2023 American Academy of Neurology Abstract Website

Objective:

To describe histopathological features on muscle biopsy in glycogen storage disease III (GSDIII).

Background:

GSDIII is a rare disease caused by autosomal recessive mutations in AGL which encodes the glycogen debranching enzyme. Enzyme deficiency leads to glycogen accumulation primarily in liver, heart and skeletal muscle. Clinical presentation varies, and given the rarity, there is a paucity of literature on the skeletal muscle histopathology.

Design/Methods:

We describe a patient suspected to have GSD based on muscle biopsy and subsequently confirmed on exome sequencing.

Results:

A 53-year-old man with history of congenital hepatomegaly and hypertrophic cardiomyopathy presented with 3 years of proximal muscle weakness and atrophy. Family history was notable for elevated liver enzymes in his mother. Examination showed symmetric proximal weakness with reduced reflexes. Electrodiagnostic testing revealed a myopathic pattern with muscle membrane irritability. CK was elevated at 7207 U/L, but testing was otherwise unremarkable including GAA enzyme activity and myositis and LGMD panels. Muscle biopsy showed a severe vacuolar myopathy with large vacuoles filled with lightly basophilic PAS-positive and diastase sensitive material, indicative of normal glycogen and arguing against polyglucosan bodies. Additional myopathic features included significant myofiber size variation, ring fibers, and necrotic and regenerating myofibers. Atrophic nonspecific esterase-positive myofibers were also present. Acid phosphatase was negative and electron microscopy demonstrated abundant non-membrane bound sarcoplasmic glycogen, consistent with a non-lysosomal glycogen storage myopathy. Subsequent exome sequencing revealed two clinically significant variants in the AGL gene, c.3965delT (p.V1322AfsX27) and c.256 C>T (p.Q86X).

Conclusions:

In GSDIII, muscle biopsy shows prominent vacuolar pathology with abundant non-membrane bound sarcoplasmic glycogen deposits. In contrast to Pompe disease, acid phosphatase is negative, demonstrating the absence of lysosomal activation in GSDIII.