Rare Variants in Autophagy and Non-Autophagy Genes in Late-Onset Pompe Disease: Suggestions of Their Disease-Modifying Role in Two Italian Families

Abstract

Pompe disease is an autosomal recessive disorder caused by a deficiency in the enzyme acid alpha-glucosidase. The late-onset form of Pompe disease (LOPD) is characterized by a slowly progressing proximal muscle weakness, often involving respiratory muscles. In LOPD, the levels of GAA enzyme activity and the severity of the clinical pictures may be highly variable among individuals, even in those who harbour the same combination of GAA mutations. The result is an unpredictable genotype–phenotype correlation. The purpose of this study was to identify the genetic factors responsible for the progression, severity and drug response in LOPD. We report here on a detailed clinical, morphological and genetic study, including a whole exome sequencing (WES) analysis of 11 adult LOPD siblings belonging to two Italian families carrying compound heterozygous GAA mutations. We disclosed a heterogeneous pattern of myopathic impairment, associated, among others, with cardiac defects, intracranial vessels abnormality, osteoporosis, vitamin D deficiency, obesity and adverse response to enzyme replacement therapy (ERT). We identified deleterious variants in the genes involved in autophagy, immunity and bone metabolism, which contributed to the severity of the clinical symptoms observed in the LOPD patients. This study emphasizes the multisystem nature of LOPD and highlights the polygenic nature of the complex phenotype disclosed in these patients.

Whole-exome sequencing of the mummified remains of Cangrande della Scala (1291–1329 CE) indicates the first known case of late-onset Pompe disease

“…in HGMD. Moreover, we identified additional variants in genes correlating with the regulatory activity of lysosomal enzymes 13 : besides 28 variants which were common in the frequency population databases (MAF > 5%), six rare exonic missense variants were present in the ATP6 gene and one rare exonic missense variant was present in the RUNX1 gene.…”

“…While abrogation of α-glucosidase enzymatic activity is causative of the classical infantile form, such condition is instead responsible of the late-onset Pompe disease, associated with α-glucosidase activity lower than 20% 36 , 37 . Additional genes have been recently demonstrated to play a role as genetic modifiers of lysosomal functions 13 , 38 , 39 . Among these we found that Cangrande genome carried six rare missense variants in ATP6 (controlling the pH of the lysosomal compartment) 38 , 39 , while RUNX1 (involved in autophagy/lysosome metabolism) 13 had one rare missense variant.…”

“…Additional genes have been recently demonstrated to play a role as genetic modifiers of lysosomal functions 13 , 38 , 39 . Among these we found that Cangrande genome carried six rare missense variants in ATP6 (controlling the pH of the lysosomal compartment) 38 , 39 , while RUNX1 (involved in autophagy/lysosome metabolism) 13 had one rare missense variant. Beside the GAA alleles causative of the late-onset Pompe disease, these other genetic variants could also contribute to Cangrande’s clinical phenotype.…”