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.
Highlights
Glycogen storage disease type II (GSDII; Online Mendelian Inheritance in Man (OMIM) 232300; Pompe disease or acid maltase deficiency) is an autosomal recessive disorder caused by mutations in the acid alpha-glucosidase (GAA) gene encoding a lysosome enzyme that hydrolyses glycogen to glucose [1].Mutations in GAA lead to a wide spectrum of clinical phenotypes, ranging from a severe infantile form, presenting with cardiomyopathy and muscular hypotonia, to a relatively mild, late-onset form of Pompe disease (LOPD) form characterized by a slowly progressing proximal muscle weakness, often involving respiratory muscles [1,2]
We identified 16 rare and deleterious variants (14 non-synonymous 1 non-frameshift insertion and 1 splicing) lying in 12 genes, involved across different interconnected pathways potentially deregulated in LOPD, including autophagy/lysosomal (RILP, Folliculin Interacting Protein 2 (FNIP2), TRAPPC11, Perilipin 2 (PLIN2), IRS1, KL, lipoprotein receptor-related protein-4 (LRP4), RUNX1), immunity (RILP, FNIP2, TRAPPC11, IRS1, KL, LRP4, RUNX1, FAM26F), bone metabolism (TRPV5, TRPV6, IRS1, KL, LRP4, RUNX1) and skeletal muscle development and/or disease (TRAPPC11, PLIN2, IRS1, LRP4, RUNX1, DCHS1) (Tables 4 and 5 and Figure 3)
At this stage of advancement of our study, we cannot offer any improvement in practicing medicine; we believe it is important to report the two main results that emerge from this study
Summary
Glycogen storage disease type II (GSDII; Online Mendelian Inheritance in Man (OMIM) 232300; Pompe disease or acid maltase deficiency) is an autosomal recessive disorder caused by mutations in the acid alpha-glucosidase (GAA) gene encoding a lysosome enzyme that hydrolyses glycogen to glucose [1].Mutations in GAA lead to a wide spectrum of clinical phenotypes, ranging from a severe infantile form, presenting with cardiomyopathy and muscular hypotonia, to a relatively mild, LOPD form characterized by a slowly progressing proximal muscle weakness, often involving respiratory muscles [1,2]. Many additional symptoms associated with LOPD came to light: dysarthria and dysphagia, osteoporosis, scoliosis, sleep apnoea, small fibre neuropathy, hearing loss, impaired gastric function, urinary tract and anal sphincter involvement, pain and fatigue, as well as a risk of cardiac arrhythmia and cerebral and intracranial aneurysms [3]. These clinical findings emphasize the multisystem nature of LOPD. GAA-mutated family members have the closest possible genetic background and might better define the genotype–phenotype correlation, including a wide spectrum of clinical parameters
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