Glycogen storage disease type IV without polyglucosan bodies: report of three cases and literature review

Glycogen storage disease type IV (GSD IV) is an autosomal recessive disorder caused by mutations in the glycogen branching enzyme 1 (GBE1) gene and is characterized by accumulation of polyglucosan bodies in liver, muscle and other tissues. We report three cases with neuromuscular forms of GSD IV, none of whom had polyglucosan bodies on muscle biopsy. They all had compound heterozygous variants in the GBE1 gene classified as either likely pathogenic or pathogenic, all including the GBE1 c.691+2T>C variant. The first case had no neonatal problems and presented with delayed walking. The other cases presented at birth: one with arthrogryposis, hypotonia, and respiratory distress, and the other with talipes and feeding problems. These two cases had presumed antenatal onset of their condition, however unlike most cases with this type of neuromuscular GSD IV described in the literature, they survived until at least toddlerhood. All three cases described developed a similar pattern of axial weakness, proximal upper limb weakness and scapular winging, and much milder proximal lower limb weakness. We review the literature and describe any previously reported cases of neuromuscular GSD IV without polyglucosan bodies on muscle biopsy as well as the reported patterns of muscle weakness. Our cases emphasize that GSD IV should be considered even in the absence of characteristic polyglucosan bodies on muscle biopsy. They also expand the phenotypic spectrum of neuromuscular GSD IV, highlighting that limb girdle weakness and congenital myopathy phenotype can both be caused by mutations in GBE1. Glycogen storage disease type IV (GSD IV) is an autosomal recessive disorder caused by mutations in the glycogen branching enzyme 1 (GBE1) gene and is characterized by accumulation of polyglucosan bodies in liver, muscle and other tissues. We report three cases with neuromuscular forms of GSD IV, none of whom had polyglucosan bodies on muscle biopsy. They all had compound heterozygous variants in the GBE1 gene classified as either likely pathogenic or pathogenic, all including the GBE1 c.691+2T>C variant. The first case had no neonatal problems and presented with delayed walking. The other cases presented at birth: one with arthrogryposis, hypotonia, and respiratory distress, and the other with talipes and feeding problems. These two cases had presumed antenatal onset of their condition, however unlike most cases with this type of neuromuscular GSD IV described in the literature, they survived until at least toddlerhood. All three cases described developed a similar pattern of axial weakness, proximal upper limb weakness and scapular winging, and much milder proximal lower limb weakness. We review the literature and describe any previously reported cases of neuromuscular GSD IV without polyglucosan bodies on muscle biopsy as well as the reported patterns of muscle weakness. Our cases emphasize that GSD IV should be considered even in the absence of characteristic polyglucosan bodies on muscle biopsy. They also expand the phenotypic spectrum of neuromuscular GSD IV, highlighting that limb girdle weakness and congenital myopathy phenotype can both be caused by mutations in GBE1.