Distribution of Exonic Variants in Glycogen Synthesis and Catabolism Genes in Late Onset Pompe Disease (LOPD)

Pompe disease (PD) is a monogenic autosomal recessive disorder caused by biallelic pathogenic variants of the GAA gene encoding lysosomal alpha-glucosidase; its loss causes glycogen storage in lysosomes, mainly in the muscular tissue. The genotype–phenotype correlation has been extensively discussed, and caution is recommended when interpreting the clinical significance of any mutation in a single patient. As there is no evidence that environmental factors can modulate the phenotype, the observed clinical variability in PD suggests that genetic variants other than pathogenic GAA mutations influence the mechanisms of muscle damage/repair and the overall clinical picture. Genes encoding proteins involved in glycogen synthesis and catabolism may represent excellent candidates as phenotypic modifiers of PD. The genes analyzed for glycogen synthesis included UGP2, glycogenin (GYG1-muscle, GYG2, and other tissues), glycogen synthase (GYS1-muscle and GYS2-liver), GBE1, EPM2A, NHLRC1, GSK3A, and GSK3B. The only enzyme involved in glycogen catabolism in lysosomes is α-glucosidase, which is encoded by GAA, while two cytoplasmic enzymes, phosphorylase (PYGB-brain, PGL-liver, and PYGM-muscle) and glycogen debranching (AGL) are needed to obtain glucose 1-phosphate or free glucose. Here, we report the potentially relevant variants in genes related to glycogen synthesis and catabolism, identified by whole exome sequencing in a group of 30 patients with late-onset Pompe disease (LOPD). In our exploratory analysis, we observed a reduced number of variants in the genes expressed in muscles versus the genes expressed in other tissues, but we did not find a single variant that strongly affected the phenotype. From our work, it also appears that the current clinical scores used in LOPD do not describe muscle impairment with enough qualitative/quantitative details to correlate it with genes that, even with a slightly reduced function due to genetic variants, impact the phenotype.

[1]  L. Salviati,et al.  Newborn screening for Pompe disease in Italy: Long-term results and future challenges , 2022, Molecular genetics and metabolism reports.

[2]  W. Pijnappel,et al.  Broad variation in phenotypes for common GAA genotypes in Pompe disease , 2021, Human mutation.

[3]  Y. Chien,et al.  GAA variants and phenotypes among 1,079 patients with Pompe disease: Data from the Pompe Registry , 2019, Human mutation.

[4]  W. Pijnappel,et al.  Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity , 2019, Human mutation.

[5]  B. Bembi,et al.  A genetic modifier of symptom onset in Pompe disease , 2019, EBioMedicine.

[6]  M. Couce,et al.  Infantile-onset Pompe disease with neonatal debut , 2017, Medicine.

[7]  M. Adeva-Andany,et al.  Glycogen metabolism in humans☆☆☆ , 2016, BBA clinical.

[8]  K. Claeys,et al.  Homozygosity for the common GAA gene splice site mutation c.-32-13T>G in Pompe disease is associated with the classical adult phenotypical spectrum , 2015, Neuromuscular Disorders.

[9]  B. Bembi,et al.  Functional characterization of the common c.-32-13T>G mutation of GAA gene: identification of potential therapeutic agents , 2013, Nucleic acids research.

[10]  W. Hop,et al.  Clinical features and predictors for disease natural progression in adults with Pompe disease: a nationwide prospective observational study , 2012, Orphanet Journal of Rare Diseases.

[11]  H. Runz,et al.  A cross-sectional single-centre study on the spectrum of Pompe disease, German patients: molecular analysis of the GAA gene, manifestation and genotype-phenotype correlations , 2012, Orphanet Journal of Rare Diseases.

[12]  E. Ralston,et al.  Autophagy and mitochondria in Pompe disease: Nothing is so new as what has long been forgotten , 2012, American journal of medical genetics. Part C, Seminars in medical genetics.

[13]  D. Halley,et al.  Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating , 2008, Human mutation.

[14]  A. D’Amico,et al.  Molecular and functional characterization of eight novel GAA mutations in Italian infants with Pompe disease , 2008, Human mutation.

[15]  M. Filocamo,et al.  Molecular genetics of late onset glycogen storage disease II in Italy. , 2007, Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology.

[16]  M. Ausems,et al.  Broad spectrum of Pompe disease in patients with the same c.-32-13T→G haplotype , 2007, Neurology.

[17]  B. Bembi,et al.  Mutation profile of the GAA gene in 40 Italian patients with late onset glycogen storage disease type II , 2006, Human mutation.

[18]  S. Scherer,et al.  Novel glycogen synthase kinase 3 and ubiquitination pathways in progressive myoclonus epilepsy. , 2005, Human molecular genetics.

[19]  D. V. Leenen,et al.  Twenty‐two novel mutations in the lysosomal α‐glucosidase gene (GAA) underscore the genotype–phenotype correlation in glycogen storage disease type II , 2004, Human mutation.

[20]  P. Enright,et al.  The 6‐min Walk Test: A Quick Measure of Functional Status in Elderly Adults. , 2003, Chest.

[21]  M. Ausems,et al.  Phenotypic expression of late-onset glycogen storage disease type II: identification of asymptomatic adults through family studies and review of reported families , 2000, Neuromuscular Disorders.

[22]  A. Reuser,et al.  Deletion of exon 18 is a frequent mutation in glycogen storage disease type II. , 1994, Biochemical and biophysical research communications.

[23]  A. Hamed,et al.  Survival and long-term outcomes in late-onset Pompe disease following alglucosidase alfa treatment: a systematic review and meta-analysis , 2016, Journal of Neurology.