Analysis of GBE1 mutations via protein expression studies in glycogen storage disease type IV: A report on a non-progressive form with a literature review

Abstract

BackgroundGlycogen storage disease type IV (GSD IV), caused by GBE1 mutations, has a quite wide phenotypic variation. While the classic hepatic form and the perinatal/neonatal neuromuscular forms result in early mortality, milder manifestations include non-progressive form (NP-GSD IV) and adult polyglucosan body disease (APBD). Thus far, only one clinical case of a patient with compound heterozygous mutations has been reported for the molecular analysis of NP-GSD IV. This study aimed to elucidate the molecular basis in a NP-GSD IV patient via protein expression analysis and to obtain a clearer genotype-phenotype relationship in GSD IV.Case presentationA Japanese boy presented hepatosplenomegaly at 2 years of age. Developmental delay, neurological symptoms, and cardiac dysfunction were not apparent. Observation of hepatocytes with periodic acid-Schiff-positive materials resistant to diastase, coupled with resolution of hepatosplenomegaly at 8 years of age, yielded a diagnosis of NP-GSD IV. Glycogen branching enzyme activity was decreased in erythrocytes. At 13 years of age, he developed epilepsy, which was successfully controlled by carbamazepine.Molecular analysisIn this study, we identified compound heterozygous GBE1 mutations (p.Gln46Pro and p.Glu609Lys). The branching activities of the mutant proteins expressed using E. coli were examined in a reaction with starch. The result showed that both mutants had approximately 50% activity of the wild type protein.ConclusionThis is the second clinical report of a NP-GSD IV patient with a definite molecular elucidation. Based on the clinical and genotypic overlapping between NP-GSD IV and APBD, we suggest both are in a continuum.

Skeletal-Muscle-Specific Overexpression of Chrono Leads to Disruption of Glucose Metabolism and Exercise Capacity

“…The highest levels of this enzyme are found in the liver and muscle. Mutations in this gene are associated with glycogen storage disease IV (also known as Andersen’s disease) [ 34 ]. Phosphorylase kinase is an essential regulator of glycogen catabolism, and its primary function is to promote glycogen breakdown [ 35 ].…”

Integrative Epigenomic and Transcriptomic Analysis Reveals Robust Metabolic Switching in the Brain During Intermittent Fasting

“…(responsible for glycogen storage (Akman et al, 2011;Iijima et al, 2018)), were uniquely upregulated in IF16 and EOD, respectively. However, in both IF16 and EOD common genes, such as Elovl2 (involved in de novo lipogenesis, lipid storage, and subsequent fat mass expansion (Pauter et al, 2014;Rennert et al, 2018)) and…”

“…These metabolic changes in both IF regimens appeared to be orchestrated by unique as well as common genes. For instance, both Aldob (responsible for glycolysis (Le et al, 2018;Peng et al, 2008)) and Gbe1 (responsible for glycogen storage (Akman et al, 2011;Iijima et al, 2018)), were uniquely upregulated in IF16 and EOD, respectively. However, in both IF16 and EOD common genes, such as Elovl2 (involved in de novo lipogenesis, lipid storage, and subsequent fat mass expansion (Pauter et al, 2014;Rennert et al, 2018)) and Fads2 (involved in biosynthesis of polyunsaturated fatty acids (Huang et al, 2017;Reynolds et al, 2018)), were upregulated and downregulated, respectively, in a temporal manner.…”

GBE1‐related disorders: Adult polyglucosan body disease and its neuromuscular phenotypes

“…Regarding neuromuscular phenotypes, based on age at onset, the molecular abnormality involved with GBE1 pathogenic variants and residual GBE activity values, most clinicians and researchers consider six main groups of presentations (Table 1) 2,10 : (a) a severe early fatal perinatal form with hydrops fetalis, fetal akinesia deformation sequence, multiple congenital contractures, arthrogryposis multiplex congenita and perinatal death due to complete loss of enzyme activity; (b) an early congenital neuromuscular form with moderate to severe hypotonia and global amyotrophy, variable central nervous system involvement, early dilated cardiomyopathy with respiratory failure and early death due to partial but severe enzyme deficiency 21 ; (c) a classic childhood form (classical Andersen disease, previously known as "familial cirrhosis of the liver with storage of abnormal glycogen") with multi-system involvement including myopathy with hypotonia, cardiomyopathy, or both, commonly associated with progressive liver compromise evolving to severe portal hypertension and lethal liver cirrhosis and related to variable GBE activity (less markedly reduced than in congenital and early neonatal presentations) 6,15 ; (d) nonprogressive childhood hepatic subtype with chronic liver dysfunction and myopathy with hypotonia; (e) childhood neuromuscular subtype with progressive myopathy with hypotonia and limb-girdle pattern of muscular weakness and dilated cardiomyopathy without liver dysfunction 19 ; and (f) adult or late adult-onset form with isolated pure myopathy or classical APBD phenotypes due to 20% or less of residual GBE activity. 35,39,40 Typical APBD presentation is characterized by slowly progressive motor syndrome involving both upper and lower motor neuron disease, presenting mainly with spastic paraparesis or quadriparesis and evolving from distal to proximal limb amyotrophy and bulbar symptoms, but also with progressive neurogenic bladder, painful or painless distal sensory neuropathy and slowly progressive cognitive disturbances disclosing executive frontal dysfunction. There is generally no marked family history of neurodegenerative or neuromuscular compromise.…”