Pyruvate Dehydrogenase Complex Deficiency
- Author: Richard E Frye, MD, PhD; Chief Editor: Luis O Rohena, MD more...
Pyruvate dehydrogenase complex (PDC) deficiency (PDCD) is one of the most common neurodegenerative disorders associated with abnormal mitochondrial metabolism. The citric acid cycle is a major biochemical process that derives energy from carbohydrates. Malfunction of this cycle deprives the body of energy. An abnormal lactate buildup results in nonspecific symptoms (eg, severe lethargy, poor feeding, tachypnea), especially during times of illness, stress, or high carbohydrate intake.
Progressive neurological symptoms usually start in infancy but may be evident at birth or in later childhood and very rarely in adults. These symptoms may include developmental delay, intermittent ataxia, poor muscle tone, abnormal eye movements, or seizures. Childhood- and adult-onset forms of this disorder are often associated with intermittent periods of decompensation but normal or mildly delayed neurological development. Therapies are suboptimal for most forms of pyruvate dehydrogenase complex deficiency; resolution of the lactic acidosis may occur, but cessation of the underlying progressive neurological damage is rare.
The key feature of this condition is gray matter degeneration with foci of necrosis and capillary proliferation in the brainstem in many but not all patients. The group of disorders that result in this pathology are termed Leigh syndrome. Defects in one of many of the mitochondrial enzymes involved in energy metabolism may demonstrate similar brain pathology.
Pyruvate dehydrogenase complex (PDC) converts pyruvate to acetyl-coenzyme A (CoA), which is one of the two essential substrates needed to produce citrate (see the image below).
A deficiency in this enzymatic complex limits the production of citrate. Because citrate is the first substrate in the citric acid cycle, the cycle cannot proceed. Alternate metabolic pathways are stimulated in an attempt to produce acetyl-CoA; however, an energy deficit remains, especially in the CNS. The magnitude of the energy deficit depends on the residual activity of the enzyme.
Severe enzyme deficiencies may lead to congenital brain malformation because of a lack of energy during neural development. Morphological abnormalities occur before 10 weeks' gestation. Maldevelopment of the corpus callosum is commonly observed in those with prenatal-onset types of pyruvate dehydrogenase complex deficiency.
Progressive neurological deterioration varies in neonates with an apparently healthy brain. Hypomyelination, cystic lesions, and gliosis of the cortex or cerebellum, with gray matter degeneration or necrotizing encephalopathy, may occur in some individuals with pyruvate dehydrogenase complex deficiency, whereas a gliosis of the brainstem and basal ganglia with capillary proliferation occurs in those with Leigh syndrome. Underlying neuropathology is not usually observed in individuals with a later onset of pyruvate dehydrogenase complex deficiency.
The most common form of pyruvate dehydrogenase complex deficiency is caused by mutations in the X-linked E1 alpha gene; all other causes are due to alterations in recessive genes.
The incidence of pyruvate dehydrogenase deficiency is not known, but it is likely to be less than 1;50,000. It may be more common than appreciated, because this condition is potentially responsible for unexplained seizures, acidosis, and developmental delays in cases in which enzyme testing is not done, as well as unexplained Leigh syndrome with demonstrable central nervous system (CNS) pathology. For X-linked cases, there is likely a 2 in 3 risk that the mother is an unexpressing carrier. For recessive cases, which are less common, there is a 1 in 4 recurrence risk. In-frame mutations of the X-linked E1 alpha gene have been shown for very mild cases.
Individuals with neonatal-onset and infantile-onset types of pyruvate dehydrogenase complex deficiency usually die during the first years of life. Later childhood onset of the disease is usually, but not always, associated with survival into adulthood.
All children are born with some residual enzyme activity, because a complete deficiency of pyruvate dehydrogenase complex is incompatible with life. Infants with 15% or less pyruvate dehydrogenase complex activity normally do not survive the newborn period.
Pyruvate dehydrogenase complex activity greater than 25% is associated with less severe disease and is usually characterized by ataxia and mild psychomotor delay. Some therapies may extend the lives of individuals who are severely affected with pyruvate dehydrogenase complex deficiency; however, the progressive nature of the neurological deterioration results in significant morbidity.
Affected males outnumber affected females, because the most common form of the pyruvate dehydrogenase deficiency is X-linked, Some female carriers may have mild symptoms. There is a wide range of presentation in the recessive forms of the disease, but most are milder than the X-linked form of the disease.
Pyruvate dehydrogenase deficiency does not appear to have a predilection for race/ethnicity.
Males are more commonly affected than females, because the most common form of the pyruvate dehydrogenase deficiency, that of the E1 alpha enzyme subunit, is X-linked, Some female carriers have mild to moderate symptoms because of variable X-chromosome inactivation. There is a wide range of presentation in the recessive forms of the disease, but many are equally as severe as the X-linked form of the disease.
West syndrome is more common in females with pyruvate dehydrogenase complex deficiency. Severe lactic acidosis with early demise and Leigh syndrome are more commonly observed in males with pyruvate dehydrogenase complex deficiency. Progressive neurological degeneration is also observed in females with pyruvate dehydrogenase complex deficiency.
Age of presentation varies from prenatal to early childhood and depends on the residual activity of the pyruvate dehydrogenase complex. Individuals with severe disease have prenatal onset with structural brain abnormalities. Moderate disease presents in infants as psychomotor delay. Individuals with less severe disease usually present in early childhood with intermittent lethargy or ataxia.
Ostergaard E, Moller LB, Kalkanoglu-Sivri HS, et al. Four novel PDHA1 mutations in pyruvate dehydrogenase deficiency. J Inherit Metab Dis. 2009 Jun 11. [Medline].
Steller J, Gargus JJ, Gibbs LH, Hasso AN, Kimonis VE. Mild phenotype in a male with pyruvate dehydrogenase complex deficiency associated with novel hemizygous in-frame duplication of the E1a subunit gene (PDHA1). Neuropediatrics. 2014 Feb. 45(1):56-60. [Medline].
Patel KP, O'Brien TW, Subramony SH, Shuster J, Stacpoole PW. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol Genet Metab. 2012 Jan. 105(1):34-43. [Medline]. [Full Text].
Patel KP, O'Brien TW, Subramony SH, Shuster J, Stacpoole PW. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol Genet Metab. 2012 Jan. 105(1):34-43. [Medline].
Giribaldi G, Doria-Lamba L, Biancheri R, Severino M, Rossi A, Santorelli FM, et al. Intermittent-relapsing pyruvate dehydrogenase complex deficiency: a case with clinical, biochemical, and neuroradiological reversibility. Dev Med Child Neurol. 2011 Dec 5. [Medline].
Han Z, Zhong L, Srivastava A, Stacpoole PW. Pyruvate dehydrogenase complex deficiency due ubiquitination and proteasome-mediated degradation of the E1beta subunit. J Biol Chem. 2007 Oct 8. [Medline].
Debray FG, Mitchell GA, Allard P, Robinson BH, Hanley JA, Lambert M. Diagnostic accuracy of blood lactate-to-pyruvate molar ratio in the differential diagnosis of congenital lactic acidosis. Clin Chem. 2007 May. 53(5):916-21. [Medline].
van Dongen S, Brown RM, Brown GK, Thorburn DR, Boneh A. Thiamine-responsive and non-responsive patients with PDHC-E1 deficiency: a retrospective assessment. JIMD Rep. 2014 Apr 10. [Medline].
Stacpoole PW, Kerr DS, Barnes C, Bunch ST, Carney PR, Fennell EM. Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics. 2006 May. 117(5):1519-31. [Medline].
Weber TA, Antognetti MR, Stacpoole PW. Caveats when considering ketogenic diets for the treatment of pyruvate dehydrogenase complex deficiency. J Pediatr. 2001 Mar. 138(3):390-5. [Medline].
Al-Essa MA, Ozand PT. Manual of Metabolic Diseases. Saudi Arabia: King Faisal Specialist Hospital and Research Centre, Riyadh; 1998.
Brown GK, Otero LJ, LeGris M, Brown RM. Pyruvate dehydrogenase deficiency. J Med Genet. 1994 Nov. 31(11):875-9. [Medline].
Byrd DJ, Krohn HP, Winkler L, et al. Neonatal pyruvate dehydrogenase deficiency with lipoate responsive lactic acidaemia and hyperammonaemia. Eur J Pediatr. 1989 Apr. 148(6):543-7. [Medline].
De Meirleir L. Defects of pyruvate metabolism and the Krebs cycle. J Child Neurol. 2002 Dec. 17 Suppl 3:3S26-33; discussion 3S33-4. [Medline].
Debray FG, Lambert M, Vanasse M, Decarie JC, Cameron J, Levandovskiy V. Intermittent peripheral weakness as the presenting feature of pyruvate dehydrogenase deficiency. Eur J Pediatr. 2006 Jul. 165(7):462-6. [Medline].
Fouque F, Brivet M, Boutron A, et al. Differential effect of DCA treatment on the pyruvate dehydrogenase complex in patients with severe PDHC deficiency. Pediatr Res. 2003 May. 53(5):793-9. [Medline].
Head RA, Brown RM, Zolkipli Z, et al. Clinical and genetic spectrum of pyruvate dehydrogenase deficiency: dihydrolipoamide acetyltransferase (E2) deficiency. Ann Neurol. 2005 Aug. 58(2):234-41. [Medline].
Head RA, de Goede CG, Newton RW, et al. Pyruvate dehydrogenase deficiency presenting as dystonia in childhood. Dev Med Child Neurol. 2004 Oct. 46(10):710-2. [Medline].
Morris AA, Leonard JV. The treatment of congenital lactic acidoses. J Inherit Metab Dis. 1996. 19(4):573-80. [Medline].
Morten KJ, Beattie P, Brown GK, Matthews PM. Dichloroacetate stabilizes the mutant E1alpha subunit in pyruvate dehydrogenase deficiency. Neurology. 1999 Aug 11. 53(3):612-6. [Medline].
Naito E, Ito M, Yokota I, et al. Diagnosis and molecular analysis of three male patients with thiamine-responsive pyruvate dehydrogenase complex deficiency. J Neurol Sci. 2002 Sep 15. 201(1-2):33-7. [Medline].
Naito E, Ito M, Yokota I, et al. 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. 2002 Oct 9. 1588(1):79-84. [Medline].
Pastoris O, Savasta S, Foppa P, et al. Pyruvate dehydrogenase deficiency in a child responsive to thiamine treatment. Acta Paediatr. 1996 May. 85(5):625-8. [Medline].
Shevell MI, Matthews PM, Scriver CR, et al. Cerebral dysgenesis and lactic acidemia: an MRI/MRS phenotype associated with pyruvate dehydrogenase deficiency. Pediatr Neurol. 1994 Oct. 11(3):224-9. [Medline].
Stacpoole PW, Barnes CL, Hurbanis MD, et al. Treatment of congenital lactic acidosis with dichloroacetate. Arch Dis Child. 1997 Dec. 77(6):535-41. [Medline].
Stacpoole PW, Bunch ST, Neiberger RE, et al. The importance of cerebrospinal fluid lactate in the evaluation of congenital lactic acidosis. J Pediatr. 1999 Jan. 134(1):99-102. [Medline].
Zand DJ, Simon EM, Pulitzer SB, et al. In vivo pyruvate detected by MR spectroscopy in neonatal pyruvate dehydrogenase deficiency. AJNR Am J Neuroradiol. 2003 Aug. 24(7):1471-4. [Medline].