title: Systemic metabolic abnormalities in adult-onset acid maltase deficiency: beyond muscle glycogen accumulation.
abstract: OBJECTIVE
  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 low-carbohydrate/high-protein, calorie-balanced diet.
  
  
  METHODS
  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/high-protein, calorie-balanced diet.
  
  
  METHODS
  Biochemical analysis of blood and urine samples.
  
  
  RESULTS
  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 insulin-like growth factor binding protein 3 (IGFBP-3).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Rare Brain Disorders Clinic and Laboratory, Departments of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Pascual
authors.forename: Charles R
authors.initials: CR
authors.lastname: Roe
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood / Q000652:urine; D050528:Diet, Carbohydrate-Restricted / Q000379:methods; D004044:Dietary Proteins / Q000008:administration & dosage*; D004734:Energy Metabolism / Q000502:physiology; D005260:Female; D006003:Glycogen / Q000378:metabolism*; D006009:Glycogen Storage Disease Type II / Q000175:diagnosis / Q000178:diet therapy* / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D004044:Dietary Proteins; D006003:Glycogen