Impaired glycogen breakdown and synthesis in phosphoglucomutase 1 deficiency

Nicolai Preisler; Jonathan Cohen; Christoffer Rasmus Vissing; Karen Lindhardt Madsen; Katja Heinicke; Lydia Jane Sharp; Lauren Phillips; Nadine Romain; Sun Young Park; Marta Newby; Phil Wyrick; Pedro Mancias; Henrik Galbo; John Vissing; Ronald Gerald Haller

doi:10.1016/j.ymgme.2017.08.007

Impaired glycogen breakdown and synthesis in phosphoglucomutase 1 deficiency

Nicolai Preisler, Jonathan Cohen, Christoffer Rasmus Vissing, Karen Lindhardt Madsen, Katja Heinicke, Lydia Jane Sharp, Lauren Phillips, Nadine Romain, Sun Young Park, Marta Newby, Phil Wyrick, Pedro Mancias, Henrik Galbo, John Vissing, Ronald Gerald Haller

Department of Clinical Medicine

8 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Molecular Genetics and Metabolism
Volume	122
Issue number	3
Pages (from-to)	117-121
ISSN	1096-7192
DOIs	https://doi.org/10.1016/j.ymgme.2017.08.007
Publication status	Published - Nov 2017

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10.1016/j.ymgme.2017.08.007

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Preisler, N., Cohen, J., Vissing, C. R., Madsen, K. L., Heinicke, K., Sharp, L. J., Phillips, L., Romain, N., Park, S. Y., Newby, M., Wyrick, P., Mancias, P., Galbo, H., Vissing, J., & Haller, R. G. (2017). Impaired glycogen breakdown and synthesis in phosphoglucomutase 1 deficiency. Molecular Genetics and Metabolism, 122(3), 117-121. https://doi.org/10.1016/j.ymgme.2017.08.007

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title = "Impaired glycogen breakdown and synthesis in phosphoglucomutase 1 deficiency",

abstract = "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.",

author = "Nicolai Preisler and Jonathan Cohen and Vissing, {Christoffer Rasmus} and Madsen, {Karen Lindhardt} and Katja Heinicke and Sharp, {Lydia Jane} and Lauren Phillips and Nadine Romain and Park, {Sun Young} and Marta Newby and Phil Wyrick and Pedro Mancias and Henrik Galbo and John Vissing and Haller, {Ronald Gerald}",

year = "2017",

month = nov,

doi = "10.1016/j.ymgme.2017.08.007",

language = "English",

volume = "122",

pages = "117--121",

journal = "Molecular Genetics and Metabolism",

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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

PY - 2017/11

Y1 - 2017/11

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

SN - 1096-7192

VL - 122

SP - 117

EP - 121

JO - Molecular Genetics and Metabolism

JF - Molecular Genetics and Metabolism

IS - 3

ER -

Impaired glycogen breakdown and synthesis in phosphoglucomutase 1 deficiency

Abstract

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