Impaired glycogen breakdown and synthesis in phosphoglucomutase 1 deficiency
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Impaired glycogen breakdown and synthesis in phosphoglucomutase 1 deficiency. / Preisler, Nicolai; Cohen, Jonathan; Vissing, Christoffer Rasmus; Madsen, Karen Lindhardt; Heinicke, Katja; Sharp, Lydia Jane; Phillips, Lauren; Romain, Nadine; Park, Sun Young; Newby, Marta; Wyrick, Phil; Mancias, Pedro; Galbo, Henrik; Vissing, John; Haller, Ronald Gerald.
I: Molecular Genetics and Metabolism, Bind 122, Nr. 3, 2017, s. 117-121.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Impaired glycogen breakdown and synthesis in phosphoglucomutase 1 deficiency
AU - Preisler, Nicolai
AU - Cohen, Jonathan
AU - Vissing, Christoffer Rasmus
AU - Madsen, Karen Lindhardt
AU - Heinicke, Katja
AU - Sharp, Lydia Jane
AU - Phillips, Lauren
AU - Romain, Nadine
AU - Park, Sun Young
AU - Newby, Marta
AU - Wyrick, Phil
AU - Mancias, Pedro
AU - Galbo, Henrik
AU - Vissing, John
AU - Haller, Ronald Gerald
N1 - Copyright © 2017 Elsevier Inc. All rights reserved.
PY - 2017
Y1 - 2017
N2 - OBJECTIVE: We investigated metabolism and physiological responses to exercise in an 18-year-old woman with multiple congenital abnormalities and exertional muscle fatigue, tightness, and rhabdomyolysis.METHODS: We studied biochemistry in muscle and fibroblasts, performed mutation analysis, assessed physiological responses to forearm and cycle-ergometer exercise combined with stable-isotope techniques and indirect calorimetry, and evaluated the effect of IV glucose infusion and oral sucrose ingestion on the exercise response.RESULTS: Phosphoglucomutase type 1 (PGM1) activity in muscle and fibroblasts was severely deficient and PGM1 in muscle was undetectable by Western blot. The patient was compound heterozygous for missense (R422W) and nonsense (Q530X) mutations in PGM1. Forearm exercise elicited no increase in lactate, but an exaggerated increase in ammonia, and provoked a forearm contracture. Comparable to patients with McArdle disease, the patient developed a 'second wind' with a spontaneous fall in exercise heart rate and perceived exertion. Like in McArdle disease, this was attributable to an increase in muscle oxidative capacity. Carbohydrate oxidation was blocked during exercise, and the patient had exaggerated oxidation of fat to fuel exercise. Exercise heart rate and perceived exertion were lower after IV glucose and oral sucrose. Muscle glycogen level was low normal.CONCLUSIONS: The second wind phenomenon has been considered to be pathognomonic for McArdle disease, but we demonstrate that it can also be present in PGM1 deficiency. We show that severe loss of PGM1 activity causes blocked muscle glycogenolysis that mimics McArdle disease, but may also limit glycogen synthesis, which broadens the phenotypic spectrum of this disorder.
AB - OBJECTIVE: We investigated metabolism and physiological responses to exercise in an 18-year-old woman with multiple congenital abnormalities and exertional muscle fatigue, tightness, and rhabdomyolysis.METHODS: We studied biochemistry in muscle and fibroblasts, performed mutation analysis, assessed physiological responses to forearm and cycle-ergometer exercise combined with stable-isotope techniques and indirect calorimetry, and evaluated the effect of IV glucose infusion and oral sucrose ingestion on the exercise response.RESULTS: Phosphoglucomutase type 1 (PGM1) activity in muscle and fibroblasts was severely deficient and PGM1 in muscle was undetectable by Western blot. The patient was compound heterozygous for missense (R422W) and nonsense (Q530X) mutations in PGM1. Forearm exercise elicited no increase in lactate, but an exaggerated increase in ammonia, and provoked a forearm contracture. Comparable to patients with McArdle disease, the patient developed a 'second wind' with a spontaneous fall in exercise heart rate and perceived exertion. Like in McArdle disease, this was attributable to an increase in muscle oxidative capacity. Carbohydrate oxidation was blocked during exercise, and the patient had exaggerated oxidation of fat to fuel exercise. Exercise heart rate and perceived exertion were lower after IV glucose and oral sucrose. Muscle glycogen level was low normal.CONCLUSIONS: The second wind phenomenon has been considered to be pathognomonic for McArdle disease, but we demonstrate that it can also be present in PGM1 deficiency. We show that severe loss of PGM1 activity causes blocked muscle glycogenolysis that mimics McArdle disease, but may also limit glycogen synthesis, which broadens the phenotypic spectrum of this disorder.
U2 - 10.1016/j.ymgme.2017.08.007
DO - 10.1016/j.ymgme.2017.08.007
M3 - Journal article
C2 - 28882528
VL - 122
SP - 117
EP - 121
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
SN - 1096-7192
IS - 3
ER -
ID: 195046791