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.
Keywords
- Leigh Syndrome
- Thiamine Pyrophosphate
- Nonresponsive Patient
- Dihydrolipoamide Dehydrogenase
- Basal Ganglion Involvement
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
Competing interests: None declared
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Abbreviations
- HIBCH:
-
3-Hydroxyisobutyryl-CoA hydrolase
- MRI:
-
Magnetic resonance imaging
- PDHC:
-
Pyruvate dehydrogenase complex
- TPP:
-
Thiamine pyrophosphate
References
Bachmann-Gagescu R, Merritt JL 2nd, Hahn SH (2009) A cognitively normal PDH-deficient 18-year-old man carrying the R263G mutation in the PDHA1 gene. J Inherit Metab Dis 32(Suppl 1):123–126
Barnerias C, Saudubray JM, Touati G et al (2010) Pyruvate dehydrogenase complex deficiency: four neurological phenotypes with differing pathogenesis. Dev Med Child Neurol 52(2):e1–e9
Benelli C, Fouque F, Redonnet-Vernhet I et al (2002) A novel Y243S mutation in the pyruvate dehydrogenase El alpha gene subunit: correlation with thiamine pyrophosphate interaction. J Inherit Metab Dis 25(4):325–327
Brown GK, Haan EA, Kirby DM et al (1988) “Cerebral” lactic acidosis: defects in pyruvate metabolism with profound brain damage and minimal systemic acidosis. Eur J Pediatr 147(1):10–14
Brown GK, Brown RM, Scholem RD, Kirby DM, Dahl HH (1989a) The clinical and biochemical spectrum of human pyruvate dehydrogenase complex deficiency. Ann N Y Acad Sci 573:360–368
Brown RM, Dahl HH, Brown GK (1989b) X-chromosome localization of the functional gene for the E1 alpha subunit of the human pyruvate dehydrogenase complex. Genomics 4(2):174–181
Chariot P, Ratiney R, Ammi-Said M, Herigault R, Adnot S, Gherardi R (1994) Optimal handling of blood samples for routine measurement of lactate and pyruvate. Arch Pathol Lab Med 118(7):695–697
Dahl HH, Hansen LL, Brown RM, Danks DM, Rogers JG, Brown GK (1992) X-linked pyruvate dehydrogenase E1 alpha subunit deficiency in heterozygous females: variable manifestation of the same mutation. J Inherit Metab Dis 15(6):835–847
Debray FG, Lambert M, Gagne R et al (2008) Pyruvate dehydrogenase deficiency presenting as intermittent isolated acute ataxia. Neuropediatrics 39(1):20–23
Di Rocco M, Lamba LD, Minniti G, Caruso U, Naito E (2000) Outcome of thiamine treatment in a child with Leigh disease due to thiamine-responsive pyruvate dehydrogenase deficiency. Eur J Paediatr Neurol 4(3):115–117
Fujii T, Naito E, Miyajima T, Ito M (2006) A six year clinical course in a patient with thiamin responsive PDHC deficiency. J Inherit Metab Dis 29(Supp 1):117
Giribaldi G, Doria-Lamba L, Biancheri R et al (2012) Intermittent-relapsing pyruvate dehydrogenase complex deficiency: a case with clinical, biochemical, and neuroradiological reversibility. Dev Med Child Neurol 54(5):472–476
Hemalatha SG, Kerr DS, Wexler ID et al (1995) Pyruvate dehydrogenase complex deficiency due to a point mutation (P188L) within the thiamine pyrophosphate binding loop of the E1 alpha subunit. Hum Mol Genet 4(2):315–318
Kinoshita H, Sakuragawa N, Tada H, Naito E, Kuroda Y, Nonaka I (1997) Recurrent muscle weakness and ataxia in thiamine-responsive pyruvate dehydrogenase complex deficiency. J Child Neurol 12(2):141–144
Lee EH, Ahn MS, Hwang JS, Ryu KH, Kim SJ, Kim SH (2006) A Korean female patient with thiamine-responsive pyruvate dehydrogenase complex deficiency due to a novel point mutation (Y161C)in the PDHA1 gene. J Kor Med Sci 21(5):800–804
Linn TC, Pettit FH, Reed LJ (1969) Alpha-keto acid dehydrogenase complexes. X. Regulation of the activity of the pyruvate dehydrogenase complex from beef kidney mitochondria by phosphorylation and dephosphorylation. Proc Natl Acad Sci U S A 62(1):234–241
Lissens W, De Meirleir L, Seneca S et al (2000) Mutations in the X-linked pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency. Hum Mutat 15(3):209–219
Marsac C, Benelli C, Desguerre I et al (1997) Biochemical and genetic studies of four patients with pyruvate dehydrogenase E1 alpha deficiency. Hum Genet 99(6):785–792
McKay N, Petrova-Benedict R, Thoene J, Bergen B, Wilson W, Robinson B (1986) Lacticacidaemia due to pyruvate dehydrogenase deficiency, with evidence of protein polymorphism in the alpha-subunit of the enzyme. Eur J Pediatr 144(5):445–450
Naito E, Ito M, Takeda E, Yokota I, Yoshijima S, Kuroda Y (1994) Molecular analysis of abnormal pyruvate dehydrogenase in a patient with thiamine-responsive congenital lactic acidemia. Pediatr Res 36(3):340–346
Naito E, Ito M, Yokota I et al (1999) Concomitant administration of sodium dichloroacetate and thiamine in west syndrome caused by thiamine-responsive pyruvate dehydrogenase complex deficiency. J Neurol Sci 171(1):56–59
Naito E, Ito M, Yokota I et al (2002a) Thiamine-responsive pyruvate dehydrogenase deficiency in two patients caused by a point mutation (F205L and L216F) within the thiamine pyrophosphate binding region. Biochim Biophys Acta 1588(1):79–84
Naito E, Ito M, Yokota I, Saijo T, Ogawa Y, Kuroda Y (2002b) Diagnosis and molecular analysis of three male patients with thiamine-responsive pyruvate dehydrogenase complex deficiency. J Neurol Sci 201(1–2):33–37
Narisawa K, Endo H, Miyabayashi S, Tada K (1992) Thiamine responsive pyruvate dehydrogenase deficiency. J Nutr Sci Vitaminol (Tokyo) Spec No:585–588
Pagliarini DJ, Dixon JE (2006) Mitochondrial modulation: reversible phosphorylation takes center stage? Trends Biochem Sci 31(1):26–34
Pastoris O, Savasta S, Foppa P, Catapano M, Dossena M (1996) Pyruvate dehydrogenase deficiency in a child responsive to thiamine treatment. Acta Paediatr 85(5):625–628
Patel KP, O'Brien TW, Subramony SH, Shuster J, Stacpoole PW (2012) The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol Genet Metab 106(3):385–394
Rahman S, Blok RB, Dahl HH et al (1996) Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol 39(3):343–351
Ridout CK, Brown RM, Walter JH, Brown GK (2008) Somatic mosaicism for a PDHA1 mutation in a female with pyruvate dehydrogenase deficiency. Hum Genet 124(2):187–193
Robinson BH, Sherwood WG (1984) Lactic acidaemia. J Inherit Metab Dis 7(Suppl 1):69–73
Robinson BH, MacMillan H, Petrova-Benedict R, Sherwood WG (1987) Variable clinical presentation in patients with defective E1 component of pyruvate dehydrogenase complex. J Pediatr 111(4):525–533
Roche TE, Reed LJ (1972) Function of the nonidentical subunits of mammalian pyruvate dehydrogenase. Biochem Biophys Res Commun 48(4):840–846
Tripatara A, Korotchkina LG, Patel MS (1999) Characterization of point mutations in patients with pyruvate dehydrogenase deficiency: role of methionine-181, proline-188, and arginine-349 in the alpha subunit. Arch Biochem Biophys 367(1):39–50
Weber TA, Antognetti MR, Stacpoole PW (2001) Caveats when considering ketogenic diets for the treatment of pyruvate dehydrogenase complex deficiency. J Pediatr 138(3):390–395
Wexler ID, Hemalatha SG, McConnell J et al (1997) Outcome of pyruvate dehydrogenase deficiency treated with ketogenic diets. Studies in patients with identical mutations. Neurology 49(6):1655–1661
Wicking CA, Scholem RD, Hunt SM, Brown GK (1986) Immunochemical analysis of normal and mutant forms of human pyruvate dehydrogenase. Biochem J 239(1):89–96
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.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
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.
Rights and permissions
Copyright information
© 2014 SSIEM and Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
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
Download citation
DOI: https://doi.org/10.1007/8904_2014_293
Received:
Revised:
Accepted:
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-43750-6
Online ISBN: 978-3-662-43751-3
eBook Packages: MedicineMedicine (R0)