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PubMedDate not supplied

Evidence for a founder effect in Sicilian patients with glycogen storage disease type II.

Glycogen storage disease type II (GSD II) is an autosomal recessive inherited disorder due to the deficiency of the enzyme acid alpha-glucosidase, which causes an accumulation of glycogen in lysosomes. The deletion of exon 18 (delta 18) is a frequent mutation associated with a severe phenotype. We analyzed 25 Italian patients, 5 of whom were found to be delta 18 carriers. All these 5 patients came from Catania, a town in Sicily. We report on the analysis of 5 intragenic single-point polymorphic markers in the delta 18 patients and on the subsequent characterization of a delta 18-associated haplotype. The frequency of this haplotype in GSD II patients and normal individuals was 1 and 0.196, respectively (chi(2) = 20.9; p < 0.001). The high frequency of the delta 18 allele in this Italian subpopulation is likely to be due to a founder effect.

Child↗
PubMed2006

Enhanced efficacy of an AAV vector encoding chimeric, highly secreted acid alpha-glucosidase in glycogen storage disease type II.

Glycogen storage disease type II (GSD-II; Pompe disease; MIM 232300) is an inherited muscular dystrophy caused by deficiency in the activity of the lysosomal enzyme acid alpha-glucosidase (GAA). We hypothesized that chimeric GAA containing an alternative signal peptide could increase the secretion of GAA from transduced cells and enhance the receptor-mediated uptake of GAA in striated muscle. The relative secretion of chimeric GAA from transfected 293 cells increased up to 26-fold. Receptor-mediated uptake of secreted, chimeric GAA corrected cultured GSD-II patient cells. High-level hGAA was sustained in the plasma of GSD-II mice for 24 weeks following administration of an AAV2/8 vector encoding chimeric GAA; furthermore, GAA activity was increased and glycogen content was significantly reduced in striated muscle and in the brain. Administration of only 1 x 10(10) vector particles increased GAA activity in the heart and diaphragm for >18 weeks, whereas 3 x 10(10) vector particles increased GAA activity and reduced glycogen content in the heart, diaphragm, and quadriceps. Furthermore, an AAV2/2 vector encoding chimeric GAA produced secreted hGAA for >12 weeks in the majority of treated GSD-II mice. Thus, chimeric, highly secreted GAA enhanced the efficacy of AAV vector-mediated gene therapy in GSD-II mice.

Animals↗
PubMed2006

Mutation profile of the GAA gene in 40 Italian patients with late onset glycogen storage disease type II.

Glycogen storage disease type II (GSDII) is a recessively inherited disorder due to the deficiency of acid alpha-glucosidase (GAA) that results in impaired glycogen degradation and its accumulation in the lysosomes. We report here the complete molecular analysis of the GAA gene performed on 40 Italian patients with late onset GSDII. Twelve novel alleles have been identified: missense mutations were functionally characterized by enzyme activity and protein processing in a human GAA-deficient cell line while splicing mutations were studied by RT-PCR and in silico analysis. A complex allele was also identified carrying three different alterations in cis. The c.-32-13T > G was the most frequent mutation, present as compound heterozygote in 85% of the patients (allele frequency 42.3%), as described in other late onset GSDII Caucasian populations. Interestingly, the c.-32-13T > G was associated with the c.2237G > A (p.W746X) in nine of the 40 patients. Genotype-phenotype correlations are discussed with particular emphasis on the subgroup carrying the c.-32-13T > G/c.2237G > A genotype.

Adolescent↗
PubMed2005

Evasion of immune responses to introduced human acid alpha-glucosidase by liver-restricted expression in glycogen storage disease type II.

Glycogen storage disease type II (GSD-II; Pompe disease) is caused by a deficiency of acid alpha-glucosidase (GAA; acid maltase) and manifests as muscle weakness, hypertrophic cardiomyopathy, and respiratory failure. Adeno-associated virus vectors containing either a liver-specific promoter (LSP) (AAV-LSPhGAApA) or a hybrid CB promoter (AAV-CBhGAApA) to drive human GAA expression were pseudotyped as AAV8 and administered to immunocompetent GAA-knockout mice. Secreted hGAA was detectable in plasma between 1 day and 12 weeks postadministration with AAV-LSPhGAApA and only from 1 to 8 days postadministration for AAV-CBGAApA. No anti-GAA antibodies were detected in response to AAV-LSPhGAApA (<1:200), whereas AAV-CBhGAApA provoked an escalating antibody response starting 2 weeks postadministration. The LSP drove approximately 60-fold higher GAA expression than the CB promoter in the liver by 12 weeks following vector administration. Furthermore, the detected cellular immunity was provoked by AAV-CBhGAApA, as detected by ELISpot and CD4+/CD8+ lymphocyte immunodetection. GAA activity was increased to higher than normal and glycogen content was reduced to essentially normal levels in the heart and skeletal muscle following administration of AAV-LSPhGAApA. Therefore, liver-restricted GAA expression with an AAV vector evaded immunity and enhanced efficacy in GSD-II mice.

Animals↗
PubMed2005

Efficacy of an adeno-associated virus 8-pseudotyped vector in glycogen storage disease type II.

Glycogen storage disease type II (GSD-II; Pompe disease) causes death in infancy from cardiorespiratory failure. The underlying deficiency of acid alpha-glucosidase (GAA; acid maltase) can be corrected by liver-targeted gene therapy in GSD-II, if secretion of GAA is accompanied by receptor-mediated uptake in cardiac and skeletal muscle. An adeno-associated virus (AAV) vector encoding human (h) GAA was pseudotyped as AAV8 (AAV2/8) and injected intravenously into immunodeficient GSD-II mice. High levels of hGAA were maintained in plasma for 24 weeks following AAV2/8 vector administration. A marked increase in vector copy number in the liver was demonstrated for the AAV2/8 vector compared to the analogous AAV2/2 vector. GAA deficiency in the heart and skeletal muscle was corrected with the AAV2/8 vector in male GSD-II mice, consistent with receptor-mediated uptake of hGAA. Male GSD-II mice demonstrated complete correction of glycogen storage in heart and diaphragm with the AAV2/8 vector, while female GSD-II mice had correction only in the heart. A biomarker for GSD-II was reduced in both sexes following AAV2/8 vector administration. Therefore, GAA production with an AAV2/8 vector in a depot organ, the liver, generated evidence for efficacious gene therapy in a mouse model for GSD-II.

Animals↗
PubMed2006

Two new missense mutations of GAA in late onset glycogen storage disease type II.

Glycogen storage disease type II (GSD II) is an autosomal recessive disorder resulting from a deficiency of acid alpha-glucosidase (GAA, or acid maltase). In this study, we aimed to characterize phenotype and genotype in three patients with late onset GSD II in Korea. Clinically, all of our patients showed typical features of late onset GSD II with the reduced GAA enzyme activities. The respiratory difficulty preceding ambulatory failure seems to be one of the most remarkable clinical features characterizing late onset GSD II. By direct sequence analysis of PCR-amplified genomic DNA obtained from patients' skeletal muscle or peripheral leukocytes, we identified four missense mutations. Two of them (p.266Pro>Ser and p.439Met>Lys) were new missense mutations causing late onset GSD II, which had not been reported elsewhere before. One of them (p.439Met>Lys) was found in two alleles from each patient, suggesting it could be a recurrent mutation among Korean population.

Adult↗
PubMed1996

Identification of a small deletion in one allele of patients with infantile form of glycogen storage disease type II.

Glycogen storage disease type II (GSD II, Pompe's disease) is an autosomal recessive inherited disease caused by the deficiency of acid alpha-D-glucosidase. In this paper we report two unrelated Chinese patients with infantile form of GSD II who had compound heterozygotes containing a small deletion in one of the acid alpha-D-glucosidase alleles. In both of these compound heterozygotes, one allele contains the C1935A transversion which is the most common mutation in Chinese patients and the other allele contains the newly identified 4 nt deletion of coding sequence (deletion nt 1411-1414). This small deletion causes a reading frameshift and translational premature termination signal in exon 9.

Alleles↗
PubMed2005

Impact of humoral immune response on distribution and efficacy of recombinant adeno-associated virus-derived acid alpha-glucosidase in a model of glycogen storage disease type II.

Glycogen storage disease type II (GSDII) is a lysosomal storage disease caused by a deficiency in acid alpha-glucosidase (GAA), and leads to cardiorespiratory failure by the age of 2 years. In this study, we investigate the impact of anti-GAA antibody formation on cross-correction of the heart, diaphragm, and hind-limb muscles from liver-directed delivery of recombinant adeno-associated virus (rAAV)5- and rAAV8-GAA vectors. GAA(-/-) mice receiving 1 x 10(12) vector genomes of rAAV5- or rAAV8-DHBV-hGAA were analyzed for anti-GAA antibody response, GAA levels, glycogen reduction, and contractile function. We demonstrate that restoration of GAA to the affected muscles is dependent on the presence or absence of the antibody response. Immune-tolerant mice had significantly increased enzyme levels in the heart and skeletal muscles, whereas immune-responsive mice had background levels of GAA in all tissues except the diaphragm. The increased levels of activity in immune-tolerant mice correlated with reduced glycogen in the heart and diaphragm and, overall, contractile function of the soleus muscle was significantly improved. These findings highlight the importance of the immune response to rAAV-encoded GAA in correcting GSDII and provide additional understanding of the approach to treatment of GSDII.

Animals↗
PubMed2003

Identification of four novel mutations in the alpha glucosidase gene in five Italian patients with infantile onset glycogen storage disease type II.

Glycogen storage disease type II (GSDII) is an autosomal recessive disorder due to the deficiency of the lysosomal enzyme acid alpha glucosidase. Four novel mutations (C670T, G989A, G2188T, and Delta 23 nt 828-850) were identified in five Italian patients with the infantile form of the disease. The C670T mutation was present in two unrelated patients in heterozygosity; the effect on enzyme activity was assessed by in vitro expression. COS-1 cells expressing the C670T allele had a twofold higher activity than the negative control cells. The G989A and G2188T point mutations lead to the introduction of premature stop signals that results in truncated forms of alpha glucosidase. The in vitro expression of G2188T allele demonstrated no increment in activity compared to negative control. The frame shifting deletion of nucleotides 828-850 was identified in one patient in heterozygosity. The shift in the reading frame introduces a stop codon 135 nucleotides downstream the deletion junction that results in a truncated protein without catalytic activity. Nested PCR screening showed that the mutation was carried by the mother and was absent in the other members of the family. The four novel severe mutations herein described concerned only infantile onset GSDII patients; the loss of enzyme activity is correlated with the severity of the disease.

Age of Onset↗
PubMed2006

Chemical chaperones improve transport and enhance stability of mutant alpha-glucosidases in glycogen storage disease type II.

Glycogen storage disease type II (GSDII; Pompe disease or acid maltase deficiency) is an autosomal recessive disorder caused by lysosomal acid alpha-glucosidase (AalphaGlu) deficiency and manifests predominantly as skeletal muscle weakness. Defects in post-translational modification and transport of mutant AalphaGlu species are frequently encountered and may potentially be corrected with chaperone-mediated therapy. In the present study, we have tested this hypothesis by using deoxynojirimycin and derivatives as chemical chaperones to correct the AalphaGlu deficiency in cultured fibroblasts from patients with GSDII. Four mutant phenotypes were chosen: Y455F/Y455F, P545L/P545L, 525del/R600C and D645E/R854X. In case of Y455F/Y455F and P545L/P545L, N-(n-butyl)deoxynojirimycin (NB-DNJ) restored the transport, maturation and activity of AalphaGlu in a dose dependent manner, while it had no effect on the reference enzyme beta-hexosaminidase. NB-DNJ promoted export from the endoplasmic reticulum (ER) to the lysosomes and stabilized the activity of mutant AalphaGlu species, Y455F and P545L, inside the lysosomes. In long-term culture, the AalphaGlu activity in the fibroblasts from the patients with mutant phenotypes, Y455F/Y455F and P545L/P545L, increased up to 14.0- and 7.9-fold, respectively, in the presence of 10mumol/L NB-DNJ. However, the effect of NB-DNJ on Y455F/Y455F subsided quickly after removal of the compound. We conclude that NB-DNJ acts in low concentration as chemical chaperone for certain mutant forms of AalphaGlu that are trapped in the ER, poorly transported or labile in the lysosomal environment. Chemical chaperone therapy could create new perspectives for therapeutic intervention in GSDII.

1-Deoxynojirimycin↗
PubMed1994

The effect of a single base pair deletion (delta T525) and a C1634T missense mutation (pro545leu) on the expression of lysosomal alpha-glucosidase in patients with glycogen storage disease type II.

Glycogen storage disease type II (GSDII, Pompe's disease) is caused by an autosomal recessive inheritance of lysosomal alpha-glucosidase deficiency. By sequence analysis we have identified the mutations in the lysosomal alpha-glucosidase gene (GAA) of two unrelated patients, who have one and two copies, respectively, of the same missense mutation. The milder affected adult patient was found to be homozygous for a C1634T transition resulting in the substitution of pro545 by leu. The more severely affected adolescent patient had this same mutant allele combined with a 1 base pair deletion (delta T525) in the second allele causing premature termination at nucleotide positions 658-660. Both these mutations were introduced in wild-type alpha-glucosidase cDNA and expressed in COS-1 cells to analyse their effect. The delta T525 mutation prohibits the formation of lysosomal alpha-glucosidase completely. The pro545-->leu substitution is compatible with normal synthesis but hampers enzyme maturation and results in a 92% net loss of lysosomal alpha-glucosidase activity. The patient with adult GSDII has, in accordance with the allelic constitution, a 2-fold higher residual activity than the patient with juvenile GSDII. The delta T525 deletion was detected in two other unrelated patients, and also the C1634T transition was encountered in two more Caucasian patients with GSDII.

Adolescent↗
PubMed1978

Glucose-containing oligosaccharides in the urine of patients with glycogen storage disease type II and type III.

Patients with glycogen storage disease type II and type III were recently found to excrete increased amounts of a glucose-containing tetrasaccharide DGlcp(alpha1 leads to 6)DGlcp(alpha1 leads to 4)DGlcp(alpha1 leads to 4)DGlc [Lennartson, G., Lundblad, A., Sjöblad, S., Svensson, S. and Ockerman, P.A. (1976) Biomed. Mass Spectrom. 3, 51--54]. In addition to this tetrasaccharide, urine from these patients also contains larger oligosaccharides containing only glucose. From urine of patients with glycogen storage disease type II and type III, three and four oligosaccharides respectively have been isolated. Structural studies including sugar analyses, methylation analyses, partial acid hydrolysis and optical rotation revealed that three compounds were present in the urine of both patients. Their proposed structures or partial structures are as follows: DGlcp(alpha1--6)DGlcp(alpha1--6)DGlcp(alpha1--4)DGlcp(alpha1--4)DGlcp(alpha1--4)DGlc, DGlcp(alpha1--4)DGlcp(alpha1--6)DGlcp(alpha1--6)DGlcp(alpha1--4)DGlcp(alpha1--4)DGlc, and DGlcp(alpha1--6)DGlcp(alpha1--4)DGlcp(alpha1--4)DGlcp(alpha1--4)DGlcp(alpha1--6)DGlcp(alpha1--4)DGlcp(alpha1--4)DGlc. A fourth compound has been partially characterized as a branched heptasaccharide with four (1 leads to 4) linkages and two (1 lead to 6) linkages. Glycogen is possibly the origin of these compounds. However, the number of (1 leads to 6) linkages is higher than expected and may indicate a shorter distance between branches in glycogen than has been generally assumed.

Child↗
PubMed1999

A large Alu-mediated deletion, identified by PCR, as the molecular basis for glycogen storage disease type II (GSDII).

Glycogen storage disease type II (GSDII) is an autosomal recessive disorder resulting from inherited deficiency of the enzyme lysosomal acid alpha-glucosidase. Over 40 different mutations have been described but no large deletions have been previously identified. We now describe a homozygous large (9-kb) deletion extending from IVS 15 to 4 kb downstream of the terminal exon (exon 20), detected by polymerase chain reaction (PCR)-based methods. The deletion was initially suspected because of failure to amplify a contiguous group of exons by PCR. We hypothesized an Alu/Alu recombination, based on our prior demonstration by Southern blotting of Alu elements in the regions potentially flanking the deletion. Additional sequence analysis of genomic fragments confirmed the presence of Alu elements and allowed the design of flanking primers for PCR amplification. Amplification resulted in a smaller than normal fragment (0.7 vs. 10 kb) in homozygosity in the proband and in heterozygosity in her parents. Cloning and sequencing of the smaller than normal 0.7-kb deletion fragment revealed an Alu/Alu deletion junction. In heterozygosity this deletion would not be detected by currently standard PCR mutation detection methods. Based on other Alu-mediated deletions, this deletion is likely to be recurrent and should be screened for in all non-consanguineous GSDII patients, particularly when only one mutation has been identified and none of the 12 single-nucleotide polymorphisms in the deleted region are heterozygous. These observations also suggest that initial characterization of genes at disease-causing loci should include a search for Alu and other repetitive elements to facilitate subsequent PCR-based mutation analysis.

Alu Elements↗
PubMed1993

The conservative substitution Asp-645-->Glu in lysosomal alpha-glucosidase affects transport and phosphorylation of the enzyme in an adult patient with glycogen-storage disease type II.

Glycogen-storage disease type II (GSDII) is caused by the deficiency of lysosomal alpha-glucosidase (acid maltase). This paper reports on the analysis of the mutant alleles in an American black patient with an adult form of GSDII (GM1935). The lysosomal alpha-glucosidase precursor of this patient has abnormal molecular features: (i) the molecular mass is decreased, (ii) the phosphorylation is deficient and (iii) the proteolytic processing is impaired. Sequence analysis revealed four mutations leading to amino acid alterations: Asp-645-->Glu, Val-816-->Ile, Arg-854-->Stop and Thr-927-->Ile. By using allele-specific oligonucleotide hybridization on PCR-amplified cDNA we have demonstrated that the Arg-854-->Stop mutation is located in one allele that is not expressed, and that the other allele contains the remaining three mutations. Each of the mutations was introduced in wild-type cDNA and expressed in COS cells to analyse the effect on biosynthesis, transport and phosphorylation of lysosomal alpha-glucosidase. The Val-816-->Ile substitution appeared to have no significant effect in contrast with results [Martiniuk, Mehler, Bodkin, Tzall, Hirshhorn, Zhong and Hirschhorn (1991) DNA Cell Biol. 10, 681-687] and was therefore defined as a polymorphism. The Thr-927-->Ile substitution deleting one of the seven glycosylation sites was found to be responsible for the decrease in molecular-mass, but not for the deficient proteolytic processing and phosphorylation. It did not cause the enzyme deficiency either. The third mutation leading to the Asp-645-->Glu substitution was proven to account in full for the observed defects in transport, phosphorylation and proteolytic processing of the newly synthesized alpha-glucosidase precursor of the patient.

Adult↗
PubMed2002

Identification of six novel mutations in the acid alpha-glucosidase gene in three Spanish patients with infantile onset glycogen storage disease type II (Pompe disease).

Glycogen storage disease type II is an autosomal recessive muscle disorder due to deficiency of lysosomal acid alpha-glucosidase and the resulting intralysosomal accumulation of glycogen. We found six novel mutations in three Spanish classic infantile onset glycogen storage disease type II patients with involvement of both cardiac and skeletal muscle; three missense mutations (G219R, E262K, M408V), a nonsense mutation (Y191X), a donor splice site mutation (IVS18 +2gt>ga) and an in frame deletion of an asparagine residue (nt1408-1410). The missense mutations were not found in 100 normal chromosomes and therefore are not normal polymorphic variants. The splice site mutation was subsequently detected in an additional 'Spanish' infantile onset glycogen storage disease type II patient from El Salvador. Further studies will be required to determine if the IVS18 +2gt>ga splice site mutation might in fact be a relatively common Spanish mutation. Mutations among Spanish glycogen storage disease type II patients appear to be genetically heterogeneous and differ from common mutations in neighboring countries.

Age of Onset↗
PubMed2000

Towards a molecular therapy for glycogen storage disease type II (Pompe disease).

Glycogen storage disease type II (GSD-II), also known as Pompe disease, is a fatal genetic muscle disorder caused by a deficiency of acid alpha-glucosidase, a glycogen-degrading lysosomal enzyme. Currently, there is no treatment for this fatal disorder. However, several lines of research suggest the possibility of future treatment. Enzyme replacement strategies hold the greatest hope for patients currently affected by GSD-II, but future strategies could include in vivo or ex vivo gene therapy approaches and/or mesenchymal stem cell or bone-marrow transplantation approaches. Each of the approaches might eventually be combined to further improve the overall clinical efficacy of any one treatment regimen. The lessons learned from GSD-II research will also benefit a great number of individuals affected by other genetic disorders.

Animals↗
PubMed2001

Long-term efficacy after [E1-, polymerase-] adenovirus-mediated transfer of human acid-alpha-glucosidase gene into glycogen storage disease type II knockout mice.

Glycogen storage disease type II (GSD-II) is a lethal, autosomal recessive metabolic myopathy caused by a lack of acid-alpha-glucosidase (GAA) activity in the cardiac and skeletal muscles. Absence of adequate intralysosomal GAA activity results in massive amounts of glycogen accumulation in multiple muscle groups, resulting in morbidity and mortality secondary to respiratory embarrassment and/or cardiomyopathy. In a mouse model of GSD-II, we demonstrate that infection of the murine liver with a modified adenovirus (Ad) vector encoding human GAA (hGAA) resulted in long-term persistence of the vector in liver tissues for at least 6 months. Despite both a rapid shutdown of hGAA mRNA expression from the vector, as well as the elicitation of anti-hGAA antibody responses (hGAA is a foreign antigen in this model), the hGAA secreted by the liver was taken up by all muscle groups analyzed and, remarkably, persisted in them for at least 6 months. The persistence of the protein also correlated with long-term correction of pathologic intramuscular glycogen accumulations in all muscle groups tested, but most notably the cardiac tissues, which demonstrated a significantly decreased glycogen content for at least 190 days after a single vector injection. The results suggest that gene therapy strategies may have the potential to significantly improve the clinical course for GSD-II patients.

Adenoviridae↗