Late-onset Glycogen Storage Disease Type Research Articles

Low Prevalence Estimates of Late-Onset Glycogen Storage Disease Type II in French-Speaking Belgium are not Due to Missed Diagnoses.

Late-onset glycogen storage disease type II is associated with variable muscle phenotypes. Epidemiological data suggest that its prevalence is lower in Belgium than in bordering countries like The Netherlands. We investigated whether such low estimated prevalence is due to missed diagnoses. We screened 100 patients with muscle phenotypes of undetermined origin using a dried blood spot test for alpha-acid glucosidase (GAA) activity. Patients with low activity at screening were re-tested by the same method and, if low activity was confirmed, GAA gene analysis was performed. The screening test revealed lower than normal GAA activity in 15 patients, but in only two of them it was low enough to be considered in the disease range. Retesting confirmed lower than normal GAA activity in five patients, but in all of them it was above the disease range. A single patient carried a heterozygous known pathogenic GAA mutation, whose significance in this case remains undetermined. We conclude that reported low prevalence estimates in Belgium are not likely to be due to an underdiagnosis bias. Lower prevalence compared to neighbouring The Netherlands may be due to different ethnic stratification of our patients. Diagnostic strategies should keep into account the expected prevalence of a disease in specific populations.

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.

Clinical and gene mutation analysis of three children with late-onset glycogen storage disease type Ⅱ with hypertrophic cardiomyopathy

Objective: To investigate the clinical and laboratory features of three children with late-onset type Ⅱ glycogen storage disease(GSD) who presented with hypertrophic cardiomyopathy and to analyze the effect of five mutations identified on the acid-α-glucosidase (GAA) activity and stability. Method: Three cases of children with muscle weakness were included in this study.GAA activity was analyzed in Dried Blood Spot of the patients.DNA was extracted from peripheral blood in all the patients and their parents and subjected to polymerase chain reaction and directly sequencing of GAA gene.Five mutant pcDNA3.1-myc-his-GAA expression plasmids(p.G478R, p.P361L, p.P266S, p.Q323X, p.R672Q) were constructed and transient instantaneously transfected into 293T cells to analyze the enzyme activity and stability of GAA. Result: All the three children had the onset of disease at 3 years or 1.5 years of age.They presented with developmental delay, muscle weakness and hypertrophic cardiomyopathy.GAA activity of 3 patients was 2.65, 3.55 and 1.51 pmol(punch·h)(8.00-98.02)respectively. Genetic analysis found 5 mutations (p.G478R, p. P361L, p. P266S, p. Q323X, p. R672Q), and all of these 3 cases had clinical manifestations and were diagnosed as late-onset type Ⅱ glycogen storage disease.Five mutant pcDNA3.1-myc-his-GAA expression plasmids were transfected into 293T cells.Five mutant enzyme activities were found to be only 9.9%-22.5% of the wild-type enzyme activity and the protein expression of the five mutants was 32.0%-63.9% compared with the wild type. Conclusion: This study reports 3 children with late-onset GSD Ⅱ accompanied by hypertrophic cardiomyopathy and compensatory stage of cardiac function in addition to limb muscle weakness.Five pathogenic mutations were identified, and these 5 mutations result in decreased GAA activity and GAA expression by in vitro functional analysis.

Clinical analysis of five cases of glycogen storage disease type II in PICU

Objective To investigate the clinical manifestations of infantile and late-onset glycogen storage disease type Ⅱ. Methods We analyzed the clinical manifestations and prognosis of infantile and late-onset glycogen storage disease type Ⅱ with a retrospective analysis of five cases admitted in PICU of Shengjing Hospital of China Medical University from 2013 to 2014. Results First symptoms of three infantile cases were dyspnea, cardiac hypertrophy, hepatomegaly, skeletal muscle weakness and low concentration of α-glucosidase A. Two cases completed gene detection.One case had frameshift mutation and missense mutation, and the other had two missense mutation.Three infantile cases all showed arrhythmia performance.Two cases died of fatal arrhythmia.One case received enzyme replacement therapy and survived.The main symptoms of two late-onset cases who had not get gene detection were dyspnea, low muscle strength, muscle hypotonia and low concentration of acid α-glucosidase.One case received mechanical ventilation, complicated with multiple infections, severe pneumonia and ventilator dependence, finally gave up the treatment.The other died of cardiac arrhythmia. Conclusion Infantile cases have the major symptoms of myocardial hypertrophy, hepatomegaly, low muscular tension with rapid progression, high mortality and fatal arrhythmia.Late-onset cases have the clinical features of respiratory failure, proximal limb muscle weakness and be susceptible to ventilator dependence and multiple infections.Enzyme replacement therapy can improve the clinical symptoms of infantile cases. Key words: Glycogen storage disease type Ⅱ; Infantile; Late-onset; Enzyme replacement therapy

First Case of Late-Onset Glycogen Storage Disease Type II in Russia with a Novel Mutation

recessive disorder resulting from a defi ciency of acid α-glucosidase (GAA, or acid maltase), includes two main forms – infantileand late-onset glycogen storage disease type II (GSD II). Despite the age of onset and different life prognosis, Pompe disease is a single disease continuum with variable rates of disease progression and different ages of onset. The late-onset form of Pompe disease (LOPD) is a well-known milder form of the GSD II. A 66-years-old man with diffi culties climbing stairs and walking (6MWT less than 10 m), breathing problems, particularly at night when lying down, and abnormal spinal lordosis is described here. The initial signs of the disease were subtle and unrecognized for more than 30 years: inability to whistle since childhood, diffi culties in running long distances, pull-ups and chin-ups, playing running games while being in the army, shortness of breath since age 40 years and periodical general inexplicable fatigue since 45 years; myopathic symptoms, such as force decrease of the hips, pelvic, and trunk muscles, proximal leg muscle atrophy and progressive course of motor disturbances became obvious at age 50 and the patient was classifi ed as having ‘limb–girdle muscular dystrophy of late First Case of Late-Onset Glycogen Storage Disease Type II in Russia with a Novel Mutation

Clinical study of respiratory function in patients with late-onset glycogen storage disease typeII

Background Late-onset glycogen storage disease typeⅡ(GSDⅡ, Pompe disease) is an autosomal recessive disease exhibiting progressive proximal skeletal muscle weakness and respiratory muscle involvement, caused by deficiency of the lysosomal enzyme acid α-glucosidase (GAA). Most of patients died of respiratory failure. Methods Eleven patients with late-onset glycogen storage disease type Ⅱ underwent respiratory function evaluation, whose diagnosis was confirmed by muscle pathology, GAA activity assay and gene analysis. Respiratory function evaluation included upright and supine position of forced vital capacity (FVC), forced expiratory volume at the first second (FEV1), maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP) and cough peak flow (CPF). All data were compared with predicted value. The decreased value between upright and supine position FVC ( △ FVC) were calculated. The correlation between respiratory function and the age of onset, disease course, motor function, GAA activity were analyzed. Results All of 11 patients with late-onset glycogen storage disease type Ⅱ showed declined respiratory function compared with predicted value. The upright FVC, upright FEV1, △ FVC, MIP, MEP and CPF declined in 10, 10, 8, 11, 10, and 10 patients, respectively. All patients had normal FEV1/FVC in both upright and supine position. There was no correlation between upright FVC, △ FVC and the onset age, disease course, motor function, GAA activity statistically. Conclusions Pulmonary dysfunction is common in late-onset glycogen storage disease type Ⅱ, with restrictive ventilatory impairment more predominant, which is caused by inspiratory muscle weakness. doi: 10.3969/j.issn.1672-6731.2014.05.007

Heterozygous individuals with mild phenotype in late-onset glycogen storage disease type 2: a new cohort of patients?

Late-onset glycogen storage disease type 2 (GSD2) is a genetic but heterogeneous disorder, which may present anywhere along a continuum of severity from an isolated hyperCKemia to a profound, generalized muscle weakness with pulmonary involvement. The gold standard for diagnosis is confirmation of low or absent levels of acid alpha-glucosidase (GAA) enzyme activity (usually in the range of 1-40% of normal levels), which is confirmed only in some cases by molecular analysis of the GAA gene. In the literature, heterozygous individuals are usually considered to be asymptomatic, although they can have reduced enzymatic activity. Since enzyme replacement therapy (ERT) became available in 2006, it has improved the prognosis for severe infantile-onset Pompe disease, as well as for late-onset forms by improving muscle/respiratory function and/or stabilizing clinical progression. Because the disease is now treatable, it is essential to understand which patients may benefit from ERT.

Dos nuevas mutaciones en el gen que codifica la alfa-glucosidasa ácida en un adolescente con enfermedad de Pompe de inicio tardío

INTRODUCTION. Glycogen storage disease type II, or Pompe disease, is a lysosomal disease with an autosomal recessive pattern of inheritance. Late-onset Pompe disease is a progressive metabolic myopathy caused by decreased activity of the enzyme acid alpha-glucosidase (GAA), which gives rise to reduced degradation and later accumulation of glycogen in the lysosomes and cell cytoplasm. CASE REPORT. A 16-year-old Venezuelan male, diagnosed with late-onset glycogen storage disease type II, or Pompe disease, based on the patient's clinical picture and the biochemical findings. The patient presented unmistakable signs of muscular atrophy in the upper and lower limbs, as well as positive Gowers' sign. Levels of creatinkinase in serum were high. His functional respiratory capacity was diminished. The quantification of the enzymatic activity of acid alpha-glucosidase on filter paper did not show any significant decrease in activity. A molecular genetic analysis revealed the existence of two homozygotic mutations in the gene GAA, c.547-67C>G and c.547-39T>G, both on exon 2 of chromosome 17. According to the human genome database and the review that was undertaken, the changes detected in this patient represent new mutations in the acid alpha-glucosidase gene, GAA. This claim is in agreement with the clinical features and biochemical changes found in the patient. CONCLUSION. A molecular genetic study is mandatory in patients suspected of having this disease.

Exercise testing in late-onset glycogen storage disease type II patients undergoing enzyme replacement therapy

Enzyme replacement therapy (ERT) has recently became available for patients with glycogen storage disease type II. Previous studies have demonstrated clinical efficacy of enzyme replacement therapy, however, data on physiological variables related to exercise tolerance are scarce. Four glycogen storage disease type II late-onset patients (45 ± 6 years) performed an incremental exercise on a cycle ergometer, up to voluntary exhaustion, before (BEFORE) and after 12 months of ERT (AFTER). Peak workload, oxygen uptake, heart rate, cardiac output (by impedance cardiography) and vastus lateralis oxygenation indices (by continuous-wave near-infrared spectroscopy, NIRS) were determined. Peak workload and oxygen uptake values significantly increased during ERT (54 ± 30 vs. 63 ± 31 watt, and 17.2 ± 4.4 vs. 19.7 ± 3.5 ml/kg/min, respectively, in BEFORE vs. AFTER). On the other hand, for both peak cardiac output (12.3 ± 5.3 vs. 14.8 ± 4.5 L/min) and the NIRS-determined peak skeletal muscle fractional O2 extraction, expressed as a percentage of the maximal values during a transient limb ischemia (30 ± 39% vs. 38 ± 28%), the observed increases were not statistically significant. Our findings suggest that in glycogen storage disease type II patients enzyme replacement therapy is associated with a mild improvement of exercise tolerance. The findings need to be validated during a longer follow-up on a larger group of patients.

Observational clinical study in juvenile-adult glycogenosis type 2 patients undergoing enzyme replacement therapy for up to 4 years

The objective of this study was to describe a large Italian cohort of patients with late-onset glycogen storage disease type 2 (GSDII) at various stages of disease progression and to evaluate the clinical effectiveness of alglucosidase alpha enzyme replacement therapy (ERT). Previous studies showed in late-onset patients ERT efficacy against placebo and variable response in uncontrolled studies. Seventy-four juvenile or adult GSDII patients were treated with ERT in a multicenter open label, non-randomized study, from 12 months up to 54 months. Recombinant human alpha glucosidase (rh-GAA) was injected by intravenous route at 20 mg/kg every second week. Patients were divided into three groups according to ERT duration: Group A received treatment for 12-23 months (n = 16), Group B for 24-35 months (n = 14), and Group C for more than 36 months (n = 44). Clinical assessment included a 6-min walk test (6MWT), forced vital capacity (FVC), the Walton and Gardner-Medwin score, the number of hours of ventilation, body mass index, echocardiography and blood creatine kinase (CK). Included in our cohort were 33 males and 41 females (M:F = 0.8:1), with a mean age at first symptoms of 28.3 years (range 2-55 years) and a mean age of 43 years at study entry (range 7-72 years). Seven wheelchair bound patients, as well as 27 patients requiring ventilation support, were included. After treatment we could observe an increase in distance walked on the 6MWT in the large majority of patients (48/58; 83%), with an overall mean increase of 63 m (from 320 ± 161 to 383 ± 178 m). After treatment in the majority of patients FVC was improved or unchanged (45/69; 65%). In ventilated patients we observed an improvement in average number of hours off the ventilator (from 15.6 to 12.1 h). Six patients stopped mechanical ventilation and two others started it. The effect of therapy was not related to ERT duration. Nine of 64 patients (13%) that underwent to echocardiography showed a variable degree of cardiac hypertrophy (left ventriculum or septum), and a positive effect was observed after 36 months of ERT in one adult case. Discontinuation of treatment occurred in four patients: one drop-off case, one patient died for a sepsis after 34 months of treatment and two patients stopped ERT for worsening of general clinical condition. Mild adverse effects were observed in four cases (5%). This study represents the largest cohort of late-onset GSDII patients treated with ERT, and confirm a positive effect of treatment. These results, obtained in a large case series on therapy, indicate a favourable effect of ERT therapy, even in more advanced stage of the disease.

Effects of enzyme replacement therapy on five patients with advanced late‐onset glycogen storage disease type II: a 2‐year follow‐up study

We examined the efficacy of 2-year enzyme replacement therapy (ERT) using recombinant human α-glucosidase (GAA; Myozyme®) in five long-term ventilator-dependent adults and aged patients with advanced, late-onset glycogen storage disease type II (GSDII, also known as Pompe disease). Although all patients had advanced respiratory failure and were ventilator-dependent for more than 6 years, four showed obvious improvements in muscle strength, pulmonary function, and activities of daily living after ERT. Improvement in each parameter was more prominent in the first year than in the second year. Values in the second year were still significantly better than those at study entry and indicate stabilization in the clinical status of all patients. These results suggest that ERT continues to be effective in the second year of treatment even in patients suffering from advanced late-onset GSDII disease with severe respiratory failure.

Novel Mutations in the Gene Encoding Acid .ALPHA.-1,4-glucosidase in a Patient with Late-onset Glycogen Storage Disease Type II (Pompe Disease) with Impaired Intelligence

A 17-year-old Japanese man was referred to our hospital because of highly elevated serum levels of creatine kinase (CK) and transaminases. On admission, the proximal muscles of the lower extremities were found to be predominantly affected, and a score of 3/5 was obtained on Medical Research Council (MRC) scale. Muscular atrophy was evident and Gowers' sign was positive. His functional vital capacity (FVC) was markedly reduced. The results of the third edition of the Wechsler Adult Intelligence Scale (WAIS-III) indicated impairment of the patient's intelligence. Muscle biopsy showed scattered intracytoplasmic vacuoles with basophilic amorphous materials inside which were strongly stained by both periodic acid Schiff (PAS) and acid phosphatase. Biochemical analysis of the muscle tissue confirmed the diagnosis of GSDII because the glucosidase activity was 1.0 nmol/4 MU/mg/30 min (control range, 7.3 ± 2.2). Genetic analysis revealed a novel compound heterozygous missense mutation in GAA--c.1814 G >A (p.Gly605Asp) and c.1846 G >A (p.Asp616Asn) both in exon 13.

P4.51 Effects of enzyme replacement therapy in five patients with advanced late-onset glycogen storage disease type 2: a 2-year follow-up study

P4.51 Effects of enzyme replacement therapy in five patients with advanced late-onset glycogen storage disease type 2: a 2-year follow-up study

Late-onset pompe disease: Case report of a patient with an uncommon mutation and observational clinical trial as to response to enzyme replacemant therapy (ERT) with alglucosidase alfa over a 12-month-period

Late-onset glycogen storage disease type 2 (GSD2)/Pompe disease is a progressive multi-system disease evoked by a deficiency of lysosomal acid alpha-glucosidase (GAA) activity. GSD2 is characterized by respiratory and skeletal muscle weakness and atrophy, resulting in functional disability and reduced life span. Since 2006 alglucosidase alfa has been licensed as a treatment in all types of GSD2/Pompe disease.

Enzyme replacement therapy with alglucosidase alfa in 44 patients with late-onset glycogen storage disease type 2: 12-month results of an observational clinical trial

Late-onset glycogen storage disease type 2 (GSD2)/Pompe disease is a progressive multi-system disease evoked by a deficiency of lysosomal acid alpha-glucosidase (GAA) activity. GSD2 is characterized by respiratory and skeletal muscle weakness and atrophy, resulting in functional disability and reduced life span. Since 2006 alglucosidase alfa has been licensed as a treatment in all types of GSD2/Pompe disease. We here present an open-label, investigator-initiated observational study of alglucosidase alfa enzyme replacement therapy (ERT) in 44 late-onset GSD2 patients with various stages of disease severity. Alglucosidase alfa was given i.v. at the standard dose of 20 mg/kg every other week. Assessments included serial arm function tests (AFT), Walton Gardner Medwin scale (WGMS), timed 10-m walk tests, four-stair climb tests, modified Gowers' maneuvers, 6-min walk tests, MRC sum score, forced vital capacities (FVC), creatine kinase (CK) levels and SF-36 self-reporting questionnaires. All tests were performed at baseline and every 3 months for 12 months of ERT. We found significant changes from baseline in the modified Gowers' test, the CK levels and the 6-min walk test (341 +/- 149.49 m, median 342.25 m at baseline; 393 +/- 156.98 m; median 411.50 m at endpoint; p = 0.026), while all other tests were unchanged. ERT over 12 months revealed minor allergic reactions in 10% of the patients. No serious adverse events occurred. None of the patients died or required de novo ventilation. Our clinical outcome data imply stabilization of neuromuscular deficits over 1 year with mild functional improvement.

Molecular diagnosis of German patients with late‐onset glycogen storage disease type II

In patients with late-onset glycogen storage disease type II, one mutation, c.-32-13T>G, in the α-glucosidase (GAA) gene is identified frequently in European populations from different regions along with many rarer mutations. We have performed molecular genetic investigations in 18 German index patients with late-onset disease. The c.-32-13T>G, c.525delT (p.Glu176fsX45), and c.2481+102_2646+31del mutations were detected by PCR/restriction enzyme digest. Other mutations were detected by sequencing. All patients were compound heterozygous and 17 patients harboured the c.-32-13T>G mutation. Seven other previously described mutations (including the c.-32-13T>G) were identified, of which the p.C103G (c.307T>G) and the c.2481+102_2646+31del mutations were present each in three unrelated patients. Sequencing revealed five novel mutations. Genetic testing was able to identify the genetic defects in all patients and screening of the c.-32-13T>G mutation identified 94% of the cases. This is important for quick and reliable diagnosis, especially in view of enzyme replacement. Among the rarer mutations, c.2481+102_2646+31del and p.C103G are rather frequent in Germany.

Molecular pathology and enzyme processing in various phenotypes of acid maltase deficiency

To examine at molecular, biochemical, and muscle pathology level the striking clinical heterogeneity resulting from acid alpha-glucosidase deficiency. We investigated 23 patients with infantile-onset or late-onset glycogen storage disease type II by enzyme activity, protein expression by immunoblotting, GAA gene mutations, and muscle pathology including immunolabeling for Golgi and sarcolemmal proteins. The enzyme activity was absent or minimal in infantile-onset cases and variably reduced in late-onset patients. Genotype-phenotype correlation (seven novel mutations were found) showed that most late-onset patients had the heterozygous IVS1 leaky splicing mutation (one patient was homozygous), but the course of the disease was often difficult to predict on the basis of the mutations alone. All patients showed an abnormal pattern of enzyme protein processing, with increased amounts of the inactive forms and very low or absent amounts of the mature forms. The molecular weight of the mature and the intermediate forms appeared higher in patients' samples than in the control muscle. We observed a Golgi proliferation in muscle fibers possibly caused by the retention of inactive forms of enzyme protein that cannot be correctly targeted from Golgi to lysosomes. The vacuolar membranes expressed sarcolemmal proteins in late-onset but not in infantile-onset patients, suggesting an extensive autophagy and vacuolar membrane remodeling in late-onset patients. The different protein molecular weight between patients and controls could be due to an excessive sialylation of mutant enzyme: this might be possibly caused by a delayed transport and longer transit of the inactive proteins in the Golgi apparatus.

Alglucosidase alfa effectively improves functional aspects of late-onset glycogen storage disease type II

Alglucosidase alfa effectively improves functional aspects of late-onset glycogen storage disease type II

Phenotypic expression of late-onset glycogen storage disease type II: identification of asymptomatic adults through family studies and review of reported families.

The intrafamilial variability of late-onset glycogen storage disease type II was studied in siblings of 18 patients and in reports in the literature. Siblings of seven of the 18 index cases opted for DNA testing or enzyme studies after being informed by the index case of the availability of testing, and after genetic counselling. Of the 12 siblings tested, five asymptomatic individuals were diagnosed (mean age, 32.8 years; range, 17-53). Intrafamilial variability in the age at onset (more than 10 years difference) or in the clinical symptoms was found in one of seven sibships tested in this study, and also in seven sibships reported in the literature. We advocate that testing should not be offered to healthy siblings of late-onset glycogen storage disease type II patients as a routine, because it is impossible to give a precise prognosis to an individual who is symptom-free, but has been identified with a glycogen storage disease type II genotype, nor is there any therapeutic intervention available.

The effects of l-alanine supplementation in late-onset glycogen storage disease type II.

Myopathy in glycogen storage disease type II (GSD-II) is slowly progressive. Five subjects with the late-onset form of GSD-II (age range, 15 to 47 years) and seven healthy control subjects (age range, 28 to 55 years) were studied. Following alanine supplementation, resting energy expenditure decreased in patients with GSD-II (p < 0.05) compared to values seen in control subjects. Leucine flux decreased (p < 0.004), as did leucine oxidation, to levels lower than those observed in control subjects (p < 0.001). l-Alanine reduces protein turnover and catabolism in GSD-II.