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

Int J Mol Sci 2021 Mar 31;22(7):3625. doi: 10.3390/ijms22073625.

PMID: 33807278

Filomena Napolitano, Giorgia Bruno, Chiara Terracciano

Highlights: This study emphasizes the multisystem nature of LOPD and highlights the polygenic nature of the complex phenotype disclosed in these patients.

Abstract

Background: A deficiency in the enzyme acid alpha-glucosidase causes Pompe disease, which is an autosomal recessive disorder. The late-onset type of Pompe disease (LOPD) is marked by a gradual development of proximal muscle weakness, which frequently affects the respiratory muscles. Even among individuals with the same combination of GAA mutations, the levels of GAA enzyme activity and the severity of the clinical signs and symptoms in LOPD might vary greatly. As a result, the genotype-phenotype correlation is unpredictable.

Objective: The goal of this study was to identify the genetic factors that influence LOPD progression, severity, and treatment response.

Methods: We present the results of a comprehensive clinical, morphological, and genetic investigation of 11 adult LOPD siblings from two Italian families with compound heterozygous GAA mutations, which included a whole exome sequencing (WES) analysis.

Results: We discovered a heterogeneous pattern of myopathic dysfunction that was linked to heart problems, cerebral vascular abnormalities, osteoporosis, vitamin D insufficiency, obesity, and an adverse response to enzyme replacement treatment (ERT). We discovered deleterious mutations in genes involved in autophagy, immunity, and bone metabolism, which contributed to the severity of the LOPD patients' clinical symptoms.

Conclusion: The multisystem nature of LOPD is highlighted in this study, as is the polygenic nature of the complex phenotype seen in these individuals.

Keywords: autophagy genes, genetic modifiers, late-onset form of Pompe disease, skeletal muscle biopsies, whole exome sequencing