Neonatal pyruvate dehydrogenase deficiency with lipoate responsive lactic acidaemia and hyperammonaemia

Abstract

A 2-day-old girl developed a severe lactic acidosis with a normal lactate/pyruvate ratio and hyperammonaemia. Plasma arginine and citrulline levels were below the limit of detection. In muscle total pyruvate dehydrogenase complex (PDHC) and pyruvate decarboxylase (E1) activities were reduced to a fraction of lower control values. The acute neonatal period was bridged with peritoneal dialysis, dichloroacetate therapy, supplements of arginine and branched chain amino acids, a complete vitamin B complex and lipoic acid. Lactate homeostasis responded to pharmacological supplements of lipoic acid. At age 1 year the child was hypotonic, showed severe developmental retardation, optic atrophy and cranial dysmorphism. She died aged 1 year 8 months with signs of respiratory paralysis but with normal lactate levels under assisted breathing. Pathological findings at autopsy were suggestive of Leigh syndrome, interstitial pneumonia and extensive fatty infiltration of hepatocytes. Regression analysis of data from 187 plasma amino acid determinations from the patient over a period of 1 year 8 months revealed a persistent-imbalance involving alanine, glutamic acid, glutamine, proline, citrulline and branched chain amino acids. Aspects of acute and long-term therapy in this patient and some implications of the imbalances in plasma amino acids are discussed.

A zebrafish model for pyruvate dehydrogenase deficiency: Rescue of neurological dysfunction and embryonic lethality using a ketogenic diet

“…PDH is a nuclear-encoded mitochondrial matrix multienzyme complex that provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle by catalyzing the irreversible conversion of pyruvate into acetyl-CoA (5). Defects in PDH result in decreased acetyl-CoA synthesis and the accumulation of pyruvate and lactate, causing reduced energy production and metabolic acidosis, respectively.Current treatments for PDH deficiency, which include the activation of residual PDH with dichloroacetate (6), the administration of cofactors (lipoic acid and thiamine) (7,8), and the provision of ketogenic diets (9, 10), have yielded only limited or variable success (see Fig. 1).…”

“…Current treatments for PDH deficiency, which include the activation of residual PDH with dichloroacetate (6), the administration of cofactors (lipoic acid and thiamine) (7,8), and the provision of ketogenic diets (9,10), have yielded only limited or variable success (see Fig. 1).…”

The Plasma Amino Acid Profile and its Relationships to Standard Quantities of Liver Function in Infants and Children with Extrahepatic Biliary Atresia and Preterminal Liver Cirrhosis

“…Compared with controls, the normally strong correlation of valine with isoleucine was weaker. In calorie deprivation branched chain amino acids may become a source of fuel for muscle (19,33,34). We postulate that in our extrahepatic biliary atresia children the branched chain amino acids deficit resulted from their use as alternative energy substrates, and that the low concentrations of these amino acids may indicate increased dietary requirements for them (35).…”

Mitochondrial disease

“…α-lipoic acid is given to patients with PDH deficiency due to E3 sub-unit defects with the rationale that it is a cofactor for PDH and may activate or stabilize the PDH complex [45].…”