Systemic Metabolic Abnormalities in Adult-onset Acid Maltase Deficiency

Abstract

The physiological relevance of acid maltase (acid ␣-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.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 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.

Defects in calcium homeostasis and mitochondria can be reversed in Pompe disease

“…44,45 A disturbed energy metabolism has recently been documented in Pompe patients with the adult form of the disease. 46 The autophagic defect contributes to the pathogenesis of muscle damage and alters trafficking of the replacement enzyme to the lysosome in Pompe disease. 27,45,47 In this study we have addressed mitochondrial abnormalities and mitophagy in Pompe skeletal muscle-the major site of pathology and a challenge for therapy.…”

Skeletal muscle metabolism during prolonged exercise in Pompe disease

“…A heating pad was wrapped around the hand to arterialize the venous blood (14). Background blood and breath samples were collected, expired air being sampled in an airtight collection bag (Hans Rudolph, Inc., KS, USA) for measurement of 13 and continued for 2 h before exercise began. Breath and blood samples were drawn simultaneously 20 min before exercise and then repeatedly every 10 min until the end of exercise.…”

Moonlighting newborn screening markers: the incidental discovery of a second-tier test for Pompe disease

“…A biological rationale for the elevated ratio among Pompe patients can be postulated following the observation of serum creatine and creatinine levels at the higher and lower ends of normal reference ranges, respectively, in adult-onset patients with Pompe disease. 31 Therefore, we hypothesized that the Cre/Crn ratio could be a marker of early muscle involvement already present in the newborn period and potentially an opportunity for introducing a multitier approach for Pompe disease newborn screening. Although testing of additional cases failed to confirm the initial finding (range 4.71-5.47, N = 4; Figure 1a), an attempt was made to further integrate the Cre/Crn ratio with the residual GAA activity (Figure 1b), which resulted in a clear separation from the reference population (Figure 1c).…”