A new muscle glycogen storage disease associated with glycogenin‐1 deficiency

Abstract

We describe a slowly progressive myopathy in 7 unrelated adult patients with storage of polyglucosan in muscle fibers. Genetic investigation revealed homozygous or compound heterozygous deleterious variants in the glycogenin-1 gene (GYG1). Most patients showed depletion of glycogenin-1 in skeletal muscle, whereas 1 showed presence of glycogenin-1 lacking the C-terminal that normally binds glycogen synthase. Our results indicate that either depletion of glycogenin-1 or impaired interaction with glycogen synthase underlies this new form of glycogen storage disease that differs from a previously reported patient with GYG1 mutations who showed profound glycogen depletion in skeletal muscle and accumulation of glycogenin-1.

Polyglucosan storage myopathies

“…The patient was found to have free but autoglucosylated glycogenin-1 in muscle, similar to what is seen in glycogen synthase deficiency (Malfatti et al, 2014). The impaired elongation of the glucose polymer by glycogen synthase can be explained by the fact that glycogen synthase normally binds to the C-terminus of glycogenin-1 (Skurat et al, 2006), and that this binding may be of functional importance.…”

“…The missense variant p.Asp102His, described in one patient (Malfatti et al, 2014), has also been identified in other patients (unpublished data). According to the EVS server, this mutation has been found in 17/13 006 alleles.…”

“…Later, a group of patients was identified with glycogenin-1-associated disease without cardiomyopathy but with juvenile or adult-onset muscle weakness, and with glycogen storage in a large proportion of the muscle fibers (Luo et al, 2015;Malfatti et al, 2014). The muscle weakness was slowly progressive in most cases and the distribution was variable.…”

“…One is a substitution of one base pair at the donor splice site in intron 2 (c.143 + 3G > C), and it has been found in patients of different ethnic backgrounds who are homozygous or compound heterozygous. This mutation results in aberrant splicing, with skipping of exon 2, causing a frameshift with insertion of a premature stop codon (p.Asp3Glufs*4) (Malfatti et al, 2014). At the protein level, the expression of functional glycogenin-1 is strongly reduced.…”

Muscle pathology and whole-body MRI in a polyglucosan myopathy associated with a novel glycogenin-1 mutation

“…Compound heterozygous mutations in the glycogenin-1 gene (GYG1) were first found to cause cardiomyopathy with arrhythmia in a patient with glycogen depletion in muscle and PAS-positive inclusions in cardiomyocytes [4]. Later, seven additional patients with glycogenin-1 deficiency were found with manifestation as lateonset muscle weakness with polyglucosan deposits confined to skeletal muscle [5].…”