Abstract
Phosphoglucomutase 1 deficiency has recently been reported as a novel disease that belongs to two different classes of metabolic disorders, congenital disorders of glycosylation (CDG) and glycogen storage diseases.
This paper focuses on previously reported siblings with short stature, hypothyroidism, increased transaminases, and, in one of them, dilated cardiomyopathy (DCM). An intronic point mutation in the PGM1-gene (c.1145-222 G>T) leads to a complex alternative splicing pattern and to almost complete absence of PGM1 activity.
Exercise-induced muscle fatigue, chest pain, and rhabdomyolysis persisted into adulthood. Fainting occurred during the first minutes of strong exercise due to glucose depletion and serum heart troponin was increased. A second wind phenomenon with an improvement in exercise capacity after some minutes of training was observed. Regular aerobic training improved fitness and helped to avoid acute damage. DCM improved during therapy.
Glycosylation deficiency was most prominent in childhood. Glycosylation improved with age and further improved with oral galactose supplementation even in adulthood. Optimal improvement of glycosylation-dependent phenotypes should be achieved by early and permanent galactose treatment.
However, in case of mutations in ZASP, DCM can develop as a consequence of impaired binding of PGM1 to the heart-specific isoform of ZASP, independently of overall glycosylation efficiency. Thus, even if mutations in PGM1 impair the function of the ZASP-PGM1 complex, supplementation of galactose cannot be expected to restore that function. Therefore, knowledge of PGM1 deficiency in a patient should prompt surveillance of early signs of DCM and specific treatment if necessary.
Competing interests: None declared
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Abbreviations
- CDT:
-
Carbohydrate-deficient transferrin
- DCM:
-
Dilated cardiomyopathy
- ER:
-
Endoplasmic reticulum
- FS:
-
Fractional shortening
- HPLC:
-
High-performance liquid chromatography
- IEF:
-
Isoelectric focusing
- IGF-1:
-
Insulin-like growth factor 1
- LVIDD:
-
Left ventricular internal dimension in diastole
- PGM1:
-
Phosphoglucomutase 1
- SDS-PAGE:
-
Sodium dodecyl sulfate polyacrylamide gel electrophoresis
- TF:
-
Transferrin
- ZASP:
-
Z-band alternatively spliced PDZ-motif protein
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Communicated by: Jaak Jaeken
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Author Contributions
Esther Schrapers did most of the experiments, retrieved the data from decades, analyzed data, drafted, and revised the manuscript.
Laura C. Tegtmeyer was involved in several experiments, e.g., galactose kinetics.
Gunter Simic-Schleicher discovered the patients and provided many data.
Volker Debus provided the data on DCM.
Janine Reunert supported and supervised experiments.
Sebastian Balbach was involved in glucagon test and galactose kinetics.
Karin Klingel did light and electron microscopy incl. interpretation.
Ingrid Du Chesne was involved in analysis of mutation.
Anja Seelhöfer supported detailed analysis of transcript.
Manfred Fobker analyzed the clinical chemistry data.
Thorsten Marquardt supervised the study, drafted, and revised the manuscript.
Stephan Rust supervised the study, supported detailed analysis of transcript, analyzed data, drafted, and revised the manuscript.
Thorsten Marquardt and Stephan Rust have contributed equally to the manuscript.
All authors contributed to and reviewed the manuscript.
Conflict of Interest
Esther Schrapers, Laura C. Tegtmeyer, Gunter Simic-Schleicher, Volker Debus, Janine Reunert, Sebastian Balbach, Karin Klingel, Ingrid Du Chesne, Anja Seelhöfer, Manfred Fobker, Thorsten Marquardt, and Stephan Rust declare that they have no conflict of interest.
Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for inclusion in the study.
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Schrapers, E. et al. (2015). News on Clinical Details and Treatment in PGM1-CDG. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 26. JIMD Reports, vol 26. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_471
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DOI: https://doi.org/10.1007/8904_2015_471
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