title: The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients.
abstract: BACKGROUND
  Pyruvate dehydrogenase complex (PDC) deficiency is a genetic mitochondrial disorder commonly associated with lactic acidosis, progressive neurological and neuromuscular degeneration and, usually, death during childhood. There has been no recent comprehensive analysis of the natural history and clinical course of this disease.
  
  
  OBJECTIVE
  We reviewed 371 cases of PDC deficiency, published between 1970 and 2010, that involved defects in subunits E1α and E1β and components E1, E2, E3 and the E3 binding protein of the complex.
  
  
  METHODS
  English language peer-reviewed publications were identified, primarily by using PubMed and Google Scholar search engines.
  
  
  RESULTS
  Neurodevelopmental delay and hypotonia were the commonest clinical signs of PDC deficiency. Structural brain abnormalities frequently included ventriculomegaly, dysgenesis of the corpus callosum and neuroimaging findings typical of Leigh syndrome. Neither gender nor any clinical or neuroimaging feature differentiated the various biochemical etiologies of the disease. Patients who died were younger, presented clinically earlier and had higher blood lactate levels and lower residual enzyme activities than subjects who were still alive at the time of reporting. Survival bore no relationship to the underlying biochemical or genetic abnormality or to gender.
  
  
  CONCLUSIONS
  Although the clinical spectrum of PDC deficiency is broad, the dominant clinical phenotype includes presentation during the first year of life; neurological and neuromuscular degeneration; structural lesions revealed by neuroimaging; lactic acidosis and a blood lactate:pyruvate ratio ≤20.
authors.affiliation: Departments of Medicine (Division of Endocrinology and Metabolism), College of Medicine, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Kavi P
authors.initials: KP
authors.lastname: Patel
authors.forename: Thomas W
authors.initials: TW
authors.lastname: O'Brien
authors.forename: Sankarasubramon H
authors.initials: SH
authors.lastname: Subramony
authors.forename: Jonathan
authors.initials: J
authors.lastname: Shuster
authors.forename: Peter W
authors.initials: PW
authors.lastname: Stacpoole
mesh_terms: D005260:Female; D006801:Humans; D008297:Male; D059906:Neuroimaging; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D015325:Pyruvate Dehydrogenase Complex Deficiency Disease / Q000097:blood / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D012727:Sex Characteristics; D016896:Treatment Outcome
chemical_list: D011768:Pyruvate Dehydrogenase Complex
references.citation: J Pediatr. 1987 Oct;111(4):525-33
references.pmid: 3116190
references.citation: J Pediatr. 1993 Sep;123(3):427-30
references.pmid: 8355121
references.citation: Hum Mutat. 2000;15(3):209-19
references.pmid: 10679936
references.citation: J Inherit Metab Dis. 1988;11(2):207-17
references.pmid: 3139934
references.citation: J Inherit Metab Dis. 1987;10(4):359-66
references.pmid: 3126355
references.citation: Epilepsia. 2009 Feb;50(2):304-17
references.pmid: 18823325
references.citation: Hum Mol Genet. 1998 Mar;7(3):501-5
references.pmid: 9467010
references.citation: J Child Neurol. 1994 Jan;9(1):52-5
references.pmid: 8151084
references.citation: Mol Genet Metab. 2008 Apr;93(4):371-80
references.pmid: 18164639
references.citation: Hum Genet. 2009 Apr;125(3):319-26
references.pmid: 19184109
references.citation: J Child Neurol. 1997 Feb;12(2):141-4
references.pmid: 9075024
references.citation: Eur J Pediatr. 1986 Feb;144(5):445-50
references.pmid: 3082638
references.citation: Pediatr Neurol. 1993 May-Jun;9(3):216-20
references.pmid: 8352855
references.citation: Hum Mutat. 1994;3(2):152-5
references.pmid: 8199595
references.citation: J Inherit Metab Dis. 2009 Dec;32 Suppl 1:S235-9
references.pmid: 19517265
references.citation: J Inherit Metab Dis. 1989;12(2):97-107
references.pmid: 2502681
references.citation: Mol Genet Metab. 2006 Feb;87(2):162-8
references.pmid: 16412675
references.citation: J Neurol Sci. 1999 Dec 1;171(1):56-9
references.pmid: 10567050
references.citation: Eur J Pediatr. 2003 Oct;162(10):714-8
references.pmid: 12925875
references.citation: J Histochem Cytochem. 2002 Jul;50(7):877-84
references.pmid: 12070266
references.citation: Biochem J. 1974 Sep;141(3):761-74
references.pmid: 4478069
references.citation: Hum Genet. 2002 Feb;110(2):187-91
references.pmid: 11935326
references.citation: Neurology. 1990 Aug;40(8):1312-4
references.pmid: 2381545
references.citation: Brain Dev. 1983;5(4):381-9
references.pmid: 6416099
references.citation: Eur J Pediatr. 1999 Oct;158(10):853-7
references.pmid: 10486093
references.citation: J Inherit Metab Dis. 1992;15(6):848-56
references.pmid: 1338114
references.citation: Neuroscientist. 2008 Feb;14(1):12-8
references.pmid: 17911220
references.citation: Ital J Neurol Sci. 1982 Dec;3(4):317-21
references.pmid: 6820014
references.citation: Am J Hum Genet. 1995 Oct;57(4):772-80
references.pmid: 7573035
references.citation: Hum Mutat. 2003 Dec;22(6):496-7
references.pmid: 14635113
references.citation: Neurology. 1997 Dec;49(6):1655-61
references.pmid: 9409363
references.citation: Hum Genet. 1997 Jun;99(6):785-92
references.pmid: 9187674
references.citation: Mol Genet Metab. 2002 Aug;76(4):344-7
references.pmid: 12208141
references.citation: J Pediatr Gastroenterol Nutr. 1997 May;24(5):599-601
references.pmid: 9161958
references.citation: J Inherit Metab Dis. 1989;12(4):379-85
references.pmid: 2516171
references.citation: Pediatr Radiol. 2008 May;38(5):559-62
references.pmid: 18197404
references.citation: Neurology. 2006 Feb 14;66(3):324-30
references.pmid: 16476929
references.citation: Arch Neurol. 2006 May;63(5):746-8
references.pmid: 16682545
references.citation: Pediatr Neurol. 1995 Nov;13(4):327-32
references.pmid: 8771169
references.citation: J Inherit Metab Dis. 1996;19(6):795-6
references.pmid: 8982956
references.citation: Neuropediatrics. 1992 Jun;23(3):147-52
references.pmid: 1641082
references.citation: Eur J Pediatr. 2005 Feb;164(2):99-103
references.pmid: 15558317
references.citation: J Inherit Metab Dis. 2001 Oct;24(5):551-9
references.pmid: 11757583
references.citation: Am J Hum Genet. 1990 Aug;47(2):286-93
references.pmid: 2378353
references.citation: J Pediatr. 1984 Jan;104(1):65-9
references.pmid: 6418873
references.citation: J Neurol. 2003 Feb;250(2):216-21
references.pmid: 12574954
references.citation: J Inherit Metab Dis. 2004;27(4):477-85
references.pmid: 15303005
references.citation: J Clin Invest. 1970 Mar;49(3):423-32
references.pmid: 4313434
references.citation: J Neurosci. 2007 Jul 4;27(27):7094-104
references.pmid: 17611262
references.citation: Acta Paediatr. 1996 May;85(5):625-8
references.pmid: 8827113
references.citation: Trends Biochem Sci. 2006 Jan;31(1):26-34
references.pmid: 16337125
references.citation: Ann Neurol. 2005 Aug;58(2):234-41
references.pmid: 16049940
references.citation: Eur J Pediatr. 1990 Apr;149(7):487-92
references.pmid: 2189731
references.citation: Annu Rev Neurosci. 2008;31:91-123
references.pmid: 18333761
references.citation: Magn Reson Imaging. 1999 Jul;17(6):939-44
references.pmid: 10402601
references.citation: J Inherit Metab Dis. 1995;18(5):534-46
references.pmid: 8598634
references.citation: Hum Genet. 2008 Sep;124(2):187-93
references.pmid: 18709504
references.citation: Hum Mutat. 1996;8(2):180-2
references.pmid: 8844217
references.citation: J Nutr Sci Vitaminol (Tokyo). 1992;Spec No:585-8
references.pmid: 1297818
references.citation: Pediatr Res. 1988 Jul;24(1):95-100
references.pmid: 3137520
references.citation: Pediatrics. 1987 Mar;79(3):370-3
references.pmid: 3103091
references.citation: Dev Med Child Neurol. 2006 Sep;48(9):756-60
references.pmid: 16904023
references.citation: Hum Mol Genet. 1996 Dec;5(12):1925-30
references.pmid: 8968745
references.citation: Ann Neurol. 2003 Feb;53(2):273-7
references.pmid: 12557299
references.citation: Eur Neurol. 1990;30(3):123-7
references.pmid: 2162773
references.citation: Pediatr Neurol. 1994 Jun;10(4):276-83
references.pmid: 8068153
references.citation: Clin Chim Acta. 1984 Jun 27;140(1):59-64
references.pmid: 6430599
references.citation: Eur J Pediatr. 1998 Aug;157(8):648-52
references.pmid: 9727848
references.citation: Pediatrics. 1996 Feb;97(2):267-72
references.pmid: 8584393
references.citation: Clin Chim Acta. 1983 Sep 30;133(2):133-40
references.pmid: 6688766
references.citation: J Inherit Metab Dis. 2002 Aug;25(4):325-7
references.pmid: 12227466
references.citation: J Inherit Metab Dis. 1998 Jun;21(3):224-6
references.pmid: 9686362
references.citation: Neuropediatrics. 2006 Jun;37(3):137-41
references.pmid: 16967364
references.citation: Acta Neuropathol. 1987;74(4):393-6
references.pmid: 3687391
references.citation: Brain Dev. 1993 Sep-Oct;15(5):384-6
references.pmid: 8279656
references.citation: Hum Genet. 2004 Jul;115(2):123-7
references.pmid: 15138885
references.citation: Neuropediatrics. 2001 Dec;32(6):295-8
references.pmid: 11870584
references.citation: Am J Med Genet A. 2006 Jul 15;140(14):1542-52
references.pmid: 16770810
references.citation: Tohoku J Exp Med. 1982 Aug;137(4):379-86
references.pmid: 7123539
references.citation: J Inherit Metab Dis. 2009 Dec;32 Suppl 1:
references.pmid: 19639391
references.citation: Acta Paediatr Scand. 1985 Jan;74(1):140-2
references.pmid: 3920865
references.citation: Am J Hum Genet. 1995 Mar;56(3):558-69
references.pmid: 7887409
references.citation: Neurology. 1981 Apr;31(4):398-404
references.pmid: 6783978
references.citation: Metabolism. 1989 Nov;38(11):1124-44
references.pmid: 2554095
references.citation: J Inherit Metab Dis. 1992;15(6):835-47
references.pmid: 1293379
references.citation: Am J Hum Genet. 1997 Dec;61(6):1318-26
references.pmid: 9399911
references.citation: Biochim Biophys Acta. 2002 Oct 9;1588(1):79-84
references.pmid: 12379317
references.citation: Mol Genet Metab. 2006 Sep-Oct;89(1-2):106-10
references.pmid: 16843025
references.citation: Neuropediatrics. 2008 Feb;39(1):20-3
references.pmid: 18504677
references.citation: FEBS Lett. 1974 Feb 1;39(1):17-20
references.pmid: 4854637
references.citation: Adv Neurol. 1978;21:181-9
references.pmid: 216243
references.citation: Pediatr Neurol. 1996 May;14(4):328-34
references.pmid: 8962591
references.citation: J Cereb Blood Flow Metab. 2008 Apr;28(4):712-24
references.pmid: 17940539
references.citation: Agents Actions. 1977 Sep;7(3):405-10
references.pmid: 413346
references.citation: Eur J Pediatr. 1981 Mar;136(1):35-9
references.pmid: 6894281
references.citation: J Inherit Metab Dis. 1991;14(3):301-4
references.pmid: 1770778
references.citation: J Inherit Metab Dis. 1994;17(2):189-95
references.pmid: 7967473
references.citation: Am J Hum Genet. 1989 Mar;44(3):358-64
references.pmid: 2537010
references.citation: Mov Disord. 2004 Jun;19(6):727-9
references.pmid: 15197721
references.citation: Pediatrics. 2006 May;117(5):1519-31
references.pmid: 16651305
references.citation: Pediatr Res. 1976 Jan;10(1):62-6
references.pmid: 813176
references.citation: Mol Genet Metab. 2008 Apr;93(4):381-7
references.pmid: 18206410
references.citation: Hum Mol Genet. 1993 Jun;2(6):805-7
references.pmid: 8353499
references.citation: J Inherit Metab Dis. 1991;14(5):793-9
references.pmid: 1779625
references.citation: Dev Med Child Neurol. 2004 Oct;46(10):710-2
references.pmid: 15473177
references.citation: Am J Hum Genet. 1991 Aug;49(2):414-20
references.pmid: 1907799
references.citation: Ann Neurol. 1989 Dec;26(6):746-51
references.pmid: 2513771
references.citation: Hum Mol Genet. 1995 Feb;4(2):315-8
references.pmid: 7757088
references.citation: Eur J Pediatr. 1989 Apr;148(6):543-7
references.pmid: 2501097
references.citation: Arch Neurol. 1971 Nov;25(5):449-60
references.pmid: 5110887
references.citation: Biochim Biophys Acta. 1997 Dec 31;1362(2-3):160-8
references.pmid: 9540846
references.citation: Hum Mol Genet. 1995 Feb;4(2):307-8
references.pmid: 7757085
references.citation: J Inherit Metab Dis. 2009 Dec;32 Suppl 1:S339-43
references.pmid: 19924563
references.citation: Hum Mutat. 2008 Mar;29(3):451
references.pmid: 18273899
references.citation: Acta Paediatr Scand. 1982 Mar;71(2):263-7
references.pmid: 6897146
references.citation: Pediatr Int. 2010 Aug;52(4):e181-3
references.pmid: 20958858
references.citation: Hum Mutat. 1996;7(1):46-51
references.pmid: 8664900
references.citation: J Inherit Metab Dis. 1998 Feb;21(1):9-16
references.pmid: 9501264
references.citation: Acta Neuropathol. 1993;85(6):674-8
references.pmid: 8337946
references.citation: Pediatr Res. 1993 Mar;33(3):284-8
references.pmid: 8460066
references.citation: Pediatr Res. 1977 Dec;11(12):1198-202
references.pmid: 413089
references.citation: J Cereb Blood Flow Metab. 2007 Feb;27(2):219-49
references.pmid: 16835632
references.citation: Mitochondrion. 2006 Jun;6(3):126-35
references.pmid: 16725381
references.citation: Hum Mutat. 1995;6(3):274-5
references.pmid: 8535453
references.citation: Neurology. 1976 Jul;26(7):625-8
references.pmid: 180454
references.citation: Pediatr Res. 1991 Jul;30(1):11-4
references.pmid: 1909778
references.citation: Hum Mutat. 1998;12(2):114-21
references.pmid: 9671272
references.citation: Brain Dev. 2004 Jan;26(1):57-60
references.pmid: 14729417
references.citation: Hum Mutat. 1997;10(3):256-7
references.pmid: 9298831
references.citation: Cell Mol Life Sci. 2007 Apr;64(7-8):830-49
references.pmid: 17310282
references.citation: AJNR Am J Neuroradiol. 1990 Mar-Apr;11(2):379-84
references.pmid: 2156413
references.citation: Mitochondrion. 2006 Jun;6(3):155-9
references.pmid: 16713755
references.citation: J Biol Chem. 2008 Jan 4;283(1):237-243
references.pmid: 17923481
references.citation: J Clin Invest. 1990 Jun;85(6):1821-4
references.pmid: 2112155
references.citation: Mol Genet Metab. 2008 Mar;93(3):323-30
references.pmid: 18023225
references.citation: J Inherit Metab Dis. 1991;14(2):140-51
references.pmid: 1909401
references.citation: Brain Dev. 1987;9(1):9-15
references.pmid: 3111288
references.citation: J Pediatr. 1984 Dec;105(6):961-3
references.pmid: 6502351
references.citation: J Clin Endocrinol Metab. 2004 Apr;89(4):1733-8
references.pmid: 15070938
references.citation: Pediatrics. 1984 Dec;74(6):1034-40
references.pmid: 6438601
references.citation: Eur J Paediatr Neurol. 2010 Jul;14(4):349-53
references.pmid: 20022530
references.citation: J Cereb Blood Flow Metab. 2009 Jan;29(1):44-56
references.pmid: 18714330
references.citation: Glia. 2010 Aug;58(10):1168-76
references.pmid: 20544852
references.citation: Biochem Biophys Res Commun. 1999 Aug 19;262(1):163-6
references.pmid: 10448086
references.citation: Pediatr Res. 1994 Sep;36(3):340-6
references.pmid: 7808831
references.citation: Hum Mol Genet. 1993 Apr;2(4):449-54
references.pmid: 8504306
references.citation: Eur J Pediatr. 2009 Jan;168(1):17-22
references.pmid: 18398624
references.citation: J Pediatr. 1995 Jan;126(1):72-4
references.pmid: 7815230
references.citation: Eur J Pediatr. 2006 Jul;165(7):462-6
references.pmid: 16552546
references.citation: Pediatr Neurol. 1996 Jan;14(1):69-71
references.pmid: 8652022
references.citation: Am J Med Genet. 1985 Oct;22(2):291-9
references.pmid: 4050860
references.citation: Pediatr Res. 1976 Aug;10(8):713-20
references.pmid: 821033
references.citation: J Neurol Sci. 1984 Apr;64(1):89-97
references.pmid: 6539810
references.citation: J Inherit Metab Dis. 1997 Aug;20(4):539-48
references.pmid: 9266390
references.citation: Dev Med Child Neurol. 2010 Feb;52(2):e1-9
references.pmid: 20002125
references.citation: Eur J Pediatr. 1988 Jan;147(1):10-4
references.pmid: 3123240
references.citation: Mol Genet Metab. 2005 Dec;86(4):456-61
references.pmid: 16256390
references.citation: Ann Neurol. 2006 Apr;59(4):709-14
references.pmid: 16566017
references.citation: Hum Mol Genet. 1994 Jun;3(6):1021-2
references.pmid: 7545958
references.citation: Ann Neurol. 1979 Dec;6(6):483-94
references.pmid: 119480
references.citation: Can Anaesth Soc J. 1983 Jul;30(4):413-6
references.pmid: 6409388
references.citation: Hum Mol Genet. 1993 Apr;2(4):473-4
references.pmid: 8504309
references.citation: Pediatrics. 1976 Nov;58(5):713-21
references.pmid: 824610
references.citation: Science. 1975 Mar 21;187(4181):1082-4
references.pmid: 803713
references.citation: Mol Genet Metab. 2010 Jul;100(3):296-9
references.pmid: 20462777
references.citation: Pediatr Radiol. 2009 Oct;39(10):1114-7
references.pmid: 19588132
references.citation: Hum Mol Genet. 1994 Jul;3(7):1193-4
references.pmid: 7981697
references.citation: Brain Dev. 1991 Nov;13(6):457-8
references.pmid: 1810165
references.citation: Hum Genet. 1992 Mar;88(6):649-52
references.pmid: 1551669
references.citation: Biochem J. 1986 Oct 1;239(1):89-96
references.pmid: 3800988
references.citation: J Inherit Metab Dis. 1984;7 Suppl 1:69-73
references.pmid: 6434848
references.citation: J Pediatr. 1993 Dec;123(6):915-20
references.pmid: 8229524
references.citation: Clin Genet. 2010 May;77(5):474-82
references.pmid: 20002461
references.citation: J Inherit Metab Dis. 2003;26(5):505-6
references.pmid: 14518830
references.citation: Am J Med Genet A. 2004 Nov 15;131(1):59-66
references.pmid: 15384102
references.citation: J Clin Invest. 1986 Sep;78(3):844-7
references.pmid: 3091638
references.citation: Pediatrics. 1976 Oct;58(4):564-72
references.pmid: 184426
references.citation: J Neurol Sci. 2002 Sep 15;201(1-2):33-7
references.pmid: 12163191
references.citation: Brain. 1994 Jun;117 ( Pt 3):435-43
references.pmid: 8032855
references.citation: AJNR Am J Neuroradiol. 2003 Aug;24(7):1471-4
references.pmid: 12917150
references.citation: J Neurol Neurosurg Psychiatry. 2008 Jul;79(7):846-7
references.pmid: 18559466
references.citation: Biochem Mol Biol Int. 1993 Dec;31(6):1157-66
references.pmid: 8193600