Cardiomyopathy as presenting sign of glycogenin‐1 deficiency—report of three cases and review of the literature

Abstract

We describe a new type of cardiomyopathy caused by a mutation in the glycogenin-1 gene (GYG1). Three unrelated male patients aged 34 to 52 years with cardiomyopathy and abnormal glycogen storage on endomyocardial biopsy were homozygous for the missense mutation p.Asp102His in GYG1. The mutated glycogenin-1 protein was expressed in cardiac tissue but had lost its ability to autoglucosylate as demonstrated by an in vitro assay and western blot analysis. It was therefore unable to form the primer for normal glycogen synthesis. Two of the patients showed similar patterns of heart dilatation, reduced ejection fraction and extensive late gadolinium enhancement on cardiac magnetic resonance imaging. These two patients were severely affected, necessitating cardiac transplantation. The cardiomyocyte storage material was characterized by large inclusions of periodic acid and Schiff positive material that was partly resistant to alpha-amylase treatment consistent with polyglucosan. The storage material had, unlike normal glycogen, a partly fibrillar structure by electron microscopy. None of the patients showed signs or symptoms of muscle weakness but a skeletal muscle biopsy in one case revealed muscle fibres with abnormal glycogen storage. Glycogenin-1 deficiency is known as a rare cause of skeletal muscle glycogen storage disease, usually without cardiomyopathy. We demonstrate that it may also be the cause of severe cardiomyopathy and cardiac failure without skeletal muscle weakness. GYG1 should be included in cardiomyopathy gene panels.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-016-9978-1) contains supplementary material, which is available to authorized users.

Clinical heterogeneity and phenotype/genotype findings in 5 families with GYG1 deficiency

“… 6 – 8 , 12 , 13 In reported cases of glycogenin deficiency, skeletal muscle involvement was always that of a limb-girdle myopathy, accompanied in some instances by an additional distal involvement. 6 – 13 Cardiomyopathy in patients with GSDXV is rare, 6 , 14 but mutations in the GYG1 gene can be observed with no skeletal muscle signs. 14 …”

Identification of transcription factors MYC and C/EBPβ mediated regulatory networks in heart failure

“…6a). Furthermore, through literature research, we found that 9 MYC target genes were previously reported involving the development of heart failure, including STAT3 [48], PRMT1 [49], PRKCH [50], HSPA4 [51], DDX3X [52], GYG1 [53], GADD45B [54] and PKN1 [55] (Fig. 6a, the red ones).…”

Severe asymmetric muscle weakness revealing glycogenin‐1 polyglucosan body myopathy

“…Muscle biopsies show the accumulation of polyglucosan bodies, consisting of hyper‐intense periodic acid‐Schiff (PAS)‐positive material with a variable resistance to alpha‐amylase treatment. Although cardiac involvement has been reported in 4 patients with glycogenin‐1 gene ( GYG1 ) mutations, these patients did not show any clear evidence of skeletal muscle disease …”

“…Although cardiac involvement has been reported in 4 patients with glycogenin-1 gene (GYG1) mutations, these patients did not show any clear evidence of skeletal muscle disease. 8,9 Here, we describe a 63-year-old woman born to consanguineous French parents, who developed right shoulder pain, difficulty climbing stairs and left foot weakness causing stumbling episodes at 46 years of age. Over time, the patient reported increasing difficulty elevating the right arm.…”

“…1 The c.143 1 3G>C variant is the most commonly identified mutation in polyglucosan body myopathy-2 patients, already reported in 25 alleles. 9 Among the 11 homozygous patients with the c.143 1 3G>C mutation, 2 presented with onset in their teens and 9 had adult or late-onset (>30 years). Only one patient developed facial weakness.…”