy was found in 19 patients (19/30), with vertebrobasilar dolichoectasia found in 17 patients and dilatation of the anterior circulation arteries found in 8 patients. The maximum diameter of the basilar artery was correlated with disease duration (p < 0.05). In addition, aneurysms (7/30) and fenestrations (3/30) were discovered. There were 14 patients with arterial stenosis (14/30), and both anterior and posterior circulation involvement occurred in 9 patients (9/14). Stenosis and dilative arteriopathy simultaneously occurred in 10 patients (10/30). White matter hyperintensities were present in 13 patients (13/28). Microbleeds, predominantly located in the cerebellum and brainstem, were detected in 7 patients (7/22) via susceptibility-weighted imaging. CONCLUSIONS: Intracranial vasculopathy involving both large arteries and small vessels is an important organ damage in LOPD patients. LOPD should be considered a key differential diagnosis in young adults with cryptogenic stroke, and a series of imaging evaluations of the brain and intracranial blood vessels is recommended as a routine workup in adult LOPD patients.

Enzyme replacement therapy and immunotherapy lead to significant functional improvement in two children with Pompe disease: a case report.

BACKGROUND: Pompe disease, a rare autosomal recessive disorder caused by acid alpha-glucosidase deficiency, results in progressive glycogen accumulation and multisystem dysfunction. Enzyme replacement therapy with recombinant human acid alpha-glucosidase is the standard of care; however, some patients develop anti-recombinant human acid alpha-glucosidase antibodies, leading to reduced efficacy. This case report presents two infants with early-onset Pompe disease who developed IgG antibodies to enzyme replacement therapy and were subsequently treated with methotrexate, highlighting the importance of monitoring antibody development and exploring alternative therapeutic approaches. CASE PRESENTATION: Patient 1, a 10-month-old female from Bogota, Colombia, presented with generalized hypotonia, macroglossia, hyporeflexia, and mild left ventricular hypertrophy. Diagnostic tests confirmed early-onset Pompe disease, and enzyme replacement therapy was started at 12 months. Due to a lack of improvement and high anti-recombinant human acid alpha-glucosidase IgG antibody titers (1:1800), methotrexate was started at 18 months. After 8 months of combined therapy, antibody titers were negative and significant improvement in motor function was observed using the Gross Motor Function Measure 88. Patient 2, a 7-year-old female from Bogota, Colombia, was diagnosed with early-onset Pompe disease at 12 months and initiated enzyme replacement therapy. At 5 years of age, she experienced frequent falls and grip strength alterations. Functional tests revealed motor development delay, generalized hypotonia, and positive anti-recombinant human acid alpha-glucosidase IgG antibody titers (6400). Methotrexate was initiated, leading to a reduction in falls and antibody titers (3200) after 6 months, with no adverse events or complications. Motor function improvement was assessed using the Motor Function Measurement 32. CONCLUSIONS: The presented cases highlight the importance of monitoring patients for anti-recombinant human acid alpha-glucosidase antibody development during enzyme replacement therapy and the potential benefit of methotrexate as an immunomodulatory agent in early-onset Pompe disease. Early diagnosis and timely initiation of enzyme replacement therapy, combined with prophylactic immune tolerance induction, may improve clinical outcomes and reduce the development of anti-recombinant human acid alpha-glucosidase antibodies. The cases also highlight the importance of objective motor function assessment tools, such as Gross Motor Function Measure 88 and Motor Function Measurement 32, in assessing treatment response. Further research is needed to optimize treatment regimens, monitor long-term effects, and address the current limitations of enzyme replacement therapy in Pompe disease.

Mutational spectrum and genotype-phenotype correlation in Mexican patients with infantile-onset and late-onset Pompe disease.

BACKGROUND: Pompe Disease (PD) is a metabolic myopathy caused by variants in the GAA gene, resulting in deficient enzymatic activity. We aimed to characterize the clinical features and related genetic variants in a series of Mexican patients. METHODS: We performed a retrospective study of clinical records of patients diagnosed with LOPD, IOPD or pseudodeficiency. RESULTS: Twenty-nine patients were included in the study, comprising these three forms. Overall, age of symptom onset was 0.1 to 43 years old. The most frequent variant identified was c.-32-13T>G, which was detected in 14 alleles. Among the 23 different variants identified in the GAA gene, 14 were classified as pathogenic, 5 were likely pathogenic, and 1 was a variant of uncertain significance. Two variants were inherited in cis arrangement and 2 were pseudodeficiency-related benign alleles. We identified two novel variants (c.1615 G>A and c.1076-20_1076-4delAAGTCGGCGTTGGCCTG). CONCLUSION: To the best of our knowledge, this series represent the largest phenotypic and genotypic characterization of patients with PD in Mexico. Patients within our series exhibited a combination of LOPD and IOPD associated variants, which may be related to genetic diversity within Mexican population. Further population-wide studies are required to better characterize the incidence of this disease in Mexican population.

Start, switch and stop (triple-S) criteria for enzyme replacement therapy of late-onset Pompe disease: European Pompe Consortium recommendation update 2024.

BACKGROUND AND PURPOSE: Two novel enzyme replacement therapies (ERTs), studied in phase 3 trials in late-onset Pompe patients, reached marketing authorization by the European Medicines Agency in 2022 and 2023. The European Pompe Consortium (EPOC) updates and extends the scope of the 2017 recommendations for starting, switching and stopping ERT. METHODS: The European Pompe Consortium consists of 25 neuromuscular and metabolic experts from eight European countries. This update was performed after an in-person meeting, three rounds of discussion and voting to provide a consensus recommendation. RESULTS: The patient should be symptomatic, that is, should have skeletal muscle weakness or respiratory muscle involvement. Muscle magnetic resonance imaging findings showing substantial fat replacement can support the decision to start in a patient-by-patient scenario. Limited evidence supports switching ERT if there is no indication that skeletal muscle and/or respiratory function have stabilized or improved during standard ERT of 12 months or after severe infusion-associated reactions. Switching of ERT should be discussed on a patient-by-patient shared-decision basis. If there are severe, unmanageable infusion-associated reactions and no stabilization in skeletal muscle function during the first 2 years after starting or switching treatment, stopping ERT should be considered. After stopping ERT for inefficacy, restarting ERT can be considered. Six-monthly European Pompe Consortium muscle function assessments are recommended. CONCLUSIONS: The triple-S criteria on ERT start, switch and stop include muscle magnetic resonance imaging as a supportive finding and the potential option of home infusion therapy. Six-monthly long-term monitoring of muscle function is highly recommended to cover insights into the patient's trajectory under ERT.

Generation of two induced pluripotent stem cell lines (HIMRi006-A and HIMRi007-A) from Pompe patients with infantile and late disease onset.

Here we present the generation of HIMRi006-A and HIMRi007-A Pompe disease (PD) patient derived human induced pluripotent stem cell (hiPSC) lines. HIMRi006-A represents an infantile onset disease (IOPD) phenotype caused by a homozygous c.307 T > G mutation in the GAA gene. HIMRi007-A is characterized by heterozygous mutations c.-32-13 T > G/c.1716C > G and is associated with an adult onset of disease symptoms (LOPD). Both lines are generated via lentiviral expression of OCT4, SOX2, KLF4, and c-MYC. The lines display a typical embryonic stem cell morphology, express pluripotency markers, retain a normal karyotype (46, XX/XY) and have the differentiation capacity in all three germ layers. Altogether, both lines provide a resource tool to the community for future in depth molecular studies of PD pathomechanism.

Failure of Autophagy in Pompe Disease.

Autophagy is an evolutionarily conserved lysosome-dependent degradation of cytoplasmic constituents. The system operates as a critical cellular pro-survival mechanism in response to nutrient deprivation and a variety of stress conditions. On top of that, autophagy is involved in maintaining cellular homeostasis through selective elimination of worn-out or damaged proteins and organelles. The autophagic pathway is largely responsible for the delivery of cytosolic glycogen to the lysosome where it is degraded to glucose via acid α-glucosidase. Although the physiological role of lysosomal glycogenolysis is not fully understood, its significance is highlighted by the manifestations of Pompe disease, which is caused by a deficiency of this lysosomal enzyme. Pompe disease is a severe lysosomal glycogen storage disorder that affects skeletal and cardiac muscles most. In this review, we discuss the basics of autophagy and describe its involvement in the pathogenesis of muscle damage in Pompe disease. Finally, we outline how autophagic pathology in the diseased muscles can be used as a tool to fast track the efficacy of therapeutic interventions.

Response to Comments on "Increasing Enzyme Mannose-6-Phosphate Levels but Not Miglustat Coadministration Enhances the Efficacy of Enzyme Replacement Therapy in Pompe Mice".

We thank Dr. Weimer and her colleagues for their comments related to our recent work (Anding et al., 2023) and are grateful for the opportunity to further discuss the importance of efficient lysosomal targeting of enzyme-replacement therapies (ERT) for the treatment of Pompe disease. Patients with Pompe disease have mutations in the gene that encodes for acid α glucosidase (GAA), a lysosomal enzyme necessary for the breakdown of glycogen. The first-generation ERT, alglucosidase alfa, provides a lifesaving therapy for the severe form of the disease (infantile onset Pompe disease) and improves or stabilizes respiratory and motor function in patients with less severe disease (late onset Pompe disease). Despite these gains, significant unmet need remains, particularly in patients who display respiratory and motor decline following years of treatment. Poor tissue uptake and lysosomal targeting via inefficient binding of the cation-independent mannose-6-phosphate (M6P) receptor (CIMPR) in skeletal muscle contributed to this suboptimal treatment response, prompting the development of new ERTs with increased levels of M6P.

Optimizing treatment outcomes: immune tolerance induction in Pompe disease patients undergoing enzyme replacement therapy.

Introduction: Pompe disease, a lysosomal storage disorder, is characterized by acid α-glucosidase (GAA) deficiency and categorized into two main subtypes: infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). The primary treatment, enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), faces challenges due to immunogenic responses, including the production of anti-drug antibody (ADA), which can diminish therapeutic efficacy. This study aims to assess the effectiveness of immune tolerance induction (ITI) therapy in cross-reactive immunologic material (CRIM)-positive Pompe disease patients with established high ADA levels. Method: In a single-center, open-label prospective study, we assessed ITI therapy's efficacy in Pompe disease patients, both IOPD and LOPD, with persistently elevated ADA titers (≥1:12,800) and clinical decline. The ITI regimen comprised bortezomib, rituximab, methotrexate, and intravenous immunoglobulin. Biochemical data, biomarkers, ADA titers, immune status, and respiratory and motor function were monitored over six months before and after ITI. Results: This study enrolled eight patients (5 IOPD and 3 LOPD). After a 6-month ITI course, median ADA titers significantly decreased from 1:12,800 (range 1:12,800-1:51,200) to 1:1,600 (range 1:400-1:12,800), with sustained immune tolerance persisting up to 4.5 years in some cases. Serum CK levels were mostly stable or decreased, stable urinary glucose tetrasaccharide levels were maintained in four patients, and no notable deterioration in respiratory or ambulatory status was noted. Adverse events included two treatable infection episodes and transient symptoms like numbness and diarrhea. Conclusion: ITI therapy effectively reduces ADA levels in CRIM-positive Pompe disease patients with established high ADA titers, underscoring the importance of ADA monitoring and timely ITI initiation. The findings advocate for personalized immunogenicity risk assessments to enhance clinical outcomes. In some cases, prolonged immune suppression may be necessary, highlighting the need for further studies to optimize ITI strategies for Pompe disease treatment. ClinicalTrials.gov NCT02525172; https://clinicaltrials.gov/study/NCT02525172.

Real-life effectiveness 1 year after switching to avalglucosidase alfa in late-onset Pompe disease patients worsening on alglucosidase alfa therapy: A French cohort study.

INTRODUCTION: Late-onset Pompe disease (LOPD) is characterized by a progressive myopathy resulting from a deficiency of acid α-glucosidase enzyme activity. Enzyme replacement therapy has been shown to be effective, but long-term treatment results vary. Avalglucosidase alfa demonstrated non-inferiority to alglucosidase alfa in a phase 3 study, allowing in France compassionate access for advanced LOPD patients unresponsive to alglucosidase alfa. METHODS: Data from the French Pompe registry were analyzed for patients who benefited from a switch to avalglucosidase alfa with at least 1 year of follow-up. Respiratory (forced vital capacity [FVC]) and motor functions (Six-Minute Walk Test [6MWT]) were assessed before and 1 year after switching. Individual changes in FVC and 6MWT were expressed as slopes and statistical analyses were performed to compare values. RESULTS: Twenty-nine patients were included (mean age 56 years, 11 years of prior treatment). The FVC and 6MWT values remained stable. The individual analyses showed a stabilization of motor worsening: -1 m/year on the 6MWT after the switch versus -63 m/year the year before the switch (i.e., a worsening of 33%/year before vs. an improvement of 3%/year later). Respiratory data were not statistically different. DISCUSSION: At the group level, gait parameters improved slightly with a stabilization of previous worsening, but respiratory parameters showed limited changes. At the individual level, results were discordant, with some patients with a good motor or respiratory response and some with further worsening. CONCLUSION: Switching to avalglucosidase alfa demonstrated varied responses in advanced LOPD patients with failing alglucosidase alfa therapy, with a general improvement in motor stabilization.

Long term survival in patients with classic infantile Pompe disease reveals a spectrum with progressive brain abnormalities and changes in cognitive functioning.

The aim of this longitudinal cohort study, is to provide more insight into the pattern of brain abnormalities, and possible consequences for cognitive functioning, in patients with classic infantile Pompe disease. We included 19 classic infantile Pompe patients (median age last assessment 8.9 years, range 1.5-22.5 years; 5/19 CRIM negative), treated with ERT. Using MR imaging of the brain (T1, T2, and FLAIR acquisitions), we classified progression of brain abnormalities on a 12-point rating scale at multiple time points throughout follow-up. Additionally we noted specific white matter patterns and examined atrophy. Cognitive development was studied using Wechsler IQ assessments obtained by certified neuropsychologists. The association between age and cognitive functioning, and MRI ratings and cognitive functioning was assessed by linear regression models. All but one patient developed brain abnormalities. The abnormalities progressed in a similar pattern throughout the brain, with early involvement of periventricular white matter, later followed by subcortical white matter, gray matter structures, and juxtacortical U-fibers. We found a significant decline (p < 0.01), with increasing age for full scale IQ, performance IQ and processing speed, but not for verbal IQ (p = 0.17). Each point increment in the 12-point MRI rating scale was associated with a significant decline (3.1-6.0 points) in all the IQ index scores (p < 0.05). The majority of long-term surviving patients in our cohort develop incremental brain MRI abnormalities and decline in cognitive functioning. This highlights the need for new therapies that can cross the blood-brain barrier in order to treat this CNS phenotype.

Minimal clinically important differences in six-minute walking distance in late-onset Pompe disease.

BACKGROUND: The minimal clinically important difference (MCID) is the smallest change in outcome that physicians or patients would consider meaningful and is relevant when evaluating disease progression or the efficacy of interventions. Studies of patients with late-onset Pompe disease (LOPD) have used the 6-min walk distance (6MWD) as an endpoint to assess motor function. However, an MCID for 6MWD (% predicted and meters) has yet to be established in LOPD. The objective of the study was to derive 6MWD MCID (% predicted and meters) with different analysis methods and for subgroups of different disease severity for LOPD. METHODS: Data from the PROPEL trial were used to calculate 6MWD MCID in the overall PROPEL population and subgroups of baseline severity as assessed by walking distance and body mass index (BMI), using anchor- and distribution-based approaches. RESULTS: The 6MWD MCIDs varied widely, depending on the method and subgroup, ranging from 2.27%-8.11% predicted for the overall LOPD population (23.7 m-57.2 m). For patients with baseline 6MWD < 150 m, MCIDs ranged from -0.74%-3.37% (-2.1 m-11.3 m). MCIDs increased with distance walked at baseline until a plateau was reached. For BMI subgroups, the MCIDs were generally lowest in obese patients. CONCLUSION: Our analysis shows that MCID depends on the chosen method and disease severity. The findings suggest that applying a single MCID to all patients can be misleading; consequently, a range of possible MCIDs should be considered. This may also be highly relevant for other neuromuscular diseases. This study provides a range of 6MWD MCIDs for LOPD, with lower MCIDs for more severe patients.

A rare co-occurrence of phosphorylase kinase deficiency (GSD type IXd) and alpha-glycosidase deficiency (GSD Type II) in a 53-year-old man presenting with an atypical glycogen storage disease phenotype.

Glycogen Storage Disease (GSD) IXd, caused by PHKA1 gene mutations, is an X-linked rare disorder that can be asymptomatic or associated with exercise intolerance. GSD type II is an autosomal recessive disorder caused by mutations in the GAA gene that lead to severe cardiac and skeletal muscle myopathy. We report the first case of co-occurrence of type IXd and type II GSDs in a 53-year-old man with an atypical glycogen storage disease presentation consisting in myalgia in the lower limbs at both rest and after exercise and increased levels of transaminases from the age of 16. At the age of 43, the patient presented a steppage gait, inability to run and walk on his heels, hypotrophy of the pectoral and proximal muscles, reflexes not elicitable, and CK levels 3.6 times the upper reference limit. Next Generation Sequencing (NGS) identified one variant in the PHKA1 gene, c.1360A > G p.Ile454Val (exon 14) inherited by his mother, and two heterozygous variants in the GAA gene, c.784G > A (exon 4) and c.956-6T > C (exon 6). A review of GSD IXd cases reported to date in the literature is also provided.

Diaphragm weakness in late-onset Pompe disease: A complex interplay between lower motor neuron and muscle fibre degeneration.

BACKGROUND: Late-onset Pompe disease (LOPD) patients may still need ventilation support at some point of their disease course, despite regular recombinant human alglucosidase alfa treatment. This suggest that other pathophysiological mechanisms than muscle fibre lesion can contribute to the respiratory failure process. We investigate through neurophysiology whether spinal phrenic motor neuron dysfunction could contribute to diaphragm weakness in LOPD patients. MATERIAL AND METHODS: A group of symptomatic LOPD patients were prospectively studied in our centre from January 2022 to April 2023. We collected both demographic and clinical data, as well as neurophysiological parameters. Phrenic nerve conduction studies and needle EMG sampling of the diaphragm were perfomed. RESULTS: Eight treated LOPD patients (3 males, 37.5%) were investigated. Three patients (37.5%) with no respiratory involvement had normal phrenic nerve motor responses [median phrenic compound muscle action potential (CMAP) amplitude of 0.49 mV; 1st-3rd interquartile range (IQR), 0.48-0.65]. Those with respiratory failure (under nocturnal non-invasive ventilation) had abnormal phrenic nerve motor responses (median phrenic CMAP amplitude of 0 mV; 1st-3rd IQR, 0-0.15), and were then investigated with EMG. Diaphragm needle EMG revealed both myopathic and neurogenic changes in 3 (60%) and myopathic potentials in 1 patient. In the last one, no motor unit potentials could be recruited. CONCLUSIONS: Our study provide new insights regarding respiratory mechanisms in LOPD, suggesting a contribution of spinal phrenic motor neuron dysfunction for diaphragm weakness. If confirmed in further studies, our results recommend the need of new drugs crossing the blood-brain barrier.

The value of knowing: preferences for genetic testing to diagnose rare muscle diseases.

BACKGROUND: Genetic testing can offer early diagnosis and subsequent treatment of rare neuromuscular diseases. Options for these tests could be improved by understanding the preferences of patients for the features of different genetic tests, especially features that increase information available to patients. METHODS: We developed an online discrete-choice experiment using key attributes of currently available tests for Pompe disease with six test attributes: number of rare muscle diseases tested for with corresponding probability of diagnosis, treatment availability, time from testing to results, inclusion of secondary findings, necessity of a muscle biopsy, and average time until final diagnosis if the first test is negative. Respondents were presented a choice between two tests with different costs, with respondents randomly assigned to one of two costs. Data were analyzed using random-parameters logit. RESULTS: A total of 600 online respondents, aged 18 to 50 years, were recruited from the U.S. general population and included in the final analysis. Tests that targeted more diseases, required less time from testing to results, included information about unrelated health risks, and were linked to shorter time to the final diagnosis were preferred and associated with diseases with available treatment. Men placed relatively more importance than women on tests for diseases with available treatments. Most of the respondents would be more willing to get a genetic test that might return unrelated health information, with women exhibiting a statistically significant preference. While respondents were sensitive to cost, 30% of the sample assigned to the highest cost was willing to pay $500 for a test that could offer a diagnosis almost 2 years earlier. CONCLUSION: The results highlight the value people place on the information genetic tests can provide about their health, including faster diagnosis of rare, unexplained muscle weakness, but also the value of tests for multiple diseases, diseases without treatments, and incidental findings. An earlier time to diagnosis can provide faster access to treatment and an end to the diagnostic journey, which patients highly prefer.

An updated management approach of Pompe disease patients with high-sustained anti-rhGAA IgG antibody titers: experience with bortezomib-based immunomodulation.

Introduction: High sustained anti-rhGAA antibody titers (HSAT; ≥12,800) are directly linked to reduced efficacy of enzyme replacement therapy (ERT) and subsequent clinical deterioration in infantile-onset Pompe disease (IOPD). We have previously demonstrated the safety and effectiveness of a bortezomib-based immune-tolerance induction (ITI) regimen (bortezomib, rituximab, methotrexate, and IVIG) in eliminating HSAT. Methods: Here, we describe two IOPD cases (patients 6 and 8) who developed HSAT at 8 and 10 weeks on ERT despite transient low-dose methotrexate ITI administration in the ERT-naïve setting and were treated with a bortezomib-based ITI regimen, and we compare their courses to a series of six historical patients (patients 1-5, and 7) with a similar presentation who exemplify our evolving approach to treatment. Results: In total, patients 6 and 8 received 16 and 8 doses of bortezomib (4 doses=1 cycle) respectively reducing titers from 25,600 to seronegative, but differences in the course of their therapy were instructive regarding the optimal approach to initial treatment of HSAT; specifically, patient 6 was treated initially with only a single course of bortezomib rescue therapy, while patient 8 received two back-to-back courses. Patient 8 received IVIG therapy throughout the immunosuppression whereas patient 6 received IVIG therapy and was switched to subcutaneous IgG replacement. Patient 6 had a transient reduction in anti-rhGAA antibodies, after receiving a single initial cycle of bortezomib, but had a recurrence of high anti-rhGAA antibody titer after 160 weeks that required 3 additional cycles of bortezomib to ultimately achieve tolerance. In contrast, patient 8 achieved tolerance after being given two consecutive cycles of bortezomib during their initial treatment and had B cell recovery by week 54. Since the reduction in anti-rhGAA antibodies, both patients are doing well clinically, and have decreasing ALT, AST, and CK. No major infections leading to interruption of treatment were observed in either patient. The bortezomib-based ITI was safe and well-tolerated, and patients continue to receive ERT at 40 mg/kg/week. Discussion: These case studies and our previous experience suggest that to achieve an effective reduction of anti-rhGAA antibodies in the setting of HSAT, bortezomib should be initiated at the earliest sign of high anti-rhGAA antibodies with a minimum of two consecutive cycles as shown in the case of patient 8. It is important to note that, despite initiation of ERT at age 2.3 weeks, patient 8 quickly developed HSAT. We recommend close monitoring of anti-rhGAA antibodies and early intervention with ITI as soon as significantly elevated anti-rhGAA antibody titers are noted.

Using an In Vivo Mouse Model to Determine the Exclusion Criteria of Preexisting Anti-AAV9 Neutralizing Antibody Titer of Pompe Disease Patients in Clinical Trials.

The efficacy of adeno-associated virus (AAV)-based gene therapy is dependent on effective viral transduction, which might be inhibited by preexisting immunity to AAV acquired from infection or maternal delivery. Anti-AAV neutralizing Abs (NAbs) titer is usually measured by in vitro assay and used for patient enroll; however, this assay could not evaluate NAbs' impacts on AAV pharmacology and potential harm in vivo. Here, we infused a mouse anti-AAV9 monoclonal antibody into Balb/C mice 2 h before receiving 1.2 × 1014 or 3 × 1013 vg/kg of rAAV9-coGAA by tail vein, a drug for our ongoing clinical trials for Pompe disease. The pharmacokinetics, pharmacodynamics, and cellular responses combined with in vitro NAb assay validated the different impacts of preexisting NAbs at different levels in vivo. Sustained GAA expression in the heart, liver, diaphragm, and quadriceps were observed. The presence of high-level NAb, a titer about 1:1000, accelerated vector clearance in blood and completely blocked transduction. The AAV-specific T cell responses tended to increase when the titer of NAb exceeded 1:200. A low-level NAbs, near 1:100, had no effect on transduction in the heart and liver as well as cellular responses, but decreased transduction in muscles slightly. Therefore, we propose to preclude patients with NAb titers > 1:100 from rAAV9-coGAA clinical trials.

Infantile-onset pompe disease: a case report emphasizing the role of genetic counseling and prenatal testing.

BACKGROUND: Pompe disease, classified as glycogen storage disease type II, arises from a deficiency in the acid alpha-glucosidase (GAA) enzyme, leading to glycogen accumulation in multiple tissues. The unique correlation between genotype and enzyme activity is a key feature. This case highlights an infantile-onset form, emphasizing genetic counseling and prenatal testing importance. CASE PRESENTATION: An 18-week-old infant with respiratory distress, cyanosis, and fever was admitted. Born healthy, her sibling died from Pompe disease. She presented with cardiomegaly, hypotonia, and absent reflexes. Diagnosis was confirmed by significantly reduced GAA activity. Despite treatment initiation, the patient succumbed to cardiac arrest. CONCLUSIONS: The case underscores genetic counseling's role, offering insights into prenatal testing advancements, antenatal diagnosis through echocardiography, and the significance of early intervention, particularly in infantile-onset Pompe disease. SYNOPSIS: Genetic risk assessment and prenatal testing are crucial for families with a history of Pompe disease to improve early diagnosis and management outcomes.