Deficiency Of Acid Alpha-glucosidase Research Articles

Satellite cells fail to contribute to muscle repair but are functional in Pompe disease (glycogenosis type II)

Pompe disease, which is due to acid alpha-glucosidase deficiency, is characterized by skeletal muscle dysfunction attributed to the accumulation of glycogen-filled lysosomes and autophagic buildup. Despite the extensive tissue damages, a failure of satellite cell (SC) activation and lack of muscle regeneration have been reported in patients. However, the origin of this defective program is unknown. Additionally, whether these deficits occur gradually over the disease course is unclear. Using a longitudinal pathophysiological study of two muscles in a Pompe mouse model, here, we report that the enzymatic defect results in a premature saturating glycogen overload and a high number of enlarged lysosomes. The muscles gradually display profound remodeling as the number of autophagic vesicles, centronucleated fibers, and split fibers increases and larger fibers are lost. Only a few regenerated fibers were observed regardless of age, although the SC pool was preserved. Except for the early age, during which higher numbers of activated SCs and myoblasts were observed, no myogenic commitment was observed in response to the damage. Following in vivo injury, we established that muscle retains regenerative potential, demonstrating that the failure of SC participation in repair is related to an activation signal defect. Altogether, our findings provide new insight into the pathophysiology of Pompe disease and highlight that the activation signal defect of SCs compromises muscle repair, which could be related to the abnormal energetic supply following autophagic flux impairment.

Clinical and molecular characterization of Korean children with infantile and late-onset Pompe disease: 10 years of experience with enzyme replacement therapy at a single center.

PurposePompe disease (PD) is an autosomal recessive disorder caused by a deficiency of acid alphaglucosidase resulting from pathogenic GAA variants. This study describes the clinical features, genotypes, changes before and after enzyme replacement therapy (ERT), and long-term outcomes in patients with infantile-onset PD (IOPD) and late-onset PD (LOPD) at a tertiary medical center.MethodsThe medical records of 5 Korean patients (2 male, 3 female patients) diagnosed with PD between 2002 and 2013 at Samsung Medical Center in Seoul, Republic of Korea were retrospectively reviewed for data, including clinical and genetic characteristics at diagnosis and clinical course after ERT.ResultsCommon initial symptoms included hypotonia, cyanosis, and tachycardia in patients with IOPD and limb girdle weakness in patients with LOPD. Electrocardiography at diagnosis revealed hypertrophic cardiomyopathy in all patients with IOPD who showed a stable disease course during a median follow-up period of 10 years. Patients with LOPD showed improved hepatomegaly and liver transaminase level after ERT.ConclusionAs ERT is effective for treatment of PD, early identification of this disease is very important. Thus, patients with IOPD should be considered candidates for clinical trials of new drugs in the future.

METABOLIC MYOPATHIES II: P.352A novel recombinant human acid alpha-glucosidase, ATB200, co-administered with a pharmacological chaperone, leads to greater substrate reduction and improvement in Pompe disease-relevant markers compared to alglucosidase alfa in Gaa KO mice

Pompe disease is an inherited lysosomal storage disorder caused by a deficiency in acid alpha-glucosidase (GAA) activity, and is characterized by progressive accumulation of lysosomal glycogen in cardiac and skeletal muscles. Enzyme replacement therapy using recombinant human GAA (rhGAA), alglucosidase alfa, is currently the only approved treatment for Pompe disease. However, alglucosidase alfa may have limitations in delivery to skeletal muscles due to sub-optimal levels of mannose-6-phosphate (M6P), a carbohydrate that binds cation-independent M6P receptors at the cell surface to mediate enzyme internalization and lysosomal delivery. We have developed a novel rhGAA (designated ATB200) with a significantly higher M6P content compared to alglucosidase alfa; ATB200 is further stabilized by the small molecule pharmacological chaperone, AT2221 (miglustat). In this study, we compared the effects of ATB200, orally co-administered with AT2221 (ATB200/AT2221; co-administration), to those of alglucosidase alfa in Gaa knockout (KO) mice. Repeat administration of ATB200/AT2221 resulted in substantially greater enzyme levels in lysosomes and significant glycogen reduction in key skeletal muscles. Importantly, extensive histological analysis of Gaa KO mouse muscle showed that ATB200/AT2221 is more effective compared to alglucosidase alfa in correcting overall cellular dysfunction in the endocytic-lysosomal-autophagic pathways, including lysosomal proliferation and autophagic buildup, the two known hallmarks of Pompe disease. Notably, these positive changes correlated well with improvements in muscle strength and muscle fiber size. Collectively, these data indicate that ATB200, stabilized by the pharmacological chaperone AT2221, offers potential advantages over the standard of care, and warrants further investigation as a next-generation treatment in patients with Pompe disease.

NEW THERAPEUTIC APPROACHES AND THEIR READOUT: O.20Results from ATB200-02: first-in-human, open-label, phase 1/2 study of ATB200 co-administered with AT2221 for Pompe disease

Late-onset Pompe disease (LOPD) is caused by impaired lysosomal glycogen clearance due to acid alpha-glucosidase (GAA) deficiency. Accumulation of glycogen in skeletal muscle and diaphragm leads to loss of muscle and respiratory function. Recombinant human GAA enzyme replacement therapy (rhGAA ERT; alglucosidase alfa) is standard treatment for LOPD. ATB200-02 (NCT02675465) is a first-in-human, open-label, Phase 1/2 trial to evaluate ATB200, a next-generation rhGAA ERT, co-administered with AT2221, an oral pharmacological chaperone, in adults with LOPD. Twenty patients (pts) were enrolled: ERT-switch ambulatory (Cohort 1, n=11), ERT-switch nonambulatory (Cohort 2, n=4), and ERT-naive ambulatory (Cohort 3, n=5). Mean±SD 6-minute walk test increased for ambulatory ERT-switch (Month [Mo] 6 [n=10], +23.9±52.2; Mo 9 [n=10], +24.5±40.8; Mo 12 [n=8], +57.4±34.4 m) and ERT-naive pts (Mo 6 [n=5], +41.8±29.4; Mo 9 [n=5], +63.5±23.1; Mo 12 [n=2], +86.8±11.1 m). Other motor function tests were generally consistent with these results. Increases were observed in upper extremity strength in nonambulatory ERT-switch pts at Mo 6 and 9. Forced vital capacity (% predicted) increased in ERT-naive pts (Mo 6 [n=5], +4.2; Mo 9 [n=5], +6.2; Mo 12 [n=2], +6.0) and was generally stable in ambulatory ERT-switch pts (Mo 6 [n=9], -1.3; Mo 9 [n=9], -1.7; Mo 12 [n=7], -3.1). All cohorts demonstrated improvements in the Fatigue Severity Scale. ATB200/AT2221 was associated with reductions in creatine kinase and urine hexose tetrasaccharide. The most common treatment-emergent adverse events were upper and lower abdominal pain (n=8), diarrhea (n=8), and nasopharyngitis (n=6). Three events of infusion-associated reactions occurred in 550+ infusions. Data from this interim analysis show a clinical benefit of ATB200/AT2221 in ERT-naive pts and in pts who have been on ERT for ∼5 years. ATB200/AT2221 has the potential to be a significant treatment alternative for patients with Pompe disease.

Systemic Delivery of AAVB1-GAA Clears Glycogen and Prolongs Survival in a Mouse Model of Pompe Disease.

Pompe disease is an autosomal recessive glycogen storage disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). GAA deficiency results in systemic lysosomal glycogen accumulation and cellular disruption in muscle and the central nervous system (CNS). Adeno-associated virus (AAV) gene therapy is ideal for Pompe disease, since a single systemic injection may correct both muscle and CNS pathologies. Using the Pompe mouse (B6;129-GaaTm1Rabn/J), this study sought to explore if AAVB1, a newly engineered vector with a high affinity for muscle and CNS, reduces systemic weakness and improves survival in adult mice. Three-month-old Gaa-/- animals were injected with either AAVB1 or AAV9 vectors expressing GAA and tissues were harvested 6 months later. Both AAV vectors prolonged survival. AAVB1-treated animals had a robust weight gain compared to the AAV9-treated group. Vector genome levels, GAA enzyme activity, and histological analysis indicated that both vectors transduced the heart efficiently, leading to glycogen clearance, and transduced the diaphragm and CNS at comparable levels. AAVB1-treated mice had higher GAA activity and greater glycogen clearance in the tongue. Finally, AAVB1-treated animals showed improved respiratory function comparable to wild-type animals. In conclusion, AAVB1-GAA offers a promising therapeutic option for the treatment of muscle and CNS in Pompe disease.

Therapeutic Benefit of Autophagy Modulation in Pompe Disease.

The complexity of the pathogenic cascade in lysosomal storage disorders suggests that combination therapy will be needed to target various aspects of pathogenesis. The standard of care for Pompe disease (glycogen storage disease type II), a deficiency of lysosomal acid alpha glucosidase, is enzyme replacement therapy (ERT). Many patients have poor outcomes due to limited efficacy of the drug in clearing muscle glycogen stores. The resistance to therapy is linked to massive autophagic buildup in the diseased muscle. We have explored two strategies to address the problem. Genetic suppression of autophagy in muscle of knockout mice resulted in the removal of autophagic buildup, increase in muscle force, decrease in glycogen level, and near-complete clearance of lysosomal glycogen following ERT. However, this approach leads to accumulation of ubiquitinated proteins, oxidative stress, and exacerbation of muscle atrophy. Another approach involves AAV-mediated TSC knockdown in knockout muscle leading to upregulation of mTOR, inhibition of autophagy, reversal of atrophy, and efficient cellular clearance on ERT. Importantly, this approach reveals the possibility of reversing already established autophagic buildup, rather than preventing its development.

Late-onset Pompe disease: what is the prevalence of limb-girdle muscular weakness presentation?

Pompe disease is an inherited disease caused by acid alpha-glucosidase (GAA) deficiency. A single center observational study aimed at assessing the prevalence of late-onset Pompe disease in a high-risk Brazilian population, using the dried blood spot test to detect GAA deficiency as a main screening tool. Dried blood spots were collected for GAA activity assay from 24 patients with "unexplained" limb-girdle muscular weakness without vacuolar myopathy in their muscle biopsy. Samples with reduced enzyme activity were also investigated for GAA gene mutations. Of the 24 patients with dried blood spots, one patient (4.2%) showed low GAA enzyme activity (NaG/AaGIA: 40.42; %INH: 87.22%). In this patient, genetic analysis confirmed two heterozygous mutations in the GAA gene (c.-32-13T>G/p.Arg854Ter). Our data confirm that clinicians should look for late-onset Pompe disease in patients whose clinical manifestation is an "unexplained" limb-girdle weakness even without vacuolar myopathy in muscle biopsy.

Enzyme replacement therapy for infantile-onset Pompe disease.

Infantile-onset Pompe disease is a rare and progressive autosomal-recessive disorder caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). Current treatment involves enzyme replacement therapy (with recombinant human alglucosidase alfa) and symptomatic therapies (e.g. to control secretions). Children who are cross-reactive immunological material (CRIM)-negative require immunomodulation prior to commencing enzyme replacement therapy.Enzyme replacement therapy was developed as the most promising therapeutic approach for Pompe disease; however, the evidence is lacking, especially regarding the optimal dose and dose frequency. To assess the effectiveness, safety and appropriate dose regimen of enzyme replacement therapy for treating infantile-onset Pompe disease. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register, which is compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the Cochrane Central Register of Controlled Trials (CENTRAL), Embase (Ovid), PubMed and LILACS, and CBM, CNKI, VIP, and WANFANG for literature published in Chinese. In addition, we searched three online registers: WHO International Clinical Trials Registry Platform ClinicalTrials.gov, and www.genzymeclinicalresearch.com. We also searched the reference lists of relevant articles and reviews.Date of last search of the Group's Inborn Errors of Metabolism Trials Register: 24 November 2016. Randomized and quasi-randomized controlled trials of enzyme replacement therapy in children with infantile-onset Pompe disease. Two authors independently selected relevant trials, assessed the risk of bias and extracted data. We contacted investigators to obtain important missing information. We found no trials comparing the effectiveness and safety of enzyme replacement therapy to another intervention, no intervention or placebo.We found one trial (18 participants) that fulfilled the selection criteria, comparing different doses of alglucosidase alfa. The trial provided low-quality evidence (this was a small trial, there were no numerical results available by dose group, random sequence generation and allocation concealment were unclear, and there was a lack of blinding). The duration of alglucosidase alfa treatment ranged from 52 weeks (the length of the original study) to up to three years (including the extended phase of the trial), with a median duration of treatment being 2.3 years.The trial only reported that clinical responses including cardiac function and motor development, as well as the proportion of children that were free of invasive ventilation, were similar in the 20 mg/kg every two weeks and the 40 mg/kg every two weeks groups (low-quality evidence). Long-term alglucosidase alfa treatment markedly extended survival as well as ventilation-free survival and improved cardiomyopathy (low-quality evidence). In relation to the number of children experiencing one or more infusion-related events, there was no significant difference between dose groups, risk ratio 0.83 (95% confidence interval 0.40 to 1.76) (low-quality of evidence). However, of note, at 52 weeks, five children in the 20 mg/kg every two weeks dose group experienced a total of 41 mild or moderate (none severe) infusion-related events and the six children in the 40 mg/kg every two weeks dose group experienced a total of 123 infusion-related events. By the end of the extended phase of the trial, five children in the 20 mg/kg every two weeks dose group experienced a total of 47 infusion-related events and the six children in the 40 mg/kg every two weeks dose group experienced a total of 177 infusion-related events. The trial was supported by the Genzyme Corporation. The search found no trials comparing the effectiveness and safety of enzyme replacement therapy to another intervention, no intervention or placebo. One small randomized controlled trial provided no robust evidence for which dosing schedule of alglucosidase alfa was more effective to treat infantile-onset Pompe disease. It is not deemed ethical to proceed with new placebo-controlled trials, therefore a randomized controlled trial with a large sample size comparing different dosing schedules of enzyme replacement therapy is needed. The main clinical outcomes (i.e. cardiac function, invasive ventilation, survival, motor development, adverse events (e.g. the development of antibodies)) should be standardized when evaluated and reported.

AAV-mediated transcription factor EB (TFEB) gene delivery ameliorates muscle pathology and function in the murine model of Pompe Disease

Pompe disease (PD) is a metabolic myopathy due to acid alpha-glucosidase deficiency and characterized by extensive glycogen storage and impaired autophagy. We previously showed that modulation of autophagy and lysosomal exocytosis by overexpression of the transcription factor EB (TFEB) gene was effective in improving muscle pathology in PD mice injected intramuscularly with an AAV-TFEB vector. Here we have evaluated the effects of TFEB systemic delivery on muscle pathology and on functional performance, a primary measure of efficacy in a disorder like PD. We treated 1-month-old PD mice with an AAV2.9-MCK-TFEB vector. An animal cohort was analyzed at 3 months for muscle and heart pathology. A second cohort was followed at different timepoints for functional analysis. In muscles from TFEB-treated mice we observed reduced PAS staining and improved ultrastructure, with reduced number and increased translucency of lysosomes, while total glycogen content remained unchanged. We also observed statistically significant improvements in rotarod performance in treated animals compared to AAV2.9-MCK-eGFP-treated mice at 5 and 8 months. Cardiac echography showed significant reduction in left-ventricular diameters. These results show that TFEB overexpression and modulation of autophagy result in improvements of muscle pathology and of functional performance in the PD murine model, with delayed disease progression.

High-risk screening for late-onset Pompe disease in Japan

Background: Late-onset Pompe disease (LOPD) is a rare, but treatable metabolic myopathy caused by deficiency of acid alpha-glucosidase (GAA). LOPD is characterized by progressive muscle weakness and/or respiratory failure, but some LOPD patients could be overlooked due to lack of typical signs.

Atg5flox-Derived Autophagy-Deficient Model of Pompe Disease: Does It Tell the Whole Story?

Defective autophagy is a prominent feature in Pompe disease, an inherited deficiency of acid alpha-glucosidase. An absence of this enzyme leaves cells unable to digest glycogen in the lysosome. The major tissues affected by glycogen accumulation are cardiac and skeletal muscles. The currently available enzyme replacement therapy (ERT) works well in cardiac, but not in skeletal muscle. The disappointing response to therapy is linked to the presence of large areas of autophagic debris in muscle fibers.

P.217 - Stabilized next-generation recombinant human acid alpha-glucosidase ATB200 clears accumulated glycogen and reverses cellular dysfunction to increase muscle strength in a mouse model of Pompe disease

Pompe disease is a rare inherited metabolic disease of impaired lysosomal glycogen metabolism due to acid alpha-glucosidase (GAA) deficiency, which leads to progressive muscle weakness. Our biochemical and histologic evaluation of muscles of Gaa knockout (KO) mice revealed extensive cellular dysfunction, as evidenced by pronounced autophagy and lysosomal proliferation and potentially altered membrane repair. To date, enzyme replacement therapy using the recombinant human GAA (rhGAA) alglucosidase alfa is the only approved treatment available for Pompe disease. While alglucosidase alfa provides some clinical benefits, the infused enzyme shows insufficient uptake into skeletal muscles. This distribution is likely due to suboptimal levels of mannose-6-phosphate (M6P), which is responsible for enzyme internalization and lysosomal targeting. ATB200 is a novel rhGAA with a significantly higher M6P content than alglucosidase alfa. The pharmacological chaperone AT2221 is also utilized to stabilize ATB200 in circulation. We compared the effects of ATB200 co-administered with AT2221 (ATB200/AT2221) to those of alglucosidase alfa in Gaa KO mice. Co-administration of ATB200/AT2221 led to significantly greater glycogen reduction in key muscles. Immunohistochemical analyses suggested that ATB200/AT2221 is more effective than alglucosidase alfa in reducing lysosomal proliferation, enhancing autophagy flux, and repairing damaged muscle fibers. Furthermore, ATB200/AT2221 improved muscle strength compared with alglucosidase alfa. Collectively, these data indicate that ATB200/AT2221 efficiently targets muscle fibers, reverses cellular dysfunction, and improves muscle function. Therefore, ATB200/AT2221 is currently being investigated in the ongoing ATB200-02 clinical trial (NCT02675465) as a potential next-generation treatment for Pompe disease.

P.212 - Screening for late-onset Pompe disease among high-risk population in Japan

Late-onset Pompe disease (LOPD) is a rare, but treatable metabolic myopathy due to acid alpha-glucosidase (GAA) deficiency. LOPD is characterized by progressive muscle weakness and/or respiratory failure, but some LOPD patients without typical signs could be overlooked. To evaluate the utility of Dreid Bood Spots (DBS) in the diagnostic work-up and assess the prevalence of LOPD within a Japanese high-risk population, we prospectively screened for LOPD in a Japanese cohort of undetermined myopathy patients aged one year or older with muscle weakness and/or elevated serum creatine kinase levels. Sixteen neuromuscular center hospitals, members of Muscular Dystrophy Clinical Trial Network (MDCTN), joined the Pompe disease high risk screening study in Japan (PHiRS-J). We tested GAA activity with DBS as first screening method. Patients with reduced GAA activity in DBS were re-analyzed for enzyme activity in lymphocytes, and investigated for GAA gene mutations. Among 113 patients enrolled, two were incompatible with inclution criteria. Nine patients showed reduced GAA activity with DBS. Of these patients, three showed normal GAA enzyme activity in lymphocytes; four were revealed as pseudodeficiency; two with confirmed reduction of GAA activity in lymphocytes were identified to have homozygous or compound heterozygous mutations of the GAA gene. In a Japanese high-risk cohort, we found a prevalence of LOPD around 2%. This study suggests that screening of GAA activity with DBS is useful to diagnose patients with LOPD in a high-risk population.

AB073. Classic infantile-onset Pompe disease: phenotypes and outcomes of 5 Vietnamese patients receiving enzyme replacement therapy

Background: Pompe disease (PD) or glycogen storage disease type II is a lysosomal storage disorder, caused by mutations of GAA gene which results in deficiency of acid alpha-glucosidase (GAA) enzyme that involves in metabolism of glycogen in the lysosomes. Its incidence is 1/14,000–1/100,000. PD is divided into three types: classic infantile onset, non-classic infantile onset, and late onset. Early enzyme replacement therapy (ERT) before developing respiratory distress may lead to good outcome. Since 2013, we have identified 16 cases with classic infantile-onset and 5 cases were treated with ERT. Herein, we describe phenotypes and outcomes of five infantile-onset PD patients who received ERT.

Late-onset Pompe disease: a genetic-radiological correlation on cerebral vascular anomalies.

Pompe disease is an autosomal recessive disorder in which deficiency of the lysosomal enzyme acid alpha-glucosidase results in the accumulation of glycogen mostly in muscle tissues. Several reports suggest a higher incidence of intracranial vascular abnormalities (IVAs) in this condition, as well as brain microbleeds and cerebral vasculopathy. The aim of our study was to evaluate through neuroimaging studies the incidence of these anomalies in our cohort of late-onset Pompe disease (LOPD) patients asymptomatic for cerebrovascular disease, looking for correlations with clinical and genetic data. We studied 18 LOPD patients with brain magnetic resonance angiography (MRA), or contrast-enhanced computed tomography (CECT). Diameters of individual arteries were measured and compared with average values as proposed in the literature. We found IVAs in 13 of the 18 patients, mostly dilatative arteriopathy affecting the vertebrobasilar system. The anterior circle was involved in seven of the 18 patients. The diameter of the basilar artery at 1cm was found to correlate both with age (spearman rho, p=0.037) and disease duration (p=0.004), but no other statistically significant correlation was documented. The incidence of intracranial dilatative arteriopathy in LOPD was higher than in the general population, confirming the literature data. However, we did not find intracranial aneurysms microbleeds or significant cerebrovascular disease. Abnormalities in the anterior and the posterior circle of Willis correlated with age and disease duration, but not with the severity of muscle/respiratory involvement or with genetic data. Further studies in larger cohorts of patients are needed to confirm these findings.

A study on the safety and efficacy of reveglucosidase alfa in patients with late-onset Pompe disease

BackgroundLate-onset Pompe disease is a rare genetic neuromuscular disorder caused by lysosomal acid alpha-glucosidase (GAA) deficiency that ultimately results in mobility loss and respiratory failure. Current enzyme replacement therapy with recombinant human (rh)GAA has demonstrated efficacy in subjects with late-onset Pompe disease. However, long-term effects of rhGAA on pulmonary function have not been observed, likely related to inefficient delivery of rhGAA to skeletal muscle lysosomes and associated deficits in the central nervous system. To address this limitation, reveglucosidase alfa, a novel insulin-like growth factor 2 (IGF2)-tagged GAA analogue with improved lysosomal uptake, was developed. This study evaluated the pharmacokinetics, safety, and exploratory efficacy of reveglucosidase alfa in 22 subjects with late-onset Pompe disease who were previously untreated with rhGAA.ResultsReveglucosidase alfa plasma concentrations increased linearly with dose, and the elimination half-life was <1.2 h. Eighteen of 22 subjects completed 72 weeks of treatment. The most common adverse events were hypoglycemia (63%), dizziness, fall, headache, and nausea (55% for each). Serious adverse events included hypersensitivity (n = 1), symptomatic hypoglycemia (n = 2), presyncope (n = 1), and acute cardiac failure (n = 1). In the dose-escalation study, all treated subjects tested positive for anti-reveglucosidase alfa, anti-rhGAA, anti-IGF1, and anti-IGF2 antibodies at least once. Subjects receiving 20 mg/kg of reveglucosidase alfa demonstrated increases in predicted maximum inspiratory pressure (13.9%), predicted maximum expiratory pressure (8.0%), forced vital capacity (−0.4%), maximum voluntary ventilation (7.4 L/min), and mean absolute walking distance (22.3 m on the 6-min walk test) at 72 weeks.ConclusionsAdditional studies are needed to further assess the safety and efficacy of this approach. Improvements in respiratory muscle strength, lung function, and walking endurance in subjects with LOPD may make up for the risk of hypersensitivity reactions and hypoglycemia. Reveglucosidase alfa may provide a new treatment option for patients with late-onset Pompe disease.Trial registrationISRCTN01435772 and ISRCTN01230801, registered 27 October 2011.

Clinical Analysis of Algerian Patients with Pompe Disease

Pompe's disease is a metabolic myopathy caused by a deficiency of acid alpha-glucosidase (GAA), also called acid maltase, an enzyme that degrades lysosomal glycogen. The clinical presentation of Pompe's disease is variable with respect to the age of onset and rate of disease progression. Patients with onset of symptoms in early infancy (infantile-onset Pompe disease (IOPD)) typically exhibit rapidly progressive hypertrophic cardiomyopathy and marked muscle weakness. Most of them die within the first year of life from cardiac and/or respiratory failure. In the majority of cases of Pompe's disease, onset of symptoms occurs after infancy, ranging widely from the first to sixth decade of life (late-onset Pompe's disease or LOPD). Progression of the disease is relentless and patients eventually progress to loss of ambulation and death due to respiratory failure. The objective of this study was to characterize the clinical presentation of 6 patients (3 with EOPD and the other 3 with LOPD) of 5 families from the East of Algeria. All our patients were diagnosed as having Pompe's disease based on biochemical confirmations of GAA deficiency by dried blood spots (DBS) and GAA gene mutations were analyzed in all patients who consented (n = 4). Our results are similar to other ethnic groups.

Pompe disease: clinical perspectives

Pompe disease: clinical perspectives Juan Francisco Cabello,1 Deborah Marsden2 1Genetics and Metabolic Disease Laboratory, Nutrition and Food Technology Institute (INTA), University of Chile, Santiago, Chile; 2Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA Abstract: Pompe disease (acid alpha-glucosidase deficiency, OMIM 232300) is a rare lysosomal storage disorder due to autosomal recessive mutations in the GAA gene. It has also been called acid maltase deficiency and glycogen storage disease type II. There is a broad clinical presentation: the most severe form that presents in the first few months of life with cardiomyopathy and generalized muscle weakness that rapidly progresses to death from cardio-respiratory failure in the first year of life (infant-onset Pompe disease). A more slowly progressive disease, with little or no cardiac involvement, presents with proximal myopathy and/or pulmonary insufficiency, from the second year of life to late adulthood (late-onset Pompe disease). The recent development and introduction of enzyme replacement therapy with intravenous infusion of recombinant human acid alpha-glucosidase have made a major improvement in the morbidity and mortality of this disease. New therapies are also in development. With the availability of treatment, diagnostic methods have also improved, allowing for earlier recognition and potential early therapeutic intervention. The advent of newborn screening for Pompe disease may identify patients who can be treated before significant irreversible disease has occurred. Keywords: Pompe disease, glycogen storage disease, lysosomal storage disease, enzyme replacement therapy, gene therapy, chaperone therapy, genotype/phenotype, newborn screening

Transcriptome assessment of the Pompe (Gaa-/-) mouse spinal cord indicates widespread neuropathology.

Pompe disease, caused by deficiency of acid alpha-glucosidase (GAA), leads to widespread glycogen accumulation and profound neuromuscular impairments. There has been controversy, however, regarding the role of central nervous system pathology in Pompe motor dysfunction. We hypothesized that absence of GAA protein causes progressive activation of neuropathological signaling, including pathways associated with cell death. To test this hypothesis, genomic data (Affymetrix Mouse Gene Array 2.0ST) from the midcervical spinal cord in 6 and 16 mo old Pompe (Gaa-/-) mice were evaluated (Broad Institute Molecular Signature Database), along with spinal cord histology. The midcervical cord was selected because it contains phrenic motoneurons, and phrenic-diaphragm dysfunction is prominent in Pompe disease. Several clinically important themes for the neurologic etiology of Pompe disease emerged from this unbiased genomic assessment. First, pathways associated with cell death were strongly upregulated as Gaa-/- mice aged, and motoneuron apoptosis was histologically verified. Second, proinflammatory signaling was dramatically upregulated in the Gaa-/- spinal cord. Third, many signal transduction pathways in the Gaa-/- cervical cord were altered in a manner suggestive of impaired synaptic function. Notably, glutamatergic signaling pathways were downregulated, as were "synaptic plasticity pathways" including genes related to neuroplasticity. Fourth, many genes and pathways related to cellular metabolism are dysregulated. Collectively, the data unequivocally confirm that systemic absence of GAA induces a complex neuropathological cascade in the spinal cord. Most importantly, the results indicate that Pompe is a neurodegenerative condition, and this underscores the need for early therapeutic intervention capable of targeting the central nervous system.

Prevalence of Pompe: More Common Than You Know

Pompe disease, also known as acid maltase deficiency, is a rare, autosomal-recessive disorder in which a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA) leads to impaired metabolism and breakdown of glycogen. Whereas infantile Pompe disease is typically multisystemic, the adult-onset disease form typically is dominated by skeletal muscle weakness affecting proximal limb - girdle musculature and respiration muscles. The rarity of the disease means that a high index …