Pyruvate dehydrogenase deficiency

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Pyruvate dehydrogenase deficiency
ICD-10 E74.4
OMIM 312170
DiseasesDB 30060
eMedicine ped/1969 
MeSH D015325

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Overview

Pyruvate Dehydrogenase Deficiency (PDHA) is a human genetic disease. It follows a sex-linked, dominant inheritance pattern, but is approximately equally prevalent in both males and females. It affects a gene which codes for a critical enzyme complex, the Pyruvate dehydrogenase complex (PDC) which links the metabolic pathways of glycolysis and the citric acid cycle by transforming pyruvate into Acetyl CoA

The pyruvate dehydrogenase complex facilitates oxidative decarboxylation, the chemical reaction between glycolysis and the citric acid cycle.

Presentation

PDHA causes Lactic acidosis; large amounts of lactic acid in the blood but with a normal pyruvate/lactate ratio. Symptoms are varied, and include developmental defects (especially of the brain and nervous system), muscular spasticity and early death.

Differential diagnosis

Pyruvate dehydrogenase deficiency must be differentiated from other diseases that cause neurological manifestations in infants.

Diseases Type of motor abnormality Clinical findings Laboratory findings and diagnostic tests Radiographic findings
Spasticity Hypotonia Ataxia Dystonia
Leigh syndrome - - + +
Niemann-Pick disease type C - - + +
  • Abnormal liver function tests
  • Fibroblast cell culture with filipin staining
Infantile Refsum disease - + + - Elevated plasma VLCFA levels --
Adrenoleukodystrophy + - - -
  • Elevated plasma VLCFA levels
  • Molecular genetic testing for mutations in the ABCD1 gene
--
Zellweger syndrome - + - - --
Pyruvate dehydrogenase deficiency + + + -
  • Elevated lactate and pyruvate levels in blood and CSF
  • Abnormal PDH enzymatic activity in cultured fibroblasts
--
Arginase deficiency + - - - --
Holocarboxylase synthetase deficiency - + - - Elevated levels of:
  • Beta-hydroxyisovalerate
  • Beta-methylcrotonylglycine
  • Beta-hydroxypropionate
  • Methylcitrate
  • Tiglylglycine
--
Glutaric aciduria type 1 - - - + Elevated levels of:
Ataxia telangiectasia - - + - --
Pontocerebellar hypoplasias - + - - Genetic testing for PCH gene mutations
Metachromatic leukodystrophy - + + -
  • Deficient arylsulfatase A enzyme activity in leukocytes or cultured skin fibroblasts
--
Pelizaeus-Merzbacher + - + -
Angelman syndrome - - + -
  • Methylation studies and chromosome microarray to detect chromosome 15 anomalies and UBE3A mutations
--
Rett syndrome + - - +
  • Occurs almost exclusively in females
  • Normal development during first six months followed by regression and loss of milestones
  • Loss of speech capability
  • Stereotypic hand movements
  • Seizures
  • Autistic features
  • Clinical diagnosis
  • Genetic testing for MECP2 mutations
--
Lesch-Nyhan syndrome + - - + --
Miller-Dieker lissencephaly + + - -
  • Cytogenetic testing for 17p13.3 microdeletion
--
Dopa-responsive dystonia + - - +
  • Onset in early childhood
  • Symptoms worsen with fatigue and exercise
  • Positive response to a trial of levodopa
--


Genetics

PDHA is most commonly linked to the alpha unit of E1, but recessive variants exist.

Treatment

Use of a ketogenic diet has been described.[1]

Current research is being conducted on the viability of Dichloroacetic acid to treat the lactic acidosis commonly accompanied by this disorder.[2][3] Additionally, there is research being conducted on the viability of gene therapy for sufferers of this condition as well as many other mitochondrial defects.

References

  1. Barañano KW, Hartman AL (2008). "The ketogenic diet: uses in epilepsy and other neurologic illnesses" ([dead link]). Curr Treat Options Neurol. 10 (6): 410–9. doi:10.1007/s11940-008-0043-8. PMC 2898565. PMID 18990309. Unknown parameter |month= ignored (help)
  2. Berendzen K, Theriaque DW, Shuster J, Stacpoole PW (2006). "Therapeutic potential of dichloroacetate for pyruvate dehydrogenase complex deficiency". Mitochondrion. 6 (3): 126–35. doi:10.1016/j.mito.2006.04.001. PMID 16725381. Unknown parameter |month= ignored (help)
  3. Stacpoole PW, Kurtz TL, Han Z, Langaee T (2008). "Role of dichloroacetate in the treatment of genetic mitochondrial diseases". Adv. Drug Deliv. Rev. 60 (13–14): 1478–87. doi:10.1016/j.addr.2008.02.014. PMID 18647626.


Cost Effectiveness of Pyruvate dehydrogenase deficiency

| group5 = Clinical Trials Involving Pyruvate dehydrogenase deficiency | list5 = Ongoing Trials on Pyruvate dehydrogenase deficiency at Clinical Trials.govTrial results on Pyruvate dehydrogenase deficiencyClinical Trials on Pyruvate dehydrogenase deficiency at Google


| group6 = Guidelines / Policies / Government Resources (FDA/CDC) Regarding Pyruvate dehydrogenase deficiency | list6 = US National Guidelines Clearinghouse on Pyruvate dehydrogenase deficiencyNICE Guidance on Pyruvate dehydrogenase deficiencyNHS PRODIGY GuidanceFDA on Pyruvate dehydrogenase deficiencyCDC on Pyruvate dehydrogenase deficiency


| group7 = Textbook Information on Pyruvate dehydrogenase deficiency | list7 = Books and Textbook Information on Pyruvate dehydrogenase deficiency


| group8 = Pharmacology Resources on Pyruvate dehydrogenase deficiency | list8 = AND (Dose)}} Dosing of Pyruvate dehydrogenase deficiencyAND (drug interactions)}} Drug interactions with Pyruvate dehydrogenase deficiencyAND (side effects)}} Side effects of Pyruvate dehydrogenase deficiencyAND (Allergy)}} Allergic reactions to Pyruvate dehydrogenase deficiencyAND (overdose)}} Overdose information on Pyruvate dehydrogenase deficiencyAND (carcinogenicity)}} Carcinogenicity information on Pyruvate dehydrogenase deficiencyAND (pregnancy)}} Pyruvate dehydrogenase deficiency in pregnancyAND (pharmacokinetics)}} Pharmacokinetics of Pyruvate dehydrogenase deficiency


| group9 = Genetics, Pharmacogenomics, and Proteinomics of Pyruvate dehydrogenase deficiency | list9 = AND (pharmacogenomics)}} Genetics of Pyruvate dehydrogenase deficiencyAND (pharmacogenomics)}} Pharmacogenomics of Pyruvate dehydrogenase deficiencyAND (proteomics)}} Proteomics of Pyruvate dehydrogenase deficiency


| group10 = Newstories on Pyruvate dehydrogenase deficiency | list10 = Pyruvate dehydrogenase deficiency in the newsBe alerted to news on Pyruvate dehydrogenase deficiencyNews trends on Pyruvate dehydrogenase deficiency


| group11 = Commentary on Pyruvate dehydrogenase deficiency | list11 = Blogs on Pyruvate dehydrogenase deficiency

| group12 = Patient Resources on Pyruvate dehydrogenase deficiency | list12 = Patient resources on Pyruvate dehydrogenase deficiencyDiscussion groups on Pyruvate dehydrogenase deficiencyPatient Handouts on Pyruvate dehydrogenase deficiencyDirections to Hospitals Treating Pyruvate dehydrogenase deficiencyRisk calculators and risk factors for Pyruvate dehydrogenase deficiency


| group13 = Healthcare Provider Resources on Pyruvate dehydrogenase deficiency | list13 = Symptoms of Pyruvate dehydrogenase deficiencyCauses & Risk Factors for Pyruvate dehydrogenase deficiencyDiagnostic studies for Pyruvate dehydrogenase deficiencyTreatment of Pyruvate dehydrogenase deficiency

| group14 = Continuing Medical Education (CME) Programs on Pyruvate dehydrogenase deficiency | list14 = CME Programs on Pyruvate dehydrogenase deficiency

| group15 = International Resources on Pyruvate dehydrogenase deficiency | list15 = Pyruvate dehydrogenase deficiency en EspanolPyruvate dehydrogenase deficiency en Francais

| group16 = Business Resources on Pyruvate dehydrogenase deficiency | list16 = Pyruvate dehydrogenase deficiency in the MarketplacePatents on Pyruvate dehydrogenase deficiency

| group17 = Informatics Resources on Pyruvate dehydrogenase deficiency | list17 = List of terms related to Pyruvate dehydrogenase deficiency


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