Pompe Disease Research Articles

Development and validation of a smartphone based app to guide the differential diagnosis in patients with primary left ventricular hypertrophy: the Thick Heart App

Abstract Introduction Patients presenting with primary Left Ventricular Hypertrophy (LVH) suffers from a diagnostic delay quantified in years. They are often misdiagnosed because of both physician-related and disease-related reasons including fragmented knowledge among different specialties and rarity of the conditions. Purpose We developed and validate a free digital support tool in the form of an App to provide support and to guide the physician in the differential diagnostic process of patients presenting with primary LVH. Methods We studied 712 patients with definitive diagnosis of sarcomeric HCM or one of its genocopies (414 (58%) males, 48±24 years) referred to four tertiary centers in Europe. Pre-specified RF were categorized into five domains: family history; signs/symptoms; electrocardiography, echocardiographic and laboratory. Each patient’s characteristics were inserted by two independent and blind investigators on the App of the digital support tool. The possible diagnostic outcome was categorized as follows: (a) most likely diagnosis (age range for the condition, at least 1 extremely specific RFs or >1 specific RF; (b) possible diagnosis (age range, 1 specific RF); (c) less likely diagnosis (outside age range, no RF selected). Results Ris were common in patients presenting with a genotyped HCM (2568 RFs, 3.5 per patient). RF on physical examination was associated with non sarcomeric aetiology (318/319 physical examination RF identified in non-sarcomeric HCM), whereas 68% of RF associated with sarcomeric HCM were derived from accurate ECG and echocardiography analysis. Sarcomeric HCM, TTR-amyloidosis, Danon and PRKAG2 cardiomyopathy relied extensively on ECG and echocardiographic systematic analyisis (68%, 69%, 67% and 69% respectively). In contrast, AFD, Friederich’s ataxia, Noonan syndrome with multiple lentiges (NSML), mitochondrial, Pompe and Noonan cardiomyopathy presented red flags potentially identifiable in the general practioner setting by anamnesis, physical examination and routine laboratory (57%, 59%, 52%, 57%, 57% and 58% respectively) in the vast majority of case. A total of 697/712 (97.8%) were correctly categorized in the most likely and possible diagnosis section. The App proved to be sensible for sarcomeric HCM, FD (0.99 and 0.91, NPV 0.98 and 0.83) and extremely capable in the identification of rare causes of LVH (Danon, Friederich’s ataxia, LEOPARD, Pompe, Noonan and PRKAG2 diseases). By design, specificity was not high, in particular for sarcomeric HCM and FD. Conclusions The present validation of an App based free digital support tool in the form of an App proved to be extremely sensible in providing the support to the screening of different causes of primary LVH in patients presenting with a HCM phenotype. Further external and multicenter validation is warranted.

First-in-Human Evaluation of Safety, Pharmacokinetics and Muscle Glycogen Lowering of a Novel Glycogen Synthase 1 Inhibitor for the Treatment of Pompe Disease.

Pompe disease is a rare glycogen storage disease caused by mutations in the enzyme acid α-glucosidase (GAA) resulting in pathological accumulation of glycogen in muscle tissues leading to progressive weakness and respiratory dysfunction. Enzyme replacement therapy (ERT) with GAA is currently the sole treatment option for patients with Pompe disease. ERT burdens patients with frequent intravenous infusions while insufficiently halting disease progression due to incomplete ERT skeletal muscle distribution. Glycogen synthase 1 (GYS1) has been proposed as a substrate reduction therapy (SRT) target for Pompe disease. Here, we report results from the first-in-human study of the orally available GYS1 inhibitor MZE001 in healthy subjects. In 88 participants, MZE001 was well-tolerated up to a single dose of 480 mg BID and multiple doses of 720 mg BID for 10 days. Noncompartmental analysis determined that the half-life and Ctrough concentrations of MZE001 could provide efficacious exposures with once or twice daily oral dosing. Change from baseline of peripheral blood mononuclear cell (PBMC) glycogen, which correlated with muscle glycogen levels in preclinical models, was significantly reduced dose-dependently following 10 days of MZE001 treatment in healthy subjects. A muscle biopsy sub-study demonstrated that 10 days of MZE001 (480 mg BID) dosing safely and substantially lowered muscle glycogen stores in healthy adults. This correlated with the PBMC exposure response and supports the use of PBMC glycogen reduction as a surrogate for muscle response, and MZE001 potential for development as the first oral substrate reduction therapy for patients with Pompe disease.

New Horizons in Undrestanding and Treating Pompe Disease: Diagnosis and Therapy. A review of the literature.

New Horizons in Undrestanding and Treating Pompe Disease: Diagnosis and Therapy. A review of the literature.

Pompe disease, a new approach to clearing out the trash.

Pompe disease, a new approach to clearing out the trash.

Global birth prevalence of Pompe disease: A systematic review and meta-analysis

BackgroundPompe disease, also known as Glycogen storage disease type II, is an autosomal recessive disorder caused by defects in alpha-glucosidase, resulting in abnormal glycogen accumulation. MethodsTo conduct a systematic review and meta-analysis of birth prevalence of Pompe disease, the MEDLINE and EMBASE databases were searched for original research articles on the epidemiology of Pompe disease from inception until July 01, 2024. Meta-analysis was performed to estimate global birth prevalence of Pompe disease. The funnel plot was used to describe potential publication bias. ResultsTwenty-two studies, screened out of 945 records, were included for data extraction. Studies that fulfilled inclusion criteria involved 15 areas/countries. Global birth prevalence of Pompe disease was 2.0 cases (95% CI: 1.5–2.4) per 100,000 live births. Global birth prevalence of infantile-onset Pompe disease was 1.0 cases (95% CI: 0.5–1.5) per 100,000 live births. Global birth prevalence of late-onset Pompe disease was 2.4 cases (95% CI: 1.8–3.0) per 100,000 live births. The main limitations are that no study was assessed as high-quality and approximately half of the studies were from Europe. ConclusionsQuantitative data on the global epidemiology of Pompe disease could be the fundamental to evaluate the global efforts on building a better world for Pompe disease patients.

667P Glycogen response to enzyme replacement therapy in patients with Pompe disease

667P Glycogen response to enzyme replacement therapy in patients with Pompe disease

661P Sensitivity to change and meaningful change thresholds of the Quick Motor Function Test (QMFT) in Pompe disease

661P Sensitivity to change and meaningful change thresholds of the Quick Motor Function Test (QMFT) in Pompe disease

664P From past to present: Pompe disease, pseudodeficiency, and genetic challenges

664P From past to present: Pompe disease, pseudodeficiency, and genetic challenges

672P New insights into Pompe disease using Raman-microscopy

672P New insights into Pompe disease using Raman-microscopy

660P Safety and efficacy of switching to avalglucosidase alfa in patients with late-onset Pompe disease previously deteriorating on alglucosidase alfa

660P Safety and efficacy of switching to avalglucosidase alfa in patients with late-onset Pompe disease previously deteriorating on alglucosidase alfa

663P Screening for Pompe disease and its differential diagnoses

663P Screening for Pompe disease and its differential diagnoses

675P Understanding skeletal muscle pathology and function in late-onset Pompe disease: insights from proteomic and transcriptomic analyses

675P Understanding skeletal muscle pathology and function in late-onset Pompe disease: insights from proteomic and transcriptomic analyses

668P Pompe Registry: Real-world experience of patients with late-onset Pompe disease who switched therapy from alglucosidase alfa to avalglucosidase alfa

668P Pompe Registry: Real-world experience of patients with late-onset Pompe disease who switched therapy from alglucosidase alfa to avalglucosidase alfa

673P Magnetization transfer imaging in late-onset Pompe disease

673P Magnetization transfer imaging in late-onset Pompe disease

658P High-risk screening for Late-Onset Pompe Disease in China: an expanded Multicenter Study

658P High-risk screening for Late-Onset Pompe Disease in China: an expanded Multicenter Study

657P Cipaglucosidase alfa + miglustat in late-onset Pompe disease: two non-ambulatory patients switching from high-dose, high-frequency alglucosidase alfa

657P Cipaglucosidase alfa + miglustat in late-onset Pompe disease: two non-ambulatory patients switching from high-dose, high-frequency alglucosidase alfa

529P Paucisymptomatic late onset Pompe disease: lessons from the clinical, radiological and histopathological long-term follow-up of an untreated patient

529P Paucisymptomatic late onset Pompe disease: lessons from the clinical, radiological and histopathological long-term follow-up of an untreated patient

671P Miglustat: a first-in-class enzyme stabiliser for late-onset Pompe disease

671P Miglustat: a first-in-class enzyme stabiliser for late-onset Pompe disease

670P Post-baseline outcomes of the UK Early Access to Medicines Scheme registry for cipaglucosidase alfa plus miglustat in late-onset Pompe disease

670P Post-baseline outcomes of the UK Early Access to Medicines Scheme registry for cipaglucosidase alfa plus miglustat in late-onset Pompe disease

Effectiveness of Respiratory Muscle Training in Pompe Disease: A Systematic Review and Meta-Analysis.

Background: Pompe disease is a rare metabolic myopathy caused by the lack or deficiency of the lysosomal acid alpha-glucosidase, resulting in skeletal muscle weakness and cardiomyopathy. The disease varies by onset age and genetic mutations and is categorized into infantile-onset and late-onset Pompe disease. Respiratory muscle weakness may persist regardless enzyme replacement therapy. This systemic review and meta-analysis aim to assess the effect of respiratory muscle training (RMT) on respiratory muscle strength, functional endurance, and pulmonary function in patient with Pompe disease. Methods: PubMed, EMBASE, and Cochrane databases were searched up until Aug 2024. Studies examining the therapeutic effects of RMT in patients with Pompe disease were included. Outcome measures included the change in maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), six-minute walking test (6MWT), pulmonary function before after RMT, quality of life and adverse events. Results: The meta-analysis consisted of 5 single-arm studies, including 31 patients in total. Regarding inspiratory muscle strength, RMT has significantly improving MIP (8.71 cmH2O; 95% CI, 6.23-11.19, p < 0.001) and MEP (12.15 cmH2O; 95% CI, 10.55-13.74, p < 0.001) in both types of Pompe disease. However, no significant change regarding 6MWT. No serious adverse events were reported. Conclusions: Our meta-analysis revealed that RMT may increase inspiratory muscle and expiratory muscle strength, but may not have an effect on 6MWT in patients with Pompe disease. RMT has potential to be integrated into the cardioplulmonary rehabilitation for patients with Pompe disease. Further large randomized controlled trials are needed to verify the efficacy and safety of RMT in patients with Pompe disease.