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Thiamine-Responsive and Non-responsive Patients with PDHC-E1 Deficiency: A Retrospective Assessment

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JIMD Reports, Volume 15

Part of the book series: JIMD Reports ((JIMD,volume 15))

Abstract

Pyruvate dehydrogenase complex (PDHC) deficiency is a disorder of energy metabolism that leads to a range of clinical manifestations. We sought to characterise clinical manifestations and biochemical, neuroimaging and molecular findings in thiamine-responsive and nonresponsive PDHC-deficient patients and to identify potential pitfalls in the diagnosis of PDHC deficiency. We retrospectively reviewed all medical records of all PDHC-deficient patients (n = 19; all had PDHA1 gene mutations) and one patient with severe PDHC deficiency secondary to 3-hydroxyisobutyryl-CoA hydrolase deficiency managed at our centre between 1982 and 2012. Responsiveness to thiamine was based on clinical parameters. Seventeen patients received thiamine treatment: eight did not respond, four showed sustained response and the others responded temporarily/questionably. Sustained response was noted at thiamine doses >400 mg/day. Age at presentation was 0–6 and 12–27 months in the nonresponsive (n = 8) and responsive (n = 4) patients, respectively. Corpus callosum abnormalities were noted in 4/8 nonresponsive patients. Basal ganglia involvement (consistent with Leigh disease) was found in four patients (including 2/4 thiamine-responsive patients). Diagnosis through mutation analysis was more sensitive and specific than through enzymatic analysis. We conclude that patients presenting at age >12 months with relapsing ataxia and possibly Leigh syndrome are more likely to be thiamine responsive than those presenting with neonatal lactic acidosis and corpus callosum abnormalities. However, this distinction is equivocal and treatment with thiamine (>400 mg/day) should be commenced on all patients suspected of having PDHC deficiency. Mutation analysis is the preferable first-line diagnostic test to avoid missing thiamine-responsive patients and misdiagnosing patients with secondary PDHC deficiency.

Short Summary: Thiamine responsiveness is more likely in patients presenting at age >12 months with relapsing ataxia and possibly Leigh syndrome than in those presenting with neonatal lactic acidosis and corpus callosum abnormalities. Thiamine doses >400 mg/day are required for sustained response. Mutation analysis is more sensitive and specific than enzymatic analysis as a first-line diagnostic test.

Competing interests: None declared

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Abbreviations

HIBCH:

3-Hydroxyisobutyryl-CoA hydrolase

MRI:

Magnetic resonance imaging

PDHC:

Pyruvate dehydrogenase complex

TPP:

Thiamine pyrophosphate

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Acknowledgements

This work was presented at the SSIEM annual symposium, Birmingham, 2012. J. Inherit. Metab. Dis. 35 (Supp. 1): 122, 2012. We thank Denise Kirby, Wendy Hutchison and Henrik Dahl (Melbourne) and Cheryl Ridout (Oxford) for their contributions to enzyme and molecular diagnosis of the patient cohort. This work was supported by the Victorian Government’s Operational Infrastructure Support Program.

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Authors and Affiliations

  1. Metabolic Research, Murdoch Children’s Research Institute, Royal Children’s Hospital, Flemington Road, Parkville, Melbourne, VIC, 3052, Australia

    Sanne van Dongen, David R. Thorburn & Avihu Boneh

  2. Nijmegen Medical Centre, Institute for Genetic and Metabolic Disease, Radboud University, Nijmegen, The Netherlands

    Sanne van Dongen

  3. Genetics Unit, Department of Biochemistry, University of Oxford, Oxford, UK

    Ruth M. Brown & Garry K. Brown

  4. Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia

    David R. Thorburn & Avihu Boneh

Authors
  1. Sanne van Dongen
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  2. Ruth M. Brown
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  3. Garry K. Brown
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  4. David R. Thorburn
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  5. Avihu Boneh
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Corresponding author

Correspondence to Avihu Boneh .

Editor information

Editors and Affiliations

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

    Johannes Zschocke

  2. WSU Division of Health Sciences,Clinical Pharamacology Unit, Spokane, Washington, USA

    K. Michael Gibson

  3. Department of Biochemistry Genetics Unit, University of Oxford, Oxford, United Kingdom

    Garry Brown

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

    Eva Morava

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

    Verena Peters

Additional information

Communicated by: Shamima Rahman, PhD, BMBCh

Compliance with Ethics Guidelines

Compliance with Ethics Guidelines

Conflict of Interest

All the authors of this chapter declare that there are no conflicts of interest.

Details of the Contributions of Individual Authors

Sanne Van Dongen: Reviewed the literature, reviewed all patients’ records, collected data into Excel spreadsheets, wrote first manuscript and corrected and rewrote subsequent versions. Reviewed the final version and approved it.

Ruth Brown: Performed mutation analysis, reviewed mutations results and participated in writing the methods, results and discussion sections. Critically reviewed the manuscript and approved its final version.

Garry Brown: Reviewed mutations results and participated in writing the methods, results and discussion sections. Critically reviewed the manuscript and approved its final version.

David Thorburn: Reviewed enzymology and mutation results and participated in writing the methods, results and discussion sections. Critically reviewed the manuscript and approved its final version.

Avihu Boneh: Initiated the study, supervised and reviewed all clinical and laboratory data collection and tabulation, participated in writing all versions of the manuscript and wrote the final version of the manuscript.

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van Dongen, S., Brown, R.M., Brown, G.K., Thorburn, D.R., Boneh, A. (2014). Thiamine-Responsive and Non-responsive Patients with PDHC-E1 Deficiency: A Retrospective Assessment. In: Zschocke, J., Gibson, K., Brown, G., Morava, E., Peters, V. (eds) JIMD Reports, Volume 15. JIMD Reports, vol 15. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2014_293

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  • DOI: https://doi.org/10.1007/8904_2014_293

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  • Print ISBN: 978-3-662-43750-6

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