LIPT1 deficiency presenting as early infantile epileptic encephalopathy, Leigh disease, and secondary pyruvate dehydrogenase complex deficiency

Abstract

Lipoic acid is an essential cofactor for the mitochondrial 2-ketoacid dehydrogenase complexes and the glycine cleavage system. Lipoyltransferase 1 catalyzes the covalent attachment of lipoate to these enzyme systems. Pathogenic variants in LIPT1 gene have recently been described in four patients from three families, commonly presenting with severe lactic acidosis resulting in neonatal death and/or poor neurocognitive outcomes. We report a 2-month-old male with severe lactic acidosis, refractory status epilepticus, and brain imaging suggestive of Leigh disease. Exome sequencing implicated compound heterozygous LIPT1 pathogenic variants. We describe the fifth case of LIPT1 deficiency, whose phenotype progressed to that of an early infantile epileptic encephalopathy, which is novel compared to previously described patients whom we will review. Due to the significant biochemical and phenotypic overlap that LIPT1 deficiency and mitochondrial energy cofactor disorders have with pyruvate dehydrogenase deficiency and/or nonketotic hyperglycinemia, they are and have been presumptively under-diagnosed without exome sequencing.

Functional Assessment of Lipoyltransferase-1 Deficiency in Cells, Mice, and Humans

“…All patients had prominent metabolic acidosis and neurologic involvement, with three dying in the neonatal period. Elevated glutamate and proline levels were reported in two children (Soreze et al, 2013;Stowe et al, 2018). In agreement with our patient's phenotype, glycine levels were normal when reported.…”

“…Our analysis of LIPT1 deficiency suggests that broad metabolomic profiling can help prioritize genetic variants for functional analysis. LIPT1 mutations have been observed in a few previous reports of children with lactic acidosis (Soreze et al, 2013;Stowe et al, 2018;Taché et al, 2016;Tort et al, 2014). All patients had prominent metabolic acidosis and neurologic involvement, with three dying in the neonatal period.…”

Molecular basis of Leigh syndrome: a current look

“…Its deficiency produces metabolic acidosis due to hyperlactacidemia, normal/elevated branched-chain amino acids and glycine levels in serum and/or CSF. Reposition of lipoic acid is not effective, restricting specific treatment options [65].…”

Progress in the Enzymology of the Mitochondrial Diseases of Lipoic Acid Requiring Enzymes

“…The loss of these two dehydrogenases short-circuits the citric acid cycle, resulting in severe respiratory deficiency and extreme muscle weakness (Mayr et al, 2014;Tort et al, 2016). Lack of glycine cleavage activity additionally results in elevated brain glycine levels which can result in a host of neurological disorders, including neurodegeneration, encephalopathy, and neonatal-onset epilepsy (Mayr et al, 2014;Tort et al, 2016;Stowe et al, 2018). In general, the first indicator of defective lipoic acid metabolism is the presence of very high levels of lactate (resulting from reduction of the pyruvate that accumulates due to loss pyruvate dehydrogenase activity) in urine and other bodily fluids.…”