Lipoic acid is an essential prosthetic group of four mitochondrial enzymes involved in the oxidative decarboxylation of pyruvate, alpha-ketoglutarate, and branched chain amino acids and in the glycine cleavage.
It is synthesized stepwise within mitochondria through a process that includes lipoic acid synthetase. Lipoic acid synthetase deficiency is caused by mutations in the LIAS gene (= HGCLAS, HUSSY-01, LAS, LIP1, LS, PDHLD) and is the reason for symptoms like neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation.
Pyruvate dehydrogenase lipoic acid synthetase deficiency is an autosomal recessive disorder of mitochondrial metabolism characterized by early-onset lactic acidosis, severe encephalomyopathy, and a pyruvate oxidation defect (Mayr et al., 2011).
Mayr et al. (2011) reported a boy, born of consanguineous Turkish parents, with a severe metabolic disorder resulting in death at age 4 years. He developed seizures on day 3 of life, and showed hypotonia and poor sucking. ... Mayr et al. (2011) reported a boy, born of consanguineous Turkish parents, with a severe metabolic disorder resulting in death at age 4 years. He developed seizures on day 3 of life, and showed hypotonia and poor sucking. His condition worsened, and he developed recurrent apneas and reduced consciousness associated with increased serum lactate. On day 11 of life, he had further metabolic deterioration, with acute respiratory deficiency necessitating artificial ventilation for 17 days; chest radiographs showed an infiltration of the lungs. Initial brain imaging had been normal, but he developed severe brain edema at this time. Urinalysis showed increased glutaric acid and glycine, and plasma glycine was also increased. Brain sonography showed multicystic encephalopathy and hydrocephalus ex vacuo, which was likely secondary to the metabolic crisis. Echocardiography showed a mild hypertrophic cardiomyopathy. After this episode, the child had severely retarded psychomotor development, contractures, spastic tetraparesis, epilepsy, microcephaly, sleep disturbances, and intermittently increased serum lactate. He died at home from a respiratory tract infection.
By autozygosity mapping followed by candidate gene analysis of a boy with early-onset lactic acidosis and encephalopathy, Mayr et al. (2011) identified a homozygous mutation in the LIAS gene (607031.0001).