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.

Efficacy and safety of enzyme replacement therapy with alglucosidase alfa for the treatment of patients with infantile-onset Pompe disease: a systematic review and metanalysis.

Introduction: Pompe disease (PD) is a glycogen disorder caused by the deficient activity of acid alpha-glucosidase (GAA). We sought to review the latest available evidence on the safety and efficacy of recombinant human GAA enzyme replacement therapy (ERT) for infantile-onset PD (IOPD). Methods: We systematically searched the MEDLINE (via PubMed) and Embase databases for prospective clinical studies evaluating ERT for IOPD on pre-specified outcomes. Meta-analysis was also performed. Results: Of 1,722 articles identified, 16 were included, evaluating 316 patients. Studies were heterogeneous and with very low certainty of evidence for most outcomes. A moderate/high risk of bias was present for most included articles. The following outcomes showed improvements associated with alglucosidase alfa, over natural history of PD/placebo, for a mean follow-up of 48.3 months: left ventricular (LV) mass {mean change 131.3 g/m2 [95% confidence interval (CI) 81.02, 181.59]}, time to start ventilation (TSV) [HR 0.21 (95% CI: 0.12, 0.36)], and survival [HR 0.10 (95% CI: 0.05, 0.19)]. There were no differences between the pre- and post-ERT period for myocardial function and psychomotor development. Adverse events (AEs) after ERT were mild in most cases. Conclusion: Our data suggest that alglucosidase alfa potentially improves LV mass, TSV, and survival in IOPD patients, with no important safety issues. Systematic Review Registration: PROSPERO identifier (CRD42019123700).

104-week efficacy and safety of cipaglucosidase alfa plus miglustat in adults with late-onset Pompe disease: a phase III open-label extension study (ATB200-07).

The phase III double-blind PROPEL study compared the novel two-component therapy cipaglucosidase alfa + miglustat (cipa + mig) with alglucosidase alfa + placebo (alg + pbo) in adults with late-onset Pompe disease (LOPD). This ongoing open-label extension (OLE; NCT04138277) evaluates long-term safety and efficacy of cipa + mig. Outcomes include 6-min walk distance (6MWD), forced vital capacity (FVC), creatine kinase (CK) and hexose tetrasaccharide (Hex4) levels, patient-reported outcomes and safety. Data are reported as change from PROPEL baseline to OLE week 52 (104 weeks post-PROPEL baseline). Of 118 patients treated in the OLE, 81 continued cipa + mig treatment from PROPEL (cipa + mig group; 61 enzyme replacement therapy [ERT] experienced prior to PROPEL; 20 ERT naïve) and 37 switched from alg + pbo to cipa + mig (switch group; 29 ERT experienced; 8 ERT naive). Mean (standard deviation [SD]) change in % predicted 6MWD from baseline to week 104 was + 3.1 (8.1) for cipa + mig and - 0.5 (7.8) for the ERT-experienced switch group, and + 8.6 (8.6) for cipa + mig and + 8.9 (11.7) for the ERT-naïve switch group. Mean (SD) change in % predicted FVC was - 0.6 (7.5) for cipa + mig and - 3.8 (6.2) for the ERT-experienced switch group, and - 4.8 (6.5) and - 3.1 (6.7), respectively, in ERT-naïve patients. CK and Hex4 levels improved in both treatment groups by week 104 with cipa + mig treatment. Three patients discontinued the OLE due to infusion-associated reactions. No new safety signals were identified. Cipa + mig treatment up to 104 weeks was associated with overall maintained improvements (6MWD, biomarkers) or stabilization (FVC) from baseline with continued durability, and was well tolerated, supporting long-term benefits for patients with LOPD.Trial registration number: NCT04138277; trial start date: December 18, 2019.

Lentiviral gene therapy with IGF2-tagged GAA normalizes the skeletal muscle proteome in murine Pompe disease.

Pompe disease is a lysosomal storage disorder caused by deficiency of acid alpha-glucosidase (GAA), resulting in glycogen accumulation with profound pathology in skeletal muscle. We recently developed an optimized form of lentiviral gene therapy for Pompe disease in which a codon-optimized version of the GAA transgene (LV-GAAco) was fused to an insulin-like growth factor 2 (IGF2) peptide (LV-IGF2.GAAco), to promote cellular uptake via the cation-independent mannose-6-phosphate/IGF2 receptor. Lentiviral gene therapy with LV-IGF2.GAAco showed superior efficacy in heart, skeletal muscle, and brain of Gaa -/- mice compared to gene therapy with untagged LV-GAAco. Here, we used quantitative mass spectrometry using TMT labeling to analyze the muscle proteome and the response to gene therapy in Gaa -/- mice. We found that muscle of Gaa -/- mice displayed altered levels of proteins including those with functions in the CLEAR signaling pathway, autophagy, cytoplasmic glycogen metabolism, calcium homeostasis, redox signaling, mitochondrial function, fatty acid transport, muscle contraction, cytoskeletal organization, phagosome maturation, and inflammation. Gene therapy with LV-GAAco resulted in partial correction of the muscle proteome, while gene therapy with LV-IGF2.GAAco resulted in a near-complete restoration to wild type levels without inducing extra proteomic changes, supporting clinical development of lentiviral gene therapy for Pompe disease. SIGNIFICANCE: Lysosomal glycogen accumulation is the primary cause of Pompe disease, and leads to a cascade of pathological events in cardiac and skeletal muscle and in the central nervous system. In this study, we identified the proteomic changes that are caused by Pompe disease in skeletal muscle of a mouse model. We showed that lentiviral gene therapy with LV-IGF2.GAAco nearly completely corrects disease-associated proteomic changes. This study supports the future clinical development of lentiviral gene therapy with LV-IGF2.GAAco as a new treatment option for Pompe disease.

Description of clinical and genetic features of 122 patients included in the Spanish Pompe registry.

Pompe disease is a rare genetic disorder with an estimated prevalence of 1:60.000. The two main phenotypes are Infantile Onset Pompe Disease (IOPD) and Late Onset Pompe Disease (LOPD). There is no published data from Spain regarding the existing number of cases, regional distribution, clinical features or, access and response to the treatment. We created a registry to collect all these data from patients with Pompe in Spain. Here, we report the data of the 122 patients registered including nine IOPD and 113 LOPD patients. There was a high variability in how the diagnosis was obtained and how the follow-up was performed among different centres. Seven IOPD patients were still alive being all treated with enzymatic replacement therapy (ERT) at last visit. Ninety four of the 113 LOPD patients had muscle weakness of which 81 were receiving ERT. We observed a progressive decline in the results of muscle function tests during follow-up. Overall, the Spanish Pompe Registry is a valuable resource for understanding the demographics, patient's journey and clinical characteristics of patients in Spain. Our data supports the development of agreed guidelines to ensure that the care provided to the patients is standardized across the country.

Long-term safety and efficacy of cipaglucosidase alfa plus miglustat in individuals living with Pompe disease: an open-label phase I/II study (ATB200-02).

Cipaglucosidase alfa plus miglustat (cipa + mig) is a novel, two-component therapy for Pompe disease. We report data from the Phase I/II ATB200-02 study for up to 48 months of treatment. Four adult cohorts, including one non-ambulatory ERT-experienced (n = 6) and three ambulatory cohorts, (two enzyme replacement therapy [ERT]-experienced cohorts [2-6 years (n = 11) and ≥ 7 years (n = 6)]), one ERT-naïve cohort (n = 6), received 20 mg/kg intravenous-infused cipa plus 260 mg oral mig biweekly. Change from baseline (CFBL) for multiple efficacy endpoints at 12, 24, 36, and 48 months, pharmacodynamics, pharmacokinetics, safety, and immunogenicity data were assessed. Six-minute walking distance (% predicted) improved at 12, 24, 36, and 48 months: pooled ambulatory ERT-experienced cohorts, mean(± standard deviation [SD]) CFBL: 6.1(± 7.84), n = 16; 5.4(± 10.56), n = 13; 3.4(± 14.66), n = 12; 5.9(± 17.36), n = 9, respectively; ERT-naïve cohort: 10.7(± 3.93), n = 6; 11.0(± 5.06), n = 6; 9.0(± 7.98), n = 5; 11.7(± 7.69), n = 4, respectively. Percent predicted forced vital capacity was generally stable in ERT-experienced cohorts, mean(± SD) CFBL - 1.2(± 5.95), n = 16; 1.0(± 7.96), n = 13; - 0.3(± 6.68), n = 10; 1.0(± 6.42), n = 6, respectively, and improved in the ERT-naïve cohort: 3.2(± 8.42), n = 6; 4.7(± 5.09), n = 6; 6.2(± 3.35), n = 5; 8.3(± 4.50), n = 4, respectively. Over 48 months, CK and Hex4 biomarkers improved in ambulatory cohorts. Overall, cipa + mig was well tolerated with a safety profile like alglucosidase alfa. ATB200-02 results show the potential benefits of cipa + mig as a long-term treatment option for Pompe disease. Trial registration number: NCT02675465 January 26, 2016.

Variant Classification for Pompe disease; ACMG/AMP specifications from the ClinGen Lysosomal Diseases Variant Curation Expert Panel.

Accurate determination of the clinical significance of genetic variants is critical to the integration of genomics in medicine. To facilitate this process, the NIH-funded Clinical Genome Resource (ClinGen) has assembled Variant Curation Expert Panels (VCEPs), groups of experts and biocurators which provide gene- and disease- specifications to the American College of Medical Genetics & Genomics and Association for Molecular Pathology's (ACMG/AMP) variation classification guidelines. With the goal of classifying the clinical significance of GAA variants in Pompe disease (Glycogen storage disease, type II), the ClinGen Lysosomal Diseases (LD) VCEP has specified the ACMG/AMP criteria for GAA. Variant classification can play an important role in confirming the diagnosis of Pompe disease as well as in the identification of carriers. Furthermore, since the inclusion of Pompe disease on the Recommended Uniform Screening Panel (RUSP) for newborns in the USA in 2015, the addition of molecular genetic testing has become an important component in the interpretation of newborn screening results, particularly for asymptomatic individuals. To date, the LD VCEP has submitted classifications and supporting data on 243 GAA variants to public databases, specifically ClinVar and the ClinGen Evidence Repository. Here, we describe the ACMG/AMP criteria specification process for GAA, an update of the GAA-specific variant classification guidelines, and comparison of the ClinGen LD VCEP's GAA variant classifications with variant classifications submitted to ClinVar. The LD VCEP has added to the publicly available knowledge on the pathogenicity of variants in GAA by increasing the number of expert-curated GAA variants present in ClinVar, and aids in resolving conflicting classifications and variants of uncertain clinical significance.

Two fluorimetric determinations of acid α-glucosidase activity in dried blood spot: Pompe disease in Iranian population.

INTRODUCTION: Pompe disease is a lysosomal storage disorder. This study aimed to validate and compare 2 fluorimetric methods for measuring α-glucosidase acid activity in dried blood spot sample (DBS), with potential applications in neonatal screening, and disease follow-up of Pompe patients among the Iranian population for the first time. MATERIALS AND METHODS: The evaluation involved 3 enzyme levels and 7 parameters. The analysis included 141 Healthy individuals, 8 Pompe patients, and 10 obligate heterozygotes using reference and modified methods. RESULTS: Both methods exhibited highly linear calibration curves. The limit of detection (LOD) and limit of quantification (LOQ) were obtained in the micromolar concentration range in 2 methods. Inter-day and intra-day precision, expressed as relative standard deviations (RSD%) were calculated. The normal ranges were determined in healthy individuals. Receiver operating characteristic (ROC) curves were analyzed, and 2 parameters, total neutral α-glucosidase (NAG)/acid α-glucosidase (GAA) and pH ratio, were identified as cut-off values with excellent accuracy, sensitivity, and specificity for evaluating Pompe disease in both methods. CONCLUSIONS: Establishing and implementing these 2 methods for the Iranian population effectively differentiated between healthy and patient individuals. Method II, with its shorter incubation time, demonstrated practicality in the clinical setting.

Improved Enzyme Replacement Therapy with Cipaglucosidase Alfa/Miglustat in Infantile Pompe Disease.

Pompe disease is a lysosomal storage disorder with impaired glycogen degradation caused by a deficiency of the enzyme acid α-glucosidase (GAA). Children with the severe infantile form do not survive beyond the first year of life without treatment. Since 2006, enzyme replacement therapy (ERT) with Alglucosidase alfa (Myozyme) has been available, which is a recombinant human GAA (rhGAA). Myozyme therapy has prolonged the life span of affected patients, but many patients showed a continuing, albeit slower, disease progression. A new generation of rhGAA, Cipaglucosidase alfa (Amicus) has a higher content of mannose-6-phosphate residues, which are necessary for efficient cellular uptake and lysosomal targeting. Cipaglucosidase alfa is co-administered with an enzyme stabilizer, Miglustat, which also optimizes the pharmacological properties. In mouse models, the superiority of Cipaglucosidase alfa/Miglustat compared to the previous standard therapy could be determined. Here, we report the disease course of a patient with severe infantile M. Pompe, who showed serious progression even with high-dose standard of care ERT. Changing the therapy to Cipaglucosidase alfa/Miglustat improved respiratory failure, cardiomyopathy, and motor functions significantly. The patient could be weaned from respiratory support and oxygen supplementation. Cardiac function was normalized. Most impressively, the patient, who had lost nearly all motor skills, acquired head control, learned to speak, and could move his wheelchair by himself. Overall, the patient's clinical situation has improved dramatically with the new ERT.

Calidad de vida en pacientes con enfermedad de Pompe: estudio observacional / Quality of Life in Patients with Pompe Disease: Cross-Sectional Study

Introducción: La enfermedad de Pompe es una enfermedad genética multisistémica y rápidamente progresiva, que causa compromiso muscular (esquelético, cardíaco y liso), severa hipotonía y dificultad en la deglución. Debido a la naturaleza de la enfermedad, la calidad de vida de las personas que la padecen puede verse más afectada con respecto a la población general. Método: Se llevó a cabo un estudio descriptivo de corte transversal. Se diseñó un instrumento tipo encuesta con preguntas de caracterización sociodemográfica y referentes a la enfermedad. Para medir la calidad de vida se aplicó el Medical Outcomes Study 36-Item Short Form (SF-36) Questionnaire. Se hizo una comparación entre grupos, con nivel de significancia de 0,05. Resultados: Se obtuvieron encuestas de 27 pacientes de seis países. La edad media fue de 40,52 años, el 59 % fueron mujeres, el 51 % casados, el 63 % activos laboralmente, con edad media de diagnóstico de 30,3 años (SD = 15,557). La dimensión con menor media fue el rol físico (10,2; IC 95 % = 1,5-21,9), mientras que la de mayor media fue la salud mental (65,5; IC 95 % = 56,9-74,0). El 29,7 % (IC 95 % = 11,2-48,0) de los encuestados consideró sentirse en peores condiciones de salud que el año anterior. Discusión: Se evidencia una baja calidad de vida en pacientes con EP, en comparación con la población general, si se tienen en cuenta otros estudios que utilizan el mismo cuestionario. Conclusiones: Se evidencia una baja calidad de vida en los pacientes con enfermedad de Pompe participantes; las dimensiones asociadas con parámetros físicos fueron las de menores puntuaciones.

Introduction: Pompe disease is a rapidly progressive, multisystemic genetic disease that causes muscle involvement (skeletal, cardiac and smooth), severe hypotonia and difficulty in swallowing. Due to the nature of the disease, the quality of life may be more affected compared to the general population. Method: A descriptive cross-sectional study was carried out. A survey-type instrument was designed with questions of sociodemographic characterization and those referring to the disease. To measure Quality of Life, the Medical Outcomes Study 36-Item Short Form (SF-36) questionnaire was applied. A comparison was made between groups with a significance level of 0,05. Results: 27 surveys of patients from six countries were obtained. The mean age 40.52 years, women 59 %, married 51 %, 63 % active in employment, with a mean age of diagnosis of 30.3 years (SD = 15,557). The dimension with the lowest mean was the Physical Role (10.2; 95 % CI = 1.5 - 21.9), while the one with the highest mean was the Mental Health dimension (65.5; 95 % CI = 56.9 - 74.0). 29.7 % (95 % CI = 11.2 - 48.0) of those surveyed considered they felt in worse health conditions than the previous year. Discussion: Low quality of life is evidenced in patients with PD in comparison to the general population described in other studies using the same questionnaire. Conclusions: A low quality of life is evidenced in the study individuals where the dimensions related to the physical area were lower.

Determinants and Characterization of Locomotion in Adults with Late-Onset Pompe Disease: New Clinical Biomarkers.

BACKGROUND: The late-onset form of Pompe disease (LOPD) is characterized by muscle weakness, locomotor limitations and a risk of falls. The mechanisms responsible for altered locomotion in adults with LOPD are unknown. The identification of clinical biomarkers is essential for clinical follow-up and research. OBJECTIVES: To identify muscle determinants of impaired locomotor performance, gait stability and gait pattern, and biomechanical determinants of falls in adults with LOPD. METHODS: In this cross-sectional, case-control study, LOPD and control participants underwent 3D gait analysis, locomotor performance tests and muscle strength measurements (isokinetic dynamometer). We explored the muscular determinants of locomotor performance (gait speed, 6-minute walk test distance and timed up and go test), gait stability (spatiotemporal gait variables) and the gait pattern. We also explored biomechanical gait determinants of falls. After intergroup comparisons, determinants were sought to use forward stepwise multiple regression. RESULTS: Eighteen participants with LOPD and 20 control participants were included. Locomotor performance, gait stability, and the gait pattern were significantly altered in LOPD compared to control participants. Hip abductor strength was the main common determinant of locomotor performance, gait stability and pelvic instability. Hip flexor strength was the main determinant of abnormal gait kinematics at the hip and knee. Percentage duration of single support phase during the gait cycle was the main determinant of falls. CONCLUSIONS: Hip abductor strength and percentage duration of single support during gait were the major determinants of locomotor performance, gait stability, falls and the gait pattern in LOPD. These new clinical biomarkers should therefore be systematically assessed using instrumented tools to improve the follow-up of adults with LOPD. They should also be considered in future studies to accurately assess the effects of new therapies. Hip abductor strength and single support phase should also be priority targets for rehabilitation.

From Acid Alpha-Glucosidase Deficiency to Autophagy: Understanding the Bases of POMPE Disease.

Pompe disease (PD) is caused by mutations in the GAA gene, which encodes the lysosomal enzyme acid alpha-glucosidase, causing lysosomal glycogen accumulation, mainly in muscular tissue. Autophagic buildup is considered the main factor affecting skeletal muscle, although other processes are also involved. Uncovering how these mechanisms are interconnected could be an approximation to address long-lasting concerns, like the differential skeletal and cardiac involvement in each clinical phenotype. In this sense, a network reconstruction based on a comprehensive literature review of evidence found in PD enriched with the STRING database and other scientific articles is presented. The role of autophagic lysosome reformation, PGC-1α, MCOLN1, calcineurin, and Keap1 as intermediates between the events involved in the pathologic cascade is discussed and contextualized within their relationship with mTORC1/AMPK. The intermediates and mechanisms found open the possibility of new hypotheses and questions that can be addressed in future experimental studies of PD.

Tratamiento de la enfermedad de Pompe / Treatment of Pompe Disease

Introducción: La enfermedad de Pompe es un trastorno de origen genético causado por la deficiencia de la enzima alfa-glucosidasa ácida, que se caracteriza por el acumulo anormal de glucógeno en los músculos y otros tejidos, generando una debilidad muscular progresiva, la cual debe ser diagnosticada y tratada de forma oportuna, ya que de esto dependerá el pronóstico, la sobrevida y la funcionalidad de los pacientes con esta condición. Contenidos: El abordaje multidisciplinario incluye tanto una adecuada valoración y soporte nutricional como el inicio del tratamiento modificador de enfermedad a través de la terapia de reemplazo enzimático, que a su vez dependerá de la forma de presentación, la variante genética, el perfil inicial del paciente, las condiciones especiales que puedan existir y las metas propias para cada paciente. Para garantizar un manejo adecuado, se deben realizar estudios de seguimiento con parámetros objetivos, evaluar posibles eventos secundarios e instaurar su manejo en caso de presentarlos. Conclusiones: El pronóstico de esta enfermedad dependerá del inicio oportuno del tratamiento, la implementación de pautas nutricionales adecuadas y el establecimiento del seguimiento de los parámetros clínicos y paraclínicos para cada uno de los pacientes.

Introduction: Pompe disease is a disorder of genetic origin caused by the deficiency of the acid alpha-glucosidase enzyme, which is characterized by the abnormal accumulation of glycogen in the muscles and other tissues, generating progressive muscle weakness, which must be diagnosed and treated in a timely manner, since the prognosis, survival, and functionality of patients with this condition will depend on this. Contents: The multidisciplinary approach includes both an adequate evaluation and nutritional support as well as the initiation of disease-modifying treatment through enzyme replacement therapy, which in turn will depend on the form of presentation, the genetic variant, the initial profile of the patient, the special conditions that may exist and the specific goals for each patient. To guarantee adequate management, follow-up studies must be carried out with objective parameters, evaluate possible secondary events and establish their management in case of presenting them. Conclusions: The prognosis of this disease will depend on the timely initiation of treatment, the implementation of adequate nutritional guidelines and the establishment of monitoring of clinical and paraclinical parameters for each of the patients.

Rehabilitación en la enfermedad de Pompe / Pompe disease rehabilitation management

Introducción: Gracias a la nueva herramienta de tratamiento con la terapia de reemplazo enzimático en la enfermedad de Pompe, se ha reducido la mortalidad a corto plazo. Contenidos: Esta herramienta permite a los pacientes mantener la independencia funcional y la adaptación de las habilidades motrices para su participación en varios aspectos de la vida diaria. Conclusiones: El abordaje de estos pacientes debe ser multidisciplinario, para dar un manejo integral a la condición clínica de cada individuo, y procurar el tratamiento de los sistemas físicos y emocionales que se pueden ver alterados con el curso de la enfermedad: osteomuscular, cardiovascular y respiratorio, deglución, lenguaje, nutrición y psicológico, incluidos los cuidados paliativos y el manejo del dolor.

Introduction: Enzyme replacement therapy in Pompe disease reduces short-term mortality. Contents: This therapy allows patients to maintain functional independence and adaptation of motor skills for patient participation in various aspects of daily life. Conclusions: The approach with this patients should be multidisciplinary to provide comprehensive management of the clinical condition of each individual seeking treatment of the physical and emotional aspects that may be altered in the disease progression: musculoskeletal, cardiovascular, respiratory, swallowing, language, nutritional and psychological; also including palliative care and pain management.

An artificial intelligence-based approach for identifying rare disease patients using retrospective electronic health records applied for Pompe disease.

Objective: We retrospectively screened 350,116 electronic health records (EHRs) to identify suspected patients for Pompe disease. Using these suspected patients, we then describe their phenotypical characteristics and estimate the prevalence in the respective population covered by the EHRs. Methods: We applied Symptoma's Artificial Intelligence-based approach for identifying rare disease patients to retrospective anonymized EHRs provided by the "University Hospital Salzburg" clinic group. Within 1 month, the AI screened 350,116 EHRs reaching back 15 years from five hospitals, and 104 patients were flagged as probable for Pompe disease. Flagged patients were manually reviewed and assessed by generalist and specialist physicians for their likelihood for Pompe disease, from which the performance of the algorithms was evaluated. Results: Of the 104 patients flagged by the algorithms, generalist physicians found five "diagnosed," 10 "suspected," and seven patients with "reduced suspicion." After feedback from Pompe disease specialist physicians, 19 patients remained clinically plausible for Pompe disease, resulting in a specificity of 18.27% for the AI. Estimating from the remaining plausible patients, the prevalence of Pompe disease for the greater Salzburg region [incl. Bavaria (Germany), Styria (Austria), and Upper Austria (Austria)] was one in every 18,427 people. Phenotypes for patient cohorts with an approximated onset of symptoms above or below 1 year of age were established, which correspond to infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD), respectively. Conclusion: Our study shows the feasibility of Symptoma's AI-based approach for identifying rare disease patients using retrospective EHRs. Via the algorithm's screening of an entire EHR population, a physician had only to manually review 5.47 patients on average to find one suspected candidate. This efficiency is crucial as Pompe disease, while rare, is a progressively debilitating but treatable neuromuscular disease. As such, we demonstrated both the efficiency of the approach and the potential of a scalable solution to the systematic identification of rare disease patients. Thus, similar implementation of this methodology should be encouraged to improve care for all rare disease patients.

Home-based enzyme replacement therapy in children and adults with Pompe disease; a prospective study.

BACKGROUND: Pompe disease is a lysosomal storage disease treated with life-long enzyme replacement therapy (ERT). Home-based ERT has been provided in the Netherlands since 2008 because it diminishes the burden of treatment, increases patient flexibility and autonomy, and is thus a more patient-centred approach to ERT. METHODS: All Dutch Pompe patients receiving alglucosidase alfa infusions at home were approached to participate in a questionnaire to validate the safety of home-based ERT. Prospective data on symptoms occurring during or within 48 h after infusion and retrospective data on infusion associated reactions (IARs) in the last three months were collected four times during one year. RESULTS: In total, 116 out of 120 eligible patients (17 classic infantile, 2 atypical infantile, 15 childhood onset and 82 adult) filled out 423 questionnaires (response rate: 88.1%). Symptoms during or after infusion were reported 27 times in 17 patients. Fatigue was the most commonly reported health complaint (in 9.5% of patients). Four health complaints were judged to be IARs and reported to the Erasmus MC University Medical Center. None of the IARs reported in this study warranted emergency clinical care. CONCLUSIONS: Our data demonstrate that home-based ERT in Pompe disease can be safely implemented as few, mostly mild, symptoms were reported during or after infusion. Insights from this study can be used as a base for implementing home-based ERT in other countries and to further optimize patient care, as unreported mild symptoms do not pose a health risk but may still be relevant to the patient.

Novel Mutation in the Feline GAA Gene in a Cat with Glycogen Storage Disease Type II (Pompe Disease).

Glycogen storage disease type II (Pompe disease: PD) is an autosomal recessively inherited fatal genetic disorder that results from the deficiency of a glycogen hydrolyzing enzyme, acid α-glucosidase encoded by the GAA gene. Here, we describe the molecular basis of genetic defects in an 8-month-old domestic short-haired cat with PD. The cat was previously diagnosed with PD based on the clinical and pathological findings of hypertrophic cardiomyopathy and excessive accumulation of glycogen in the cardiac muscles. Sanger sequencing was performed on 20 exons of the feline GAA gene using genomic DNA extracted from paraffin-embedded liver tissues. The affected cat was found to be homozygous for the GAA:c.1799G>A mutation resulting in an amino acid substitution (p.R600H) of acid α-glucosidase, a codon position of which is identical with three missense mutations (p.R600C, p.R600L, and p.R600H) causing human infantile-onset PD (IOPD). Several stability and pathogenicity predictors have also shown that the feline mutation is deleterious and severely decreases the stability of the GAA protein. The clinical, pathological, and molecular findings in the cat were similar to those of IOPD in humans. To our knowledge, this is the first report of a pathogenic mutation in a cat. Feline PD is an excellent model for human PD, especially IOPD.

Effects of enzyme replacement therapy on cardiac function in classic infantile Pompe disease.

OBJECTIVE: Patients with classic infantile Pompe disease are born with a hypertrophic cardiomyopathy, which resolves after treatment with Enzyme replacement therapy (ERT). We aimed to assess potential deterioration of cardiac function over time using myocardial deformation analysis. METHODS: Twenty-seven patients treated with ERT were included. Cardiac function was assessed at regular time intervals (before and after start with ERT) using conventional echocardiography and myocardial deformation analysis. Separate linear mixed effect models were used to asses temporal changes within the first year and the long-term follow-up period. Echocardiograms of 103 healthy children served as controls. RESULTS: A total of 192 echocardiograms were analyzed. Median follow-up was 9.9 years (IQR: 7.5-16.3). Mean LVMI before start of ERT was increased 292.3 g/m2 (95% CI: 202.8-381.8, mean Z-score + 7.6) and normalized after 1 year of ERT 87.3 g/m2 (CI: 67.5-107.1, mean Z-score + 0.8, p < 0.001). Mean shortening fraction was within normal limits before start of ERT, up to 22 years of follow-up. Cardiac function measured by RV/LV longitudinal, and circumferential strain was diminished before start of ERT, but normalized (<-16%) within 1 year after start of ERT, and all remained within normal limits during follow-up. Only LV circumferential strain gradually worsened in Pompe patients (+0.24%/year) during follow-up compared to controls. LV longitudinal strain was diminished in Pompe patients, but did not change significantly over time compared to controls. CONCLUSION: Cardiac function, measured using myocardial deformation analysis, normalizes after start of ERT, and seems to remain stable over a median follow-up period of 9.9 years.

Quality of Life with Late-Onset Pompe Disease: Qualitative Interviews and General Public Utility Estimation in the United Kingdom.

Background: Late-onset Pompe disease (LOPD) is a rare, progressive neuromuscular condition typically characterized by weakness of skeletal muscles, including those involved in respiration and diaphragmatic dysfunction. Individuals with LOPD typically eventually require mobility and/or ventilatory support. Objectives: This study aimed to develop health state vignettes and estimate health state utility values for LOPD in the United Kingdom. Methods: Vignettes were developed for 7 health states of LOPD with states defined in terms of mobility and/or ventilatory support. Vignettes were drafted based on patient-reported outcome data from the Phase 3 PROPEL trial (NCT03729362) and supplemented by a literature review. Qualitative interviews with individuals living with LOPD and clinical experts were conducted to explore the health-related quality-of-life (HRQoL) impact of LOPD and to review the draft vignettes. Vignettes were finalized following a second round of interviews with individuals living with LOPD and used in health state valuation exercises with people of the UK population. Participants rated the health states using the EQ-5D-5L, visual analogue scale, and time trade-off interviews. Results: Twelve individuals living with LOPD and 2 clinical experts were interviewed. Following the interviews, 4 new statements were added regarding dependence on others, bladder control problems, balance issues/fear of falling, and frustration. One hundred interviews with a representative UK population sample were completed. Mean time trade-off utilities ranged from 0.754 (SD = 0.31) (no support) to 0.132 (SD = 0.50) (invasive ventilatory and mobility support-dependent). Similarly, EQ-5D-5L utilities ranged from 0.608 (SD = 0.12) to -0.078 (SD = 0.22). Discussion: The utilities obtained in the study are consistent with utilities reported in the literature (0.670-0.853 for nonsupport state). The vignette content was based on robust quantitative and qualitative evidence and captured the main HRQoL impacts of LOPD. The general public rated the health states consistently lower with increasing disease progression. There was greater uncertainty around utility estimates for the severe states, suggesting that participants found it harder to rate them. Conclusion: This study provides utility estimates for LOPD that can be used in economic modeling of treatments for LOPD. Our findings highlight the high disease burden of LOPD and reinforce the societal value of slowing disease progression.

Phase I study of liver depot gene therapy in late-onset Pompe disease.

Gene therapy with an adeno-associated virus serotype 8 (AAV8) vector (AAV8-LSPhGAA) could eliminate the need for enzyme replacement therapy (ERT) by creating a liver depot for acid α-glucosidase (GAA) production. We report initial safety and bioactivity of the first dose (1.6 × 1012 vector genomes/kg) cohort (n = 3) in a 52-week open-label, single-dose, dose-escalation study (NCT03533673) in patients with late-onset Pompe disease (LOPD). Subjects discontinued biweekly ERT after week 26 based on the detection of elevated serum GAA activity and the absence of clinically significant declines per protocol. Prednisone (60 mg/day) was administered as immunoprophylaxis through week 4, followed by an 11-week taper. All subjects demonstrated sustained serum GAA activities from 101% to 235% of baseline trough activity 2 weeks following the preceding ERT dose. There were no treatment-related serious adverse events. No subject had anti-capsid T cell responses that decreased transgene expression. Muscle biopsy at week 24 revealed unchanged muscle glycogen content in two of three subjects. At week 52, muscle GAA activity for the cohort was significantly increased (p < 0.05). Overall, these initial data support the safety and bioactivity of AAV8-LSPhGAA, the safety of withdrawing ERT, successful immunoprophylaxis, and justify continued clinical development of AAV8-LSPhGAA therapy in Pompe disease.