Abstracts

Rationale: Lipoyltransferase 1 (LIPT1) deficiency is an exceedingly rare disorder that results in impaired attachment of lipoic acid to pyruvate dehydrogenase complex (PDHc) and other 2-oxoacid dehydrogenases, thus affecting key enzymatic processes in energy and amino acid metabolism. Only two cases of LIPT1 deficiency have been reported in the literature. We report a case of a 2-month old infant who presented with severe lactic acidosis and refractory status epilepticus that was successfully treated with the ketogenic diet. Whole exome sequencing implicates a genetic defect in LIPT1. Methods: A 2-month-old, full-term, male of reportedly normal development and a history of a previous hospitalization for severe dehydration and hypernatremia at one week of life presented to the intensive care unit with acute-on-chronic worsening of emesis, dehydration, severe lactic acidemia, and episodes of tonic posturing and bicycling concerning for seizures. Lactic acidemia persisted (values > 10mmol/L, normal 0.2 - 1.7mmol/L) despite adequate hydration suggestive of a mitochondrial metabolic disorder such as PDHc deficiency. Ammonia was normal. Pyruvate was elevated (0.710mmol/L, normal 0.030 - 0.107mmol/L). Plasma amino acids showed mildly elevated glutamate, proline, and alanine. Urine organic acids showed elevated succinic acid, fumaric acid, and 2-hydroxy glutaric acid. Brain MRI demonstrated diffusion restriction in multiple cortical regions and lateral basal ganglia. MR spectroscopy demonstrated a characteristic lactate peak at 1.3ppm. Continuous EEG revealed multifocal spike activity propagating into frequent, prolonged electrographic seizures. The antiepileptic regimen was aggressively up titrated to include levetiracetam, phenobarbital, fosphenytoin, and midazolam infusion with limited effect. The patient progressed to refractory electrographic status epilepticus. The ketogenic diet with lipoic acid supplementation was started and, as ketosis was attained, seizure control improved and antiepileptic drugs were successfully weaned. Results: Critical trio whole exome sequencing demonstrated a likely pathogenic variant in the LIPT1 gene (c.212C>T (p.S71F)) that was heterozygous in the father. Another heterozygous variant of unknown significance in LIPT1 (c.539T>C(p.L180S)) was also identified and was heterozygous in the mother. These two changes are in trans configuration, suggesting a compound heterozygous deleterious change. Conclusions: LIPT1 is responsible for the transfer of lipoic acid residues onto 2-oxoacid dehydrogenases, thus genetic defects may present similarly to PDHc deficiency and respond to similar treatment. Therapeutic interventions are limited to symptomatic treatment, e.g. antiepileptic medications, which do not address the underlying pathophysiology and, as evidenced in our patient, may be of limited efficacy. In our patient, ketogenic diet resulted in marked improvement in seizures and modest improvement in neurocognitive functioning. This case expands the phenotypic and genetic spectrum of LIPT1 deficiency, highlights the clinical utility of critical whole exome sequencing, and demonstrates the therapeutic utility of ketogenic diet for this rare disorder. Funding: None