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

Research output: Contribution to journalArticle

3 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 languageEnglish (US)
JournalMolecular Genetics and Metabolism
DOIs
StateAccepted/In press - 2017

Fingerprint

Phosphoglucomutase
Glycogen
Muscle
Glycogen Storage Disease Type V
Exercise
Muscles
Forearm
Fibroblasts
Sucrose
Heart Rate
Glucose
Oxidation
Exercise equipment
Biochemistry
Multiple Abnormalities
Glycogenolysis
Indirect Calorimetry
Muscle Tonus
Muscle Fatigue
Calorimetry

Keywords

  • Exercise
  • Glycogen storage disease
  • Metabolic myopathy
  • Phosphoglucomutase type 1
  • Second wind
  • Skeletal muscle metabolism

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

Cite this

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.

In: Molecular Genetics and Metabolism, 2017.

Research output: Contribution to journalArticle

Preisler, N, Cohen, J, Vissing, CR, Madsen, KL, Heinicke, K, Sharp, LJ, Phillips, L, Romain, N, Park, SY, Newby, M, Wyrick, P, Mancias, P, Galbo, H, Vissing, J & Haller, RG 2017, 'Impaired glycogen breakdown and synthesis in phosphoglucomutase 1 deficiency', Molecular Genetics and Metabolism. https://doi.org/10.1016/j.ymgme.2017.08.007
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. / Impaired glycogen breakdown and synthesis in phosphoglucomutase 1 deficiency. In: Molecular Genetics and Metabolism. 2017.
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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

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AU - Mancias, Pedro

AU - Galbo, Henrik

AU - Vissing, John

AU - Haller, Ronald Gerald

PY - 2017

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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.

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KW - Glycogen storage disease

KW - Metabolic myopathy

KW - Phosphoglucomutase type 1

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KW - Skeletal muscle metabolism

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