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
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
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
References
Arimura T, Inagaki N et al (2009) Impaired binding of ZASP/Cypher with phosphoglucomutase 1 is associated with dilated cardiomyopathy. Cardiovasc Res 83(1):80–88
Biffi S, Tamaro G et al (2007) Carbohydrate-deficient transferrin (CDT) as a biochemical tool for the screening of congenital disorders of glycosylation (CDGs). Clin Biochem 40(18):1431–1434
Dörre K, Olczak M et al (2015) A new case of UDP-galactose transporter deficiency (SLC35A2-CDG): molecular basis, clinical phenotype, and therapeutic approach. J Inherit Metab Dis. Epub ahead of print
Grundahl JE, Guan Z et al (2012) Life with too much polyprenol: polyprenol reductase deficiency. Mol Genet Metab 105(4):642–651
Haller RG, Vissing J (2002) Spontaneous “second wind” and glucose-induced second “second wind” in McArdle disease: oxidative mechanisms. Arch Neurol 59(9):1395–1402
Helander A, Eriksson G et al (2001) Interference of transferrin isoform types with carbohydrate-deficient transferrin quantification in the identification of alcohol abuse. Clin Chem 47(7):1225–1233
Marquardt T, Denecke J (2003) Congenital disorders of glycosylation: review of their molecular bases, clinical presentations and specific therapies. Eur J Pediatr 162(6):359–379
Mauras N, Attie KM et al (2000) High dose recombinant human growth hormone (GH) treatment of GH-deficient patients in puberty increases near-final height: a randomized, multicenter trial. Genentech, Inc., Cooperative Study Group. J Clin Endocrinol Metab 85(10):3653–3660
Miller BS, Duffy MM et al (2013) Therapy for Growth Failure and IGF-1 Deficiency in Congenital Disorder of Glycosylation Ia (PMM2 Deficiency). J Investigative Med 2013(1):1–4
Niehues R, Hasilik M et al (1998) Carbohydrate-deficient glycoprotein syndrome type Ib. Phosphomannose isomerase deficiency and mannose therapy. J Clin Invest 101(7):1414–1420
Punn R, Obayashi DY et al (2012) Supine exercise echocardiographic measures of systolic and diastolic function in children. J Am Soc Echocardiogr 25(7):773–781
Schreml J, Durmaz B et al (2014) The missing “link”: an autosomal recessive short stature syndrome caused by a hypofunctional XYLT1 mutation. Hum Genet 133(1):29–39
Tanaka C, Murata M et al (2004) Reference charts of body proportion for Japanese girls and boys. Ann Hum Biol 31(6):681–689
Tegtmeyer LC, Rust S et al (2014) Multiple phenotypes in phosphoglucomutase 1 deficiency. N Engl J Med 370(6):533–542
Tsintzas K, Simpson EJ et al (2003) Effect of exercise mode on blood glucose disposal during physiological hyperinsulinaemia in humans. Eur J Appl Physiol 89(2):217–220
Vatta M, Mohapatra B et al (2003) Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction. J Am Coll Cardiol 42(11):2014–2027
Author information
Authors and Affiliations
Corresponding authors
Editor information
Editors and Affiliations
Additional information
Communicated by: Jaak Jaeken
Compliance with Ethics Guidelines
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.
Electronic Supplementary Materials
Below is the link to the electronic supplementary material.
Rights and permissions
Copyright information
© 2015 SSIEM and Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
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
Download citation
DOI: https://doi.org/10.1007/8904_2015_471
Received:
Revised:
Accepted:
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-49832-3
Online ISBN: 978-3-662-49833-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)