A rare co-occurrence of phosphorylase kinase deficiency (GSD type IXd) and alpha-glycosidase deficiency (GSD Type II) in a 53-year-old man presenting with an atypical glycogen storage disease phenotype

Abstract

Glycogen Storage Disease (GSD) IXd, caused by PHKA1 gene mutations, is an X-linked rare disorder that can be asymptomatic or associated with exercise intolerance. GSD type II is an autosomal recessive disorder caused by mutations in the GAA gene that lead to severe cardiac and skeletal muscle myopathy. We report the first case of co-occurrence of type IXd and type II GSDs in a 53-year-old man with an atypical glycogen storage disease presentation consisting in myalgia in the lower limbs at both rest and after exercise and increased levels of transaminases from the age of 16. At the age of 43, the patient presented a steppage gait, inability to run and walk on his heels, hypotrophy of the pectoral and proximal muscles, reflexes not elicitable, and CK levels 3.6 times the upper reference limit. Next Generation Sequencing (NGS) identified one variant in the PHKA1 gene, c.1360A > G p.Ile454Val (exon 14) inherited by his mother, and two heterozygous variants in the GAA gene, c.784G > A (exon 4) and c.956-6T > C (exon 6). A review of GSD IXd cases reported to date in the literature is also provided.

Keywords: GSD type II; GSD type IXd; Phosphorylase kinase deficiency; alpha-glycosidase deficiency; co-occurrence.

Figure 1.

Graphical view of PHKA1 protein. Calmodulin-binding regions are coloured in sky blue. The nonsense, missense, frameshift and splicing pathogenic variants so far described are reported using different symbols and grouped according to their effect. The variant identified in our patient is highlighted in bold red.

Figure 2.

Electropherograms of the GAA and PHKA1 genes. In panel A and B, the electropherograms confirm the compound heterozygous missense mutations (c.784G>A and c.956-6T) in the GAA gene identified in the proband and inherited from the father and mother, respectively. In panel C, electropherograms confirm the missense mutation (c.1360 A>G ) in the PHKA1 gene identified in the proband (hemizygous) and in the mother (heterozygous).