Abstract
Intermittent hypoglycemia has been described in association with Alpers’ syndrome, a disorder caused by mutations in the mitochondrial DNA polymerase gamma gene. In some patients hypoglycemia may define the initial disease presentation well before the onset of the classical Alpers’ triad of psychomotor retardation, intractable seizures, and liver failure. Correlating with the genotype, POLG pathogenicity is a result of increased mitochondrial DNA mutability, and mitochondrial DNA depletion resulting in energy deficient states. Hypoglycemia therefore could be secondary to any metabolic pathway affected by ATP deficiency. Although it has been speculated that hypoglycemia is due to secondary fatty acid oxidation defects or abnormal gluconeogenesis, the exact underlying etiology is still unclear. Here we present detailed studies on carbohydrate metabolism in an Alpers’ patient who presented initially exclusively with intermittent episodes of hypoglycemia and ketosis. Our results do not support a defect in gluconeogenesis or fatty acid oxidation as the cause of hypoglycemia. In contrast, studies performed on liver biopsy suggested abnormal glycogenolysis. This is shown via decreased activities of glycogen brancher and debrancher enzymes with normal glycogen structure and increased glycogen on histology of the liver specimen. To our knowledge, this is the first report documenting abnormalities in glycogen metabolism in a patient with Alpers’ syndrome.
Competing interests: None declared
The first two authors contributed equally
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Barrett T, Wilhite SE, Ledoux P et al (2012) NCBI GEO: archive for functional genomics data sets–update. Nucleic Acids Res 41:D991
Blau N, Duran M, Gibson KM (2008) Laboratory guide to the methods in biochemical genetics. Springer, Berlin/London
Bonilla E, Sciacco M, Tanji K, Sparaco M, Petruzzella V, Moraes CT (1992) New morphological approaches to the study of mitochondrial encephalomyopathies. Brain Pathol 2:113–119
Bortot B, Barbi E, Biffi S et al (2009) Two novel POLG mutations causing hepatic mitochondrial DNA depletion with recurrent hypoketotic hypoglycaemia and fatal liver dysfunction. Dig Liver Dis 41:494–499
Brown BI, Brown DH (1989) Branching enzyme activity of cultured amniocytes and chorionic villi: prenatal testing for type IV glycogen storage disease. Am J Hum Genet 44:378–381
Dainese L, Monin M, Demeret S et al (2013) Abnormal glycogen in astrocytes is sufficient to cause adult polyglucosan body disease. Gene 515:376–379
Dallabona C, Marsano RM, Arzuffi P et al (2010) Sym1, the yeast ortholog of the MPV17 human disease protein, is a stress-induced bioenergetic and morphogenetic mitochondrial modulator. Hum Mol Genet 19:1098–1107
de Lonlay P, Giurgea I, Touati G, Saudubray J (2004) Neonatal hypoglycaemia: aetiologies. Semin Neonatol 9:49–58
de Vries MC, Rodenburg RJ, Morava E et al (2007) Multiple oxidative phosphorylation deficiencies in severe childhood multi-system disorders due to polymerase gamma (POLG1) mutations. Eur J Pediatr 166:229–234
Del Bo R, Bordoni A, Sciacco M et al (2003) Remarkable infidelity of polymerase gammaA associated with mutations in POLG1 exonuclease domain. Neurology 61:903–908
Dimmock DP, Zhang Q, Dionisi-Vici C et al (2008) Clinical and molecular features of mitochondrial DNA depletion due to mutations in deoxyguanosine kinase. Hum Mutat 29:330–331
Edgar R (2002) Gene expression omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res 30:207–210
Elanchezhian R, Palsamy P, Madson CJ et al (2012) Low glucose under hypoxic conditions induces unfolded protein response and produces reactive oxygen species in lens epithelial cells. Cell Death Dis 3:e301
Ferrari G, Lamantea E, Donati A et al (2005) Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-gammaA. Brain 128:723–731
Haymond MW (1989) Hypoglycemia in infants and children. Endocrinol Metab Clin North Am 18:211–252
Hiona A, Sanz A, Kujoth GC et al (2010) Mitochondrial DNA mutations induce mitochondrial dysfunction, apoptosis and sarcopenia in skeletal muscle of mitochondrial DNA mutator mice. PLoS One 5:e11468
Horvath R, Hudson G, Ferrari G et al (2006) Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. Brain 129:1674–1684
Karadimas CL, Vu TH, Holve SA et al (2006) Navajo neurohepatopathy is caused by a mutation in the MPV17 gene. Am J Hum Genet 79:544–548
Lavoie S, Allaman I, Petit J, Do KQ, Magistretti PJ (2011) Altered glycogen metabolism in cultured astrocytes from mice with chronic glutathione deficit; relevance for neuroenergetics in schizophrenia. PLoS One 6:e22875
Mochel F, Slama A, Touati G et al (2005) Respiratory chain defects may present only with hypoglycemia. J Clin Endocrinol Metab 90:3780–3785
Nakayama A, Yamamoto K, Tabata S (2001) Identification of the catalytic residues of bifunctional glycogen debranching enzyme. J Biol Chem 276:28824–28828
Naviaux RK, Nguyen KV (2004) POLG mutations associated with Alpers’ syndrome and mitochondrial DNA depletion. Ann Neurol 55:706–712
Naviaux RK, Nyhan WL, Barshop BA, Poulton J, Markusic D, Karpinski NC, Haas RH (1999) Mitochondrial DNA polymerase gamma deficiency and mtDNA depletion in a child with Alpers’ syndrome. Ann Neurol 45:54–58
Nguyen KV, Ostergaard E, Ravn SH et al (2005) POLG mutations in Alpers’ syndrome. Neurology 65:1493–1495
Parini R, Furlan F, Notarangelo L et al (2009) Glucose metabolism and diet-based prevention of liver dysfunction in MPV17 mutant patients. J Hepatol 50:215–221
Roels F, Verloo P, Eyskens F et al (2009) Mitochondrial mosaics in the liver of 3 infants with mtDNA defects. BMC Clin Pathol 9:4
Scalais E, Francois B, Schlesser P et al (2012) Polymerase gamma deficiency (POLG): clinical course in a child with a two stage evolution from infantile myocerebrohepatopathy spectrum to an Alpers’ syndrome and neuropathological findings of Leigh’s encephalopathy. Eur J Paediatr Neurol 16:542–548
Scharfe C, Lu HH, Neuenburg JK et al (2009) Mapping gene associations in human mitochondria using clinical disease phenotypes. PLoS Comput Biol 5:e1000374
Stumpf JD, Saneto RP, Copeland WC (2013) Clinical and molecular features of POLG-related mitochondrial disease. Cold Spring Harb Perspect Biol 5
Tang S, Wang J, Lee N et al (2011) Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum. J Med Genet 48:669–681
Uusimaa J, Evans J, Smith C et al (2013) Clinical, biochemical, cellular and molecular characterization of mitochondrial DNA depletion syndrome due to novel mutations in the MPV17 gene. Eur J Hum Genet. doi: 10.1038/ejhg.2013.112
van Goethem G, Martin J, van Broeckhoven C (2002) Progressive external ophthalmoplegia and multiple mitochondrial DNA deletions. Acta Neurol Belg 102:39–42
Voets AM, Lindsey PJ, Vanherle SJ et al (2012) Patient-derived fibroblasts indicate oxidative stress status and may justify antioxidant therapy in OXPHOS disorders. Biochim Biophys Acta 1817:1971–1978
Wapnir RA (1985) Congenital metabolic diseases: diagnosis and treatment, vol 2nd edn, Clinical pediatrics. Marcel Dekker, New York
Wong LC, Naviaux RK, Brunetti-Pierri N et al (2008) Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Hum Mutat 29:E150–72
Acknowledgments
MS was partially supported by grants from Haley’s Wish Foundation. We thank Karen Leydiker and Leighann Sremba for editing the manuscript.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Additional information
Communicated by: Wolfgang Sperl
Appendices
Competing Interest
The authors have no competing interests.
Synopsis
Hypoglycemia associated with mitochondrial disease mimicking glycogen storage disease may be underrecognized or underreported and may manifest prior to the onset of typical mitochondrial disease symptoms like seizures or liver failure.
Compliance with Ethics Guidelines
Conflict of Interest
Mariella Simon declares that she has been partially supported by Hailey’s wish foundation, a charitable foundation interested in supporting causes concerning mitochondrial disease.
Richard Chang declares that he has no conflict of interest.
Deeksha Bali declares that she has no conflict of interest.
Lee-Jun Wong declares that she has no conflict of interest.
Ying Peng declares that she has no conflict of interest.
Jose Abdenur declares that he has 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 (5). The study does not qualify as human subject research since the patient is deceased and there are no subject identifiers.
Animal Rights
This article does not contain any studies with animal subjects performed by the any of the authors.
Contributions of Individual Authors
Mariella Simon wrote the abstract, introduction, and discussion.
Richard Chang wrote the case report and cared for the patient.
Deeksha Bali was in charge of enzyme studies for glycogen storage disease.
Lee-Jun Wong was in charge of POLG testing.
Ying Peng oversaw neurological testing and cared for the patient.
Jose E. Abdenur designed clinical and laboratory testing strategy and planned and edited the manuscript.
All authors have reviewed the final version of the manuscript.
Rights and permissions
Copyright information
© 2013 SSIEM and Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Simon, M., Chang, R.C., Bali, D.S., Wong, LJ., Peng, Y., Abdenur, J.E. (2013). Abnormalities in Glycogen Metabolism in a Patient with Alpers’ Syndrome Presenting with Hypoglycemia. In: Zschocke, J., Gibson, K., Brown, G., Morava, E., Peters, V. (eds) JIMD Reports, Volume 14. JIMD Reports, vol 14. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2013_280
Download citation
DOI: https://doi.org/10.1007/8904_2013_280
Received:
Revised:
Accepted:
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-43747-6
Online ISBN: 978-3-662-43748-3
eBook Packages: MedicineMedicine (R0)