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JIMD Reports, Volume 40 pp 77–83Cite as

Fumarase Deficiency: A Safe and Potentially Disease Modifying Effect of High Fat/Low Carbohydrate Diet

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Part of the book series: JIMD Reports ((JIMD,volume 40))

Abstract

Fumarate hydratase deficiency (FHD) caused by biallelic alterations of the FH (fumarate hydratase) gene is a rare disorder of the tricarboxylic acid cycle, classically characterized by encephalopathy, profound psychomotor retardation, seizures, a spectrum of brain abnormalities and early death in childhood. Less common milder phenotypes with moderate cognitive impairment and long-term survival have been reported. In addition, heterozygous mutations of the FH gene are responsible for hereditary leiomyomatosis and renal cell cancer (HLRCC). There is currently no recommended disease modifying treatment for FHD and only isolated reports of unsuccessful dietary modifications. Herein, we describe the safe and possibly disease modifying effect of a high fat, low carbohydrate diet in a 14-year-old female with severe FHD.

J. Christodoulou and S. Balasubramaniam contributed equally to this work.

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References

  • Allegri G, Fernandes MJ, Scalco FB (2010) Fumaric aciduria: an overview and the first Brazilian case report. J Inherit Metab Dis 33(4):411–419

    Article  PubMed  Google Scholar 

  • Baştuğ O, Kardaş F, Öztür MA et al (2014) A rare cause of opistotonus; fumaric aciduria: the first case presentation in Turkey. Turk Pediatri Ars 49(1):74–76

    Article  PubMed  PubMed Central  Google Scholar 

  • Bayley J-P, Launonen V, Tomlinson I (2008) The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumour syndrome and congenital fumarase deficiency. BMC Med Genet 9(20):1–98

    Google Scholar 

  • Deschauer M, Gizatullina Z, Schulze A et al (2006) Molecular and biochemical investigations in fumarase deficiency. Mol Genet Metab 88:146–152

    Article  CAS  PubMed  Google Scholar 

  • Ewbank C, Kerrigan JF, Aleck K (2013) Fumarate hydratase deficiency. In: Pagon RA, Adam MP, Ardinger HH et al (eds) Gene reviews. University of Washington, Seattle

    Google Scholar 

  • Ezgu F, Pavel K, Wilcox W (2013) Mild clinical presentation and prolonged survival of a patient with fumarase deficiency due to the combination of a known and a novel mutation in FH gene. Gene 524:403–406

    Article  CAS  PubMed  Google Scholar 

  • Gardie B, Remenieras A, Kattygnarath D (2011) Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma. J Med Genet 48(4):226–234. http://www.hlrccinfo.org/hlrcc-handbook.php

    Article  CAS  Google Scholar 

  • Kerrigan JF, Aleck KA, Tarby TJ et al (2000) Fumaric aciduria: clinical and imaging features. Ann Neurol 47(5):583–588

    Article  CAS  PubMed  Google Scholar 

  • Kimonis VE, Steller J, Sahai I et al (2012) Mild fumarase deficiency and trial of a low protein diet. Mol Genet Metab 107(1–2):241–242

    Article  CAS  PubMed  Google Scholar 

  • Lehtonen HJ (2011) Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics. Familial Cancer 10(2):397–411

    Article  PubMed  Google Scholar 

  • Loeffen J, Smeets R, Voit T, Hoffmann G, Smeitink J (2005) Fumarase deficiency presenting with periventricular cysts. J Inherit Metab Dis 28(5):799–800

    Article  CAS  PubMed  Google Scholar 

  • Maradin M, Fumić K, Hansikova H et al (2006) Fumaric aciduria: mild phenotype in an 8-year-old girl with novel mutations. J Inherit Metab Dis 29(5):683

    Article  CAS  PubMed  Google Scholar 

  • Menko F, Maher ER, Schmidt LS et al (2014) Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment. Familial Cancer 13(4):637–644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morava E, Carrozzo R (2014) Disorders of the Krebs cycle. In: Blau N et al (eds) Physician’s guide to the diagnosis, treatment, and follow-up of inherited metabolic diseases. Springer-Verlag, Berlin, pp 313–322

    Chapter  Google Scholar 

  • Mroch AR, Laudenschloager M, Flanagan JD (2012) Detection of a novel FH whole gene deletion in the propositus leading to subsequent prenatal diagnosis in a sibship with fumarase deficiency. Am J Med Genet A 158A:155–158

    Article  CAS  PubMed  Google Scholar 

  • Ottolenghi C, Hubert L, Allanore Y et al (2011) Clinical and biochemical heterogeneity associated with fumarase deficiency. Hum Mutat 32(9):1046–1052

    Article  CAS  PubMed  Google Scholar 

  • Phillips TM, Gibson JB, Ellison DA (2006) Fumarate hydratase deficiency in monozygotic twins. Pediatr Neurol 35:150–153

    Article  PubMed  Google Scholar 

  • Prasad C, Napier P, Rupar C, Prasad C (2017) Fumarase deficiency: a rare disorder on the crossroads of clinical and metabolic genetics, neurology and cancer. Clin Dysmorphol 26:117–120

    Article  PubMed  Google Scholar 

  • Smith AC, Robinson AJ (2011) A metabolic model of the mitochondrion and its use in modelling diseases of the tricarboxylic acid cycle. BMC Syst Biol 5:102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sudarshan S, Linehan WM, Neckers L (2007) HIF and fumarate hydratase in renal cancer. Br J Cancer 96:403–407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xiao M, Yang H, Xu W et al (2012) Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev 26(12):1326–1338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang M, Soga T, Pollard PJ, Adam J (2012) The emerging role of fumarate as an oncometabolite. Front Oncol 2:85

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

No funding was received in the writing of this chapter.

Author information

Authors and Affiliations

  1. Western Sydney Genetics Program, The Children’s Hospital at Westmead, Sydney, NSW, Australia

    B. Ryder, S. Thompson, J. Christodoulou & S. Balasubramaniam

  2. NSW Biochemical Genetics Service, The Children’s Hospital at Westmead, Sydney, NSW, Australia

    F. Moore

  3. Metabolic Dietetic Service, The Children’s Hospital at Westmead, Sydney, NSW, Australia

    A. Mitchell & S. Thompson

  4. Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, Sydney, NSW, Australia

    J. Christodoulou & S. Balasubramaniam

  5. Discipline of Child & Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia

    J. Christodoulou & S. Balasubramaniam

  6. Neurodevelopmental Genomics Research Group, Murdoch Children’s Research Institute, Melbourne, VIC, Australia

    J. Christodoulou

  7. Department of Paediatrics, Melbourne Medical School, University of Melbourne, Melbourne, VIC, Australia

    J. Christodoulou

Authors
  1. B. Ryder
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  2. F. Moore
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  3. A. Mitchell
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  4. S. Thompson
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  5. J. Christodoulou
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  6. S. Balasubramaniam
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Corresponding author

Correspondence to S. Balasubramaniam .

Editor information

Editors and Affiliations

  1. Tulane University Medical School, New Orleans, Louisiana, USA

    Eva Morava

  2. Division of Metabolism & Children’s Research Centre, University Children’s Hospital Zürich, Zürich, Switzerland

    Matthias Baumgartner

  3. Division of Child and Adolescent Neurology, Mayo Clinic, Rochester, Minnesota, USA

    Marc Patterson

  4. Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, United Kingdom

    Shamima Rahman

  5. Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

    Johannes Zschocke

  6. Center for Child and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany

    Verena Peters

Additional information

Communicated by: John H Walter, MD FRCPCH

Appendices

Key Synopsis

Long-term use of a high fat, low carbohydrate diet in severe fumarate hydratase deficiency is safe and may result in a milder outcome.

Details of the Contributions of Individual Authors

Bryony Ryder, John Christodoulou and Shanti Balasubramaniam were involved in the clinical management of the patient. Sue Thompson and Ashleigh Mitchell provided dietary advice in the management. Francesca Moore performed and interpreted metabolic laboratory investigations. John Christodoulou advised on the diagnostic work-up and initiating dietary management. Bryony Ryder and Shanti Balasubramaniam drafted the manuscript. All authors have read/critically revised the manuscript.

Corresponding Author

Bryony Ryder.

Compliance with Ethics Guidelines

Conflict of Interest

Bryony Ryder, Francesca Moore, Ashleigh Mitchell, Sue Thompson and Shanti Balasubramaniam declare that they have no conflict of interest. John Christodoulou is a communicating editor of the Journal of Inherited Metabolic Disease.

Ethics Approval

Ethics approval was not required for publication of this case report.

Informed Consent

Parental consent was obtained for the publication of this chapter.

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© 2017 Society for the Study of Inborn Errors of Metabolism (SSIEM)

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Ryder, B., Moore, F., Mitchell, A., Thompson, S., Christodoulou, J., Balasubramaniam, S. (2017). Fumarase Deficiency: A Safe and Potentially Disease Modifying Effect of High Fat/Low Carbohydrate Diet. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 40. JIMD Reports, vol 40. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2017_65

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  • DOI: https://doi.org/10.1007/8904_2017_65

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  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-662-57879-7

  • Online ISBN: 978-3-662-57880-3

  • eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)

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