Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase

Orphanet J Rare Dis. 2013 Dec 17;8:192. doi: 10.1186/1750-1172-8-192.


Background: Synthesis and apoenzyme attachment of lipoic acid have emerged as a new complex metabolic pathway. Mutations in several genes involved in the lipoic acid de novo pathway have recently been described (i.e., LIAS, NFU1, BOLA3, IBA57), but no mutation was found so far in genes involved in the specific process of attachment of lipoic acid to apoenzymes pyruvate dehydrogenase (PDHc), α-ketoglutarate dehydrogenase (α-KGDHc) and branched chain α-keto acid dehydrogenase (BCKDHc) complexes.

Methods: Exome capture was performed in a boy who developed Leigh disease following a gastroenteritis and had combined PDH and α-KGDH deficiency with a unique amino acid profile that partly ressembled E3 subunit (dihydrolipoamide dehydrogenase / DLD) deficiency. Functional studies on patient fibroblasts were performed. Lipoic acid administration was tested on the LIPT1 ortholog lip3 deletion strain yeast and on patient fibroblasts.

Results: Exome sequencing identified two heterozygous mutations (c.875C > G and c.535A > G) in the LIPT1 gene that encodes a mitochondrial lipoyltransferase which is thought to catalyze the attachment of lipoic acid on PDHc, α-KGDHc, and BCKDHc. Anti-lipoic acid antibodies revealed absent expression of PDH E2, BCKDH E2 and α-KGDH E2 subunits. Accordingly, the production of 14CO2 by patient fibroblasts after incubation with 14Cglucose, 14Cbutyrate or 14C3OHbutyrate was very low compared to controls. cDNA transfection experiments on patient fibroblasts rescued PDH and α-KGDH activities and normalized the levels of pyruvate and 3OHbutyrate in cell supernatants. The yeast lip3 deletion strain showed improved growth on ethanol medium after lipoic acid supplementation and incubation of the patient fibroblasts with lipoic acid decreased lactate level in cell supernatants.

Conclusion: We report here a putative case of impaired free or H protein-derived lipoic acid attachment due to LIPT1 mutations as a cause of PDH and α-KGDH deficiencies. Our study calls for renewed efforts to understand the mechanisms of pathology of lipoic acid-related defects and their heterogeneous biochemical expression, in order to devise efficient diagnostic procedures and possible therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases / genetics*
  • Amino Acids / blood
  • Amino Acids / cerebrospinal fluid
  • Amino Acids / urine
  • Carrier Proteins / genetics
  • Cells, Cultured
  • Fibroblasts / metabolism
  • Humans
  • Immunoblotting
  • Ketoglutarate Dehydrogenase Complex / deficiency
  • Ketoglutarate Dehydrogenase Complex / genetics
  • Ketone Oxidoreductases / deficiency
  • Ketone Oxidoreductases / genetics
  • Leigh Disease / blood
  • Leigh Disease / genetics*
  • Leigh Disease / urine
  • Pyruvate Dehydrogenase (Lipoamide) / genetics
  • Thioctic Acid / blood
  • Thioctic Acid / cerebrospinal fluid
  • Thioctic Acid / urine


  • Amino Acids
  • Carrier Proteins
  • NFU1 protein, human
  • Thioctic Acid
  • Ketone Oxidoreductases
  • pyruvate dehydrogenase (NADP+)
  • Pyruvate Dehydrogenase (Lipoamide)
  • pyruvate dehydrogenase E1alpha subunit
  • Ketoglutarate Dehydrogenase Complex
  • Acyltransferases
  • lipoyltransferase I