Biallelic Variants in LIPT2 as a Cause of Infantile-Onset Dystonia: Expanding the Clinical and Molecular Spectrum.

Background: Lipoyl transferase 2 is involved in the biosynthesis of lipoate. Lipoate is the cofactor for the glycine cleavage system and four dehydrogenase enzymes. Biallelic variants in LIPT2 causing severe neonatal encephalopathy was first described in 2017.

Methods: Clinical data were collected by retrospective chart review after obtaining consent from parents. The pathogenicity of these variants was further delineated using a yeast model. The YEp352-LIPT2 plasmid was used as a template to generate the two patient variants using QuickChange Lightning Site-Directed Mutagenesis Kit.

Results: The patient was a 15-month-old female who presented at one month with dystonia, developmental delay, and feeding difficulties. Brain magnetic resonance imaging showed cortical malformations including colpocephaly, polymicrogyria, and heterotopia. Patient had elevations in lactate (6.1 mmol/L) and glycine. Exome sequencing showed two variants of uncertain significance in trans in the LIPT2 gene: c.346 G>T and c.418C>T. Patient was started on lipoic acid, thiamine, and COQ10. Yeast complementation experiments indicate that both patient mutant variants result in diminished function versions of the LIPT2 protein.

Conclusion: We report the fourth case of LIPT2-related disorder. Proband shared significant overlap with previous patients; however, there was a distinct movement disorder and brain malformations, which have not been previously described. Unlike most neurometabolic disorders where dystonia develops later after metabolic stroke in basal ganglia, LIPT2-related disorder seems unique due to early onset of dystonia due to energy deficit in the developing brain. Lipoic acid supplementation has not led to significant clinical improvement. Analyses in yeast indicate that novel variants are deleterious but have retained some functionality.