Systemic metabolic abnormalities in adult-onset acid maltase deficiency beyond muscle glycogen accumulation

Importance: The physiological relevance of acid maltase (acid α-glucosidase, an enzyme that degrades lysosomal glycogen) is well recognized in liver and muscle. In late (adult)-onset acid maltase deficiency (glycogen storage disease type II [GSD II]), glycogen accumulates inside muscular lysosomes in the context of reduced enzymatic activity present not only in muscle, but also throughout the organism. Yet, disease manifestations are commonly attributed to lysosomal disruption and autophagic vesicle buildup inside the myofiber due to a lack of obvious hepatic or broader metabolic dysfunction. However, current therapies primarily focused on reducing glycogen deposition by dietary or enzyme replacement have not been consistently beneficial, providing the motivation for a better understanding of disease mechanisms. Objective : To provide a systematic overview of metabolism and methylation capacity using widely available analytical methods by evaluating secondary compromise of (1) the citric acid cycle, (2) methylation capacity, and (3) nutrient sensor interaction in as many as 33 patients with GSD II (ie, not all patients were available for all assessments) treated with only a lowcarbohydrate/ high-protein, calorie-balanced diet. Design, Setting, and Patients: Case series including clinical and analytical characterization in an academic setting involving 33 enzymatically proved adults with GSD II treated only with a low-carbohydrate/highprotein, calorie-balanced diet. Main Outcome and Measure: Biochemical analysis of blood and urine samples. ults: Patients exhibited evidence for disturbed energy metabolism contributing to a chronic catabolic state and those who were studied further also displayed diminished plasma methylation capacity and elevated levels of insulin-like growth factor type 1 and its carrier protein in-sulin-like growth factor binding protein 3 (IGFBP-3). Conclusions and Relevance: The simplest unifying interpretation of these abnormalities is nutrient sensor disturbance with secondary energy failure leading to a chronic catabolic state. Data also provide the framework for the investigation of potentially beneficial interventions, including methylation supplementation, as adjuncts specifically targeted to ameliorate the systemic metabolic abnormalities of this disorder.