Muscle Pathology in a Case of Glycogen Storage Disease III (P6-8.014)

Abstract

<h3>Objective:</h3> To describe histopathological features on muscle biopsy in glycogen storage disease III (GSDIII). <h3>Background:</h3> GSDIII is a rare disease caused by autosomal recessive mutations in <i>AGL</i> 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. <h3>Design/Methods:</h3> We describe a patient suspected to have GSD based on muscle biopsy and subsequently confirmed on exome sequencing. <h3>Results:</h3> 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 <i>AGL</i> gene, c.3965delT (p.V1322AfsX27) and c.256 C&gt;T (p.Q86X). <h3>Conclusions:</h3> 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. <b>Disclosure:</b> Dr. Alrasheed has nothing to disclose. Dr. Mozaffar has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Alexion Pharmaceuticals. Dr. Mozaffar has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Argenx. Dr. Mozaffar has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sanofi-Genzyme. Dr. Mozaffar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amicus. Dr. Mozaffar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Modis Therapeutics. Dr. Mozaffar has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for UCB/ Ra Pharmaceuticals. Dr. Mozaffar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Maze Therapeutics. Dr. Mozaffar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Spark Therapeutics. Dr. Mozaffar has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sarepta. Dr. Mozaffar has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for National Institutes of Health. Dr. Mozaffar has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Argenx. Dr. Mozaffar has received personal compensation in the range of $500-$4,999 for serving as an officer or member of the Board of Directors for Neuromuscular Disease Foundation. The institution of Dr. Mozaffar has received research support from NIH. The institution of Dr. Mozaffar has received research support from Muscular Dystrophy Association. The institution of Dr. Mozaffar has received research support from Sanofi-Genzyme. The institution of Dr. Mozaffar has received research support from Argenx. The institution of Dr. Mozaffar has received research support from Amicus Therapeutics. The institution of Dr. Mozaffar has received research support from Spark Therapeutics. The institution of Dr. Mozaffar has received research support from Audentes Therapeutics. The institution of Dr. Mozaffar has received research support from Cartesian. Dr. Mozaffar has received personal compensation in the range of $500-$4,999 for serving as a Study Section Member with NIH. Mari Perez-Rosendahl has nothing to disclose.