Genotype-phenotype Correlation in Late-onset Glycogen Storage Disease Type II, Early Diagnosis and Prognostic Determinants

Glycogen storage disease type II (GSDII) is an autosomal recessive lysosomal storage disorder caused by acid alpha-1,4-glucosidase (GAA) deficiency. This study aimed to provide an in-depth description of a late-onset GSDII (LO-GSDII) cohort (n=36) and assess potential genotype-phenotype correlation. We performed a clinical record-based study, some patients (n= 19) were also followed prospectively. Phenotypes were highly variable. We focused our clinical assessment onrespiratory failure, as it is the most frequent cause of death in LO-GSDII. In addition to standard spirometric measures, in a subgroup of patients (n = 10) we utilized a new tool, optoelectronic plethysmography (OEP), to investigate the pathophysiology of respiratory muscle impairment.The GAA gene was sequenced in every patient, and pathogenic mutations were identified inall of them. Almost all (35/36) patients carried the same mutation on one allele, IVS1-32-13T>G, which was in compound heterozygosity with a variety of other GAA mutations. To investigate genotype-phenotype correlation, we divided the patient cohort in two groups, according to the severity of the mutation on the second allele. The respiratory function study focused on diaphragmatic weakness. According to the change in forced vital capacity in supine position (ΔFVC), we defined patients with ΔFVC>25% ashaving diaphragmatic weakness (DW) and those with ΔFVC