Pyruvate dehydrogenase, deficiency in

Prevalence < 1/106. Metabolic disease due to the X-linked transmission of a mutation of the PDHA1 gene (Xp22.12) or to the autosomal recessive transmission of a mutation of the PDHB (3p1 DLAT (11q23.1), PDHX (11p13), DLD (7q31.1) or PDP1 (8q22.1) gene. Dehydrogenase pyruvate is a complex of 3 sub-units (E1, E2, E3) and 2 cofactors that catalyzes the irreversible oxidative decarboxylation of pyruvate in acetyl-coA providing ATP via the Krebs cycle.

Depending on the faulty unit and the residual activity level of the complex, 6 subtypes can be observed:

DPD E1-alpha, the most common: due to a mutation of the PDHA1 gene (pyruvate dehydrogenase) [MIM 312 170] the cofactor of which is thiamine pyrophosphatase;

acute metabolic presentation (< 15 % activity): neonatal lactic acidosis with hyperammonemia, tachypnea, drowsiness
neurological presentation affecting also the heterozygous girls: developmental retardation, growth retardation, delayed acquisition or loss of motor gain, hypotonia, convulsions, ataxia, dystonia. Moderate or intermittent lactic acidosis following prolonged fasting or infection. Structural brain anomalies is often found: corpus callosum abnormalities, brain cysts (activity < 30 %).
ataxia triggered by the ingestion of carbohydrates (activity = 30 %), which only affects boys and responds well to a ketogenic diet
presentation similar to Leigh syndrome (see this term) (activity close to 20%)
in 30 % of cases: facial dysmorphism with a narrow skull, frontal bumps, a long philtrum, dilated nostrils and sometimes a cleft lip or palate

DPD E1-beta: due to a mutation of the PDHB gene [MIM 614 111];
DPD E2: due to a mutation of the DLAT gene (dihydrolipoamide S-acetyltransferase) [MIM 245 348]: dystonia and lesions of the globus pallidus
DPD E3: due to a mutation of PDHX (dihydrolipoyl dehydrogenase) [MIM 245 349]: progressive hypotonia, psychomotor delay, microcephaly, spasticity, Leigh syndrome
E3 linkage deficit of the PD complex: due to a mutation of the DLD gene [MIM 246,900]
phosphatase deficiency of the PD complex: due to a mutation of the PDP1 gene [MIM 608 782].

Diagnosis: high lactate levels in the blood and/or CSF, with a lactate/pyruvate ratio <20. Lactates and pyruvates decrease with fasting.

Treatment: thiamine supplements, a ketogenic diet (in case of convulsions, dystonia or ataxia linked to carbohydrate intake), sometimes dichloroacetate (but risk of peripheral neuropathy).

Anesthetic implications:

anesthesia of a patient with mitochondrial cytopathy: administration of an glucose containing electrolytic solution at the start of the fasting period except in case of ketogenic diet (no glucose, avoid possible causes of increased glycemia such as corticosteroids). Some cases of difficult intubation. Avoid the administration of propofol by continuous infusion. Monitoring of blood glucose, lactic acid and ketone bodies (urine). Avoid hypocapnia, which aggravates lactic acidosis by inhibiting pyruvate decarboxylase.

preoperative
period

- take advice from the neuropediatrician: efficacy of the diet, which treatment in case of seizure, side effects (urinary lithiases ?)

- evaluation: RBC, WC, platelets, electrolytes, urea, creatinine, Ca, Mg, albumin and prealbumin (nutrition). SGOT and SGPT levels are often moderately elevated

- avoid prolonged fasting: clear unsweetened fluids allowed

- avoid sweetened fluids in the premedication

- avoid IV administration of carbohydrates containing IV fluids

- check glycemia at induction: ideally 50-80 mg/dL

anesthesia

- propofol: OK for induction but avoid TIVA: source of glycerol, risk of PRIS and pancreatitis

- fluids: 0.9 % NaCl (risk of worsening metabolic acidosis) or Ringer lactate (but lactate promotes gluconeogenesis)

- avoid corticosteroids: dexamethasone?

- avoid carbohydrate-containing medications (glucose, mannitol, glycerol) if possible

- the transfusion of labile blood products is a hidden intake of carbohydrates

- in case of hypoglycemia, correct with low doses of glucose (0.25g/kg)

- monitor glycemia, pH, electrolytes, NaHCO3

postoperative

- resume the ketogenic diet as soon as possible

- check ketone bodies (urine): between 40 and 160 mg/dL or at least 2 ++

Ketogenic diet: perianesthetic recommendations

References :

- Dierdorf SF, McNiece WL.
Anaesthesia and pyruvate dehydrogenase deficiency.
Can Anaesth Soc J 1983 ; 30 :413-6

- Acharya D, Dearlove OR.
Anaesthesia in pyruvate dehydrogenase deficiency.
Anaesthesia 2001 ; 56 : 808-9

- Mayhew JF.
Anesthesia in a child with pyruvate dehydrogenase deficiency.
Pediatr Anesth 2006 ; 16 :93

- Gilmore DA, Mayhew J.
Anesthesia in a child with pyruvate deshydrogenase deficiency.
AANA Journal 2008 ; 76 :432-3

- Milojevic I, Simic D.
Anaesthesia in pyruvate dehydrogenase deficiency.
Pediatr Anesth 2008 ; 18 : 794-5

- Dewhirst E, Rehman S, Tobias JD.
Perioperative care of an infant with pyruvate deshydrogenase deficiency.
South Afr J Anaesth Analg 2012 ; 18 :115-8

- Conover ZR, Talai A, Klockau KS, Ing RJ, Chaterjee D.
Perioperative management of children on ketogenic dietary therapies.
Anesth Analg 2020 ; 131 :1872-82.

- Hau V, Bonilla-Velez J, Low D.
Anesthesia management for ENT surgery in a child with X-linked pyruvate dehydrogenase deficiency.
Pediatr Anesth 2021; 31 :499-500

Updated: April 2021