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Case Reports
. 2011 Dec 9;89(6):792-7.
doi: 10.1016/j.ajhg.2011.11.011.

Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation

Johannes A Mayr  1 , Franz A Zimmermann, Christine Fauth, Christa Bergheim, David Meierhofer, Doris Radmayr, Johannes Zschocke, Johannes Koch, Wolfgang Sperl
Affiliations
Case Reports

Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation

Johannes A Mayr et al. Am J Hum Genet. .

Abstract

Lipoic acid is an essential prosthetic group of four mitochondrial enzymes involved in the oxidative decarboxylation of pyruvate, α-ketoglutarate, and branched chain amino acids and in the glycine cleavage. Lipoic acid is synthesized stepwise within mitochondria through a process that includes lipoic acid synthetase. We identified the homozygous mutation c.746G>A (p.Arg249His) in LIAS in an individual with neonatal-onset epilepsy, muscular hypotonia, lactic acidosis, and elevated glycine concentration in plasma and urine. Investigation of the mitochondrial energy metabolism showed reduced oxidation of pyruvate and decreased pyruvate dehydrogenase complex activity. A pronounced reduction of the prosthetic group lipoamide was found in lipoylated proteins.

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Figures

Figure 1
Figure 1
Lipoic Acid Synthetase Catalysis the Formation of the Protein-Bound Prosthetic Group Dihydrolipoamide
Figure 2
Figure 2
Immunoblot Analysis of PDHC Subunits Immunoblot analysis with an antibody cocktail against subunits of the pyruvate dehydrogenase complex performed with samples of muscle from the affected individual showed a decrease of E2 and E3 subunit binding protein, whereas the subunits E1α and E1β were found in normal amounts in comparison to the subunit OSCP of the ATP synthase.
Figure 3
Figure 3
Mutation Analysis of LIAS Sequence analysis (A) revealed the mutation c.746G>A (p.Arg249His) in LIAS, which affects a phylogenetically conserved amino acid (B).
Figure 4
Figure 4
Immunoblot Analysis and Immunoflorescence Staining of Lipoic Acid Immunoblot analysis with an antibody against lipoic acid (A) showed a severe decrease of the E2 subunits of both PDHC and α-KGDH in the affected individual (P-LIAS) in comparison to control muscle. Subunit OSCP of the ATP synthase (B) was used as a loading control. Immunocytochemical staining of fibroblasts showed a decreased staining with the antibody against lipoic acid (red) compared to porin (green) in cells from the affected individual (C) compared to the control (D).
Figure 5
Figure 5
Lipoic Acid Synthetase Complementation Analysis in Escherichia coli Complementation analysis in the lipoic acid synthetase-deficient E. coli strain JRG33 revealed a clear growth retardation on lipoic acid-free growth medium (A and C) of cells expressing the mutant (LIAS-mut) versus the wild-type (LIAS-wt) human LIAS. The strain that expressed the E. coli wild-type lipA grew at a rate similar to that expressing the wild-type human LIAS, whereas there was no growth with the empty vector (vector). Fast growth was observed with all constructs on the same medium when supplemented with 1 ng/l lipoic acid (B and D).
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References

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