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

• Published in: International journal of molecular sciences Vol. 22; no. 7; p. 3625
• Main Authors: Napolitano, Filomena, Bruno, Giorgia, Terracciano, Chiara, Franzese, Giuseppina, Palomba, Nicole Piera, Scotto di Carlo, Federica, Signoriello, Elisabetta, De Blasiis, Paolo, Navarro, Stefano, Gialluisi, Alessandro, Melone, Mariarosa Anna Beatrice, Sampaolo, Simone, Esposito, Teresa
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 31-03-2021; MDPI
• Subjects: Adult; Age; Aged; alpha-Glucosidases - genetics; alpha-Glucosidases - metabolism; Aneurysms; Autophagy; Autophagy - genetics; Autophagy - physiology; autophagy genes; Biomedical materials; Body mass index; Bone turnover; Disease; Enzymatic activity; Enzyme activity; Enzyme Replacement Therapy - methods; Enzymes; Family; Fatigue; Female; Fractures; Genes; Genetic factors; genetic modifiers; Genetic Variation - genetics; Genotype & phenotype; Genotypes; Glucosidase; Glycogen Storage Disease Type II - genetics; Hereditary diseases; Humans; Italy; late-onset form of Pompe disease; Male; Middle Aged; modifiers factors; Muscle, Skeletal - metabolism; Muscles; Mutation; Osteoporosis; Patients; Pedigree; Phagocytosis; Phenotypes; Respiratory Muscles; Siblings; Signs and symptoms; skeletal muscle biopsies; Vitamin D; Vitamin deficiency; whole exome sequencing; α-Glucosidase; Italy; autophagy genes; genetic modifiers; late-onset form of Pompe disease; skeletal muscle biopsies; modifiers factors; whole exome sequencing
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22073625

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
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
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.