Search Results (127)

Pompe disease (PD) is a neuromuscular autosomal recessive disorder caused by mutation in the GAA gene, which encodes acid α-glucosidase (GAA), an enzyme responsible for hydrolyzing glycogen to glucose. Deficiency of this enzyme leads to pathological accumulation of glycogen in almost all tissues of the body, with the most pronounced effects in cardiac and skeletal muscle, as well as in the central nervous system. Two major clinical forms of PD are recognized: infantile-onset PD, characterized by almost complete absence of GAA activity and severe cardiomyopathy and neurological abnormalities, and late-onset PD, which primarily presents with impairment of respiratory and motor function. Since 2006, enzyme replacement therapy with recombinant GAA has been used to treat PD, improving survival and quality of life. However, this approach has several limitations: the need for lifelong infusions, the risk of immune responses, and the inability of the enzyme to cross the blood–brain barrier, which is particularly critical for infantile-onset PD. Consequently, alternative strategies are being developed, including gene therapy using adeno-associated virus vectors for GAA delivery to target tissues; these approaches are currently in phase I/II clinical trials. Transplantation of genetically modified hematopoietic stem cells also represents a promising therapeutic strategy, offering a single-intervention treatment with long-lasting effects. This review discusses the molecular mechanisms of PD, current and emerging disease models, and therapeutic approaches, which together open prospects for the development of potentially one-time curative treatments, despite persistent challenges such as immunogenicity and the need for long-term efficacy monitoring. Full article

We conducted a cost-effectiveness analysis of a universal newborn screening (NBS) program for infantile-onset Pompe disease (IOPD) compared with clinical identification in newborns. The analytical model combined a decision tree and a Markov model. The incremental cost-effectiveness ratio (ICER) was estimated over a lifetime horizon, applying a 2% annual discount rate from the public healthcare payer’s perspective. In a cohort of 727,288 individuals, 2.4 patients were expected to have IOPD. The cumulative quality-adjusted life years (QALYs) gained per patient were estimated to be 7.9 when clinically diagnosed and treated with enzyme replacement therapy, and 28.9 when identified through universal NBS. The ICER was 174 million JPY per QALY. Sensitivity and scenario analyses indicated that the parameters most affecting the ICER were the NBS test cost, the quality-of-life value for ambulatory patients, the prevalence of IOPD, and the cost of enzyme replacement therapy. Although considerable uncertainty exists in the analysis, the findings suggest that implementing NBS solely for detecting infantile-onset cases poses challenges in terms of cost-effectiveness, primarily due to the rarity of the disease and the high costs associated with testing and treatment. Full article

Growth impairment is a clinical manifestation frequently observed in pediatric patients with cardiomyopathy associated with various inherited disorders, including RASopathies, lysosomal storage diseases, neuromuscular disorders, and metabolic conditions. In this narrative review, we explored the genetic and pathophysiological mechanisms underlying the development of both growth and myocardial impairment in Noonan syndrome (NS)—the most common RASopathy—Duchenne and Becker muscular dystrophies, Pompe disease, mucopolysaccharidoses, and mitochondrial diseases. For each condition, we described the cardiac and growth phenotypes, focusing on epidemiology, clinical implications, and disease-specific therapeutic strategies. In the era of precision medicine, innovative etiologic treatments targeting the underlying molecular mechanisms have emerged. Therefore, elucidating the molecular pathways responsible for growth impairment in pediatric inherited cardiomyopathies remains essential for optimizing multidisciplinary management and improving patient outcomes. Full article

Background and Clinical Significance: Classic infantile-onset Pompe disease (IOPD) is the most severe form of Pompe disease, manifesting within the first months of life with hypertrophic cardiomyopathy and severe hypotonia. Avalglucosidase alfa is a next-generation recombinant human α-glucosidase that was recently approved for use. Clinical trials, conducted on IOPD patients already treated with alglucosidase alfa, have recommended a dosage ranging from 20 to 40 mg/kg every other week. The optimal dosage for treatment-naïve patients has not yet been established. We present a case of a severe IOPD patient who received a short-term high-dose, high-frequency regimen of avalglucosidase alfa (40 mg/kg/week). Case Presentation: The patient, a 3-month-old infant, presented with hypotonia and severe hypertrophic cardiomyopathy (left ventricular mass index (LVMI) of 136 g/m²; ejection fraction (EF) of 60%). Treatment with avalglucosidase alfa was initiated at a dose of 40 mg/kg every other week. After two weeks, cardiac function further deteriorated (LVMI of 168 g/m²; EF of 46%), so the treatment was intensified to a dose of 40 mg/kg weekly for two months. This resulted in significant clinical, biochemical, and motor improvements without adverse reactions. Following this improvement, the dosage of 40 mg/kg every other week was reinstated. At 18 months of age, the patient demonstrated normal motor development, normal cardiac function (LVMI of 49 g/m²; EF of 68%), and normal biomarkers. Conclusions: Although limited to a single patient, this case illustrates that short-term high-dose, high-frequency administration of avalglucosidase alfa could be both effective and safe, even in patients with severe, late-diagnosed IOPD. Full article

The liver is a primary metabolic hub and a pivotal target for gene therapy, owing to its capacity for protein secretion, role in metabolic homeostasis and immune tolerance. Liver-directed gene therapies are used to treat numerous inherited metabolic disorders and coagulation factor deficiencies including hemophilia (A and B), Crigler–Najjar syndrome, mucopolysaccharidoses, phenylketonuria, Fabry, Gaucher, Wilson and Pompe diseases. The efficacy and safety of liver-directed gene therapy rely on the use of strong tissue-specific promoters. To date, there are many different liver-specific promoters used in preclinical and clinical studies, including novel completely synthetic promoters. This review provides a comprehensive analysis of the design, engineering and application of liver-specific promoters. Furthermore, we discuss fundamental principles of gene expression regulation in the liver and the physiological and immunological characteristics that make it a suitable target organ for gene therapy delivery. Full article

Lysosomal storage disorders (LSDs) are a group of rare inherited diseases caused by mutations in the genes encoding the proteins involved in normal lysosomal functions, leading to an accumulation of undegraded substrates within lysosomes. Among the most prominent clinical features are neurological impairment and neurodegeneration, arising from widespread cellular dysfunction. The development of powerful and reliable animal model systems that can in vivo recapitulate human LSD pathologies is critical for understanding disease mechanisms and advancing therapeutic strategies. In this study, we identified the Drosophila melanogaster orthologs of human LSD-related genes using the DIOPT tool and performed tissue-specific gene silencing along the brain–midgut axis via the use of GAL4/UAS and RNAi combined technologies. Transgenic fly models presented key features of human LSD pathologies, including significantly shortened lifespans and a progressive locomotor decline that serves as a measure for neuromuscular disintegration, following age- and sex-dependent patterns. These phenotypic parallels in pathology strongly support the functional relevance of the selected orthologs and underscore the value of Drosophila as a versatile in vivo model system for advanced LSD pathology research, offering state-of-the-art genetic tools for molecularly dissecting disease mechanisms and providing cutting-edge novel platforms for high-throughput genetic and/or pharmacological screening, moving towards development of new therapeutically beneficial drug-based regimens and mutant gene-rescue schemes. Full article

The goal of newborn screening (NBS) has remained the same despite its significant expansion from its inception as a public health initiative. This goal is to identify infants that are at risk for a set list of conditions and to implement a care plan to prevent, delay, or mitigate adverse health outcomes for those affected. The role of genetic counselors (GCs) in the NBS space is currently evolving, and there is limited research on parental experiences with genetic counseling for more recently added conditions on a list approved by the U.S. Secretary of Health and Human Services called the Recommended Uniform Screening Panel (RUSP). This qualitative study interviewed parents who have spoken to a genetic counselor after their child was diagnosed with one of three following conditions in the past five years: Pompe disease, X-linked Adrenoleukodystrophy, and Spinal Muscular Atrophy. A total of 13 interviews were conducted and results were organized into five thematic areas: (1) NBS/Results Disclosure, (2) Diagnostic Process after NBS, (3) Treatment/Follow-Up, (4) Communication, and (5) Holistic Support. The findings of this study highlighted parental preferences for early involvement of genetic counselors, provider, and parent education on NBS, and the provision of family support beyond genetic resources. Full article

Pompe disease is an autosomal recessive metabolic disorder caused by acid alpha-glucosidase (GAA) deficiency. The use of umbilical cord blood (UCB) for newborn screening (NBS) of Pompe disease, compared to heel-prick sampling, has not been widely studied. This study compared GAA activity in UCB from term newborns with peripheral or heel-prick blood samples obtained on days 1, 2, and 3 after birth. Enzyme assays were performed using UPLC-MS/MS. Sanger sequencing was conducted in infants with low GAA activity to identify pathogenic variants. Among 4091 UCB samples analyzed over 18 months, the mean GAA activity was 10.04 ± 5.95 μM/h, higher in females than males [Median (IQR): 9.83 (5.45) vs. 9.08 (4.97) μM/h, respectively, p < 0.001], and similar across ethnicities. GAA levels in UCB and Day 3 heel-prick samples were comparable. A GAA cut-off value of 1.54 μM/h (0.1% of study population) identified one infant (0.024% prevalence) with a novel bi-allelic variant—c.2005_2010del (p.Pro669_Phe670del) and c.1123C>T (p.Arg375Cys), and 12 infants with non-pathogenic pseudodeficiency alleles. This study supports GAA measurement in UCB as a viable alternative for NBS, with enzyme activity remaining stable for up to 72 h post-collection. Larger-scale multicenter nationwide studies are warranted to confirm this prevalence in our population. Full article

Background/Objectives: Pompe disease (PD) is a rare autosomal recessive disorder caused by a deficiency of the lysosomal acid α-1,4-glucosidase (GAA) encoded by the GAA gene, leading to muscular dysfunctions due to pathological accumulation of glycogen in skeletal and cardiac muscles. PD has been reported in several animals and Japanese quails (JQ; Coturnix japonica), but a causative mutation has yet to be found in JQs with PD. Here, we aimed to identify a pathogenic mutation in JQs associated with PD. Methods: Paraffin-embedded skeletal muscle blocks from four JQs stored since the 1970s were used in this study. After confirming the histopathological phenotypes of PD, Sanger sequencing was performed to identify a pathological mutation in the GAA I gene of JQs. A genotyping survey was conducted using a real-time polymerase chain reaction assay targeting a candidate mutation using DNA samples extracted from 70 new-hatched JQs and 10 eggs from commercial farms. Results: Microscopic analysis confirmed the presence of the PD phenotype in three affected JQs based on abnormal histopathological changes and accumulated glycogen in the affected muscles, while one JQ was unaffected and served as a control. Sanger sequencing revealed that the three affected JQs were homozygous for the deletion of guanine at position 1096 in the open reading frame (c.1096delG). A genotyping survey of 70 JQs and 10 eggs from commercial farms showed that none carried this deletion mutation. Conclusions: This study identified c.1096delG as the pathogenic mutation for PD in JQs. This mutation induces a frameshift and substitution of amino acids at position 366 (alanine to histidine), resulting in premature termination at the 23rd codon (p.A366Hfs*23). This suggests that this mutation causes the deficient activity of GAA in JQs with PD. The identification of the c.1096delG mutation enabled the systematic maintenance of the flock colony in the PD model. Furthermore, this PD model can be used to clarify unknown aspects of PD pathogenesis and develop therapeutic strategies. Full article

Skeletal muscle, constituting ~40% of body mass, serves as a primary effector for movement and a key metabolic regulator through myokine secretion. Hereditary myopathies, including dystrophinopathies (DMD/BMD), limb–girdle muscular dystrophies (LGMD), and metabolic disorders like Pompe disease, arise from pathogenic mutations in structural, metabolic, or ion channel genes, leading to progressive weakness and multi-organ dysfunction. Gene therapy has emerged as a transformative strategy, leveraging viral and non-viral vectors to deliver therapeutic nucleic acids. Adeno-associated virus (AAV) vectors dominate clinical applications due to their efficient transduction of post-mitotic myofibers and sustained transgene expression. Innovations in AAV engineering, such as capsid modification (chemical conjugation, rational design, directed evolution), self-complementary genomes, and tissue-specific promoters (e.g., MHCK7), enhance muscle tropism while mitigating immunogenicity and off-target effects. Non-viral vectors (liposomes, polymers, exosomes) offer advantages in cargo capacity (delivering full-length dystrophin), biocompatibility, and scalable production but face challenges in transduction efficiency and endosomal escape. Clinically, AAV-based therapies (e.g., Elevidys^® for DMD, Zolgensma^® for SMA) demonstrate functional improvements, though immune responses and hepatotoxicity remain concerns. Future directions focus on AI-driven vector design, hybrid systems (AAV–exosomes), and standardized manufacturing to achieve “single-dose, lifelong cure” paradigms for muscular disorders. Full article

Background/Objectives: Glycogen storage disease type II, also known as Pompe disease (PD), is a rare autosomal recessive genetic disorder triggered by a deficiency in lysosomal acid α-glucosidase (GAA). Recently, we discovered two deleterious missense variants of the GAA gene, c.1799G>A (p.Arg600His) (a pathogenic mutation) and c.55G>A (p.Val19Met), in a domestic short-haired cat with PD. This study aimed to design genotyping assays for these two variants and ascertain their allele frequencies in Japanese cat populations. Methods: We developed fluorescent probe-based real-time polymerase chain reaction assays to genotype the c.1799G>A and c.55G>A variants. A total of 738 cats, comprising 99 purebred cats from 20 breeds and 540 mixed-breed cats, were screened using these assays. Results: Genotyping assays clearly differentiated all known genotypes of the two variants. None of the 738 cats tested carried the c.1799G>A variant. However, we identified cats with c.55G/A and c.55A/A genotypes in the purebred (A allele frequency: 0.081) and mixed-breed cats (0.473). A significant difference (p < 0.001) was observed in the A allele frequency between the two groups. Conclusions: The c.1799G>A mutation appears rare in cat populations, suggesting it may be confined to specific pedigree Japanese mixed-breed cats. The c.55G>A variant was detected in purebred and mixed-breed cats, suggesting that it may not be directly linked to feline PD. However, additional studies are required to elucidate the precise relationship between this variant and cardiac function. Genotyping assays will serve as valuable tools for diagnosing and genotyping feline PD. Full article

Pompe disease is a rare autosomal-recessive neuromuscular disorder caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA), leading to the pathological accumulation of glycogen and impaired autophagy. Enzyme replacement therapy (ERT) with recombinant human alpha-glucosidase (rhGAA) has been available since 2006, but may lead to the formation of anti-drug antibodies (ADAs) against the recombinant human enzyme, which, in turn, may adversely affect the response to ERT. Knowledge of the antigenic determinants of rhGAA involved in interaction with ADAs may facilitate the development of strategies to attenuate the anti-drug immune response in patients. Here, we determined the rhGAA ADA epitopes in the plasma of Pompe disease patients using a series of affinity purifications combined with epitope extraction and label free quantitation LC-MS. Full article

Newborn screening laboratories are increasingly adding lysosomal storage disorders (LSDs), such as Mucopolysaccharidosis I (MPS I) and Pompe disease, to their screening panels. Without newborn screening, LSDs are frequently diagnosed only after the onset of symptoms; late detection can lead to profound and irreversible organ damage and mortality. While screening of these disorders has accelerated over the past five years, there is little published information regarding the potential correlation of demographic variables (age at sample collection, birthweight, gestational age, gender, etc.) with lysosomal enzyme activity. The Missouri State Public Health Laboratory prospectively screened more than 475,000 newborns for MPS I, Pompe disease, Gaucher disease, and Fabry disease between 15 January 2013 and 15 May 2018. This report investigates trends between several demographic variables and activities of four lysosomal enzymes: α-L-iduronidase (IDUA), acid α-glucosidase (GAA), acid β-glucocerebrosidase (GBA), and acid α-galactosidase (GLA). This information provides a valuable resource to newborn screening laboratories for the implementation of screening for lysosomal storage disorders and the establishment of screening cutoffs. Full article

Newborn screening (NBS) is leading to the diagnosis of a large number of children with late-onset Pompe disease (LOPD), yet many remain asymptomatic until later years. A high-protein, low-carbohydrate diet is recommended for adults with LOPD. Nutrition guidelines are not available for young children. Methods: 37 children with LOPD aged 1–6 years participated. Early diet history, feeding practices, and 24 h dietary intake were collected via questionnaire. Anthropometric measurements, blood creatine kinase (CK), blood urea nitrogen (BUN)/creatinine ratio, and urine glucose tetrasaccharide (Glc4) were collected at clinic visits. A subset of 19 children received a clinical feeding assessment (CFA). Results: All patients derived their nutrition orally. Breastfeeding was successfully initiated in 73% of infants. Body weight ranged between 3 and 99% and height ranged from 4 to 97%. A tendency to be overweight and obese was noted in older children with LOPD. A total of 24% of the children who had CFA were diagnosed with dysphagia that was typically mild in severity and rarely affected their ability to eat a normal diet. Limiting added sugar and processed foods was the most widely used dietary practice followed by encouraging protein. Protein intake was three–four times higher than the recommended dietary intake (RDA). A high BUN/creatinine ratio was observed in some children, which may indicate incompatibility with protein intake and need for individualizing the diet. Conclusions: The results of this study provide a framework for developing future nutrition guidelines for children with LOPD by performing an individualized assessment of dietary intake, growth, feeding/swallowing, and laboratory parameters. Full article

Background: Lysosomal storage disorders (LSDs) are rare inherited metabolic diseases characterized by defects in lysosomal enzyme function or membrane transport. These defects lead to substrate accumulation and multisystemic manifestations. This review focuses on gastrointestinal (GI) involvement in LSDs, which is a significant but often overlooked aspect of these disorders. Methods: A comprehensive literature review was conducted to examine the pathophysiology, clinical presentation, diagnosis and management of GI manifestations in several LSDs, including Fabry disease, Gaucher disease, Pompe disease, Niemann–Pick disease type C, mucopolysaccharidoses and Wolman disease. Results: The pathogenesis of GI involvement in LSDs varies and encompasses substrate accumulation in enterocytes, mesenteric lymphadenopathy, mass effects, smooth muscle dysfunction, vasculopathy, neuropathy, inflammation and alterations to the microbiota. Clinical presentations range from non-specific symptoms, such as abdominal pain, diarrhea and malabsorption, to more severe complications, such as protein-losing enteropathy and inflammatory bowel disease. Diagnosis often requires a high level of suspicion, as GI symptoms may precede the diagnosis of the underlying LSD or be misattributed to more common conditions. Management strategies include disease-specific treatments, such as enzyme replacement therapy or substrate reduction therapy, as well as supportive care and targeted interventions for specific GI complications. Conclusions: This review highlights the importance of recognizing and properly managing GI manifestations in LSDs to improve patient outcomes and quality of life. It also emphasizes the need for further research to develop more effective treatments for life-threatening GI complications associated with these rare genetic disorders. Full article