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.

• Authors: Filomena Napolitano, Giorgia Bruno, Chiara Terracciano, Giuseppina Franzese, Nicole Piera Palomba, Federica Scotto di Carlo, Elisabetta Signoriello, Paolo De Blasiis, Stefano Navarro, Alessandro Gialluisi, Mariarosa Anna Beatrice Melone, Simone Sampaolo, Teresa Esposito
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 7 (Mar 31 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 33807278 (Publication Type: Case Reports, Journal Article)

Chemical References

• GAA protein, human
• alpha-Glucosidases

Topics

• Adult
• Aged
• Autophagy (genetics, physiology)
• Enzyme Replacement Therapy (methods)
• Family
• Female
• Genetic Variation (genetics)
• Glycogen Storage Disease Type II (genetics)
• Humans
• Italy
• Male
• Middle Aged
• Muscle, Skeletal (metabolism)
• Mutation
• Pedigree
• Respiratory Muscles
• Siblings
• alpha-Glucosidases (genetics, metabolism)