Biallelic Variants in SLC27A3 Cause a Complex Form of Neurodegeneration with Brain Iron Accumulation

Background Complex lipid metabolism is one of the main biological pathways disrupted in neurodegeneration with brain iron accumulation (NBIA). SLC27A3 gene encodes for the very long‐chain acyl‐CoA synthetase 3, an acyl‐CoA ligase that activates long and very long‐chain fatty acids. Objective We report on a 19‐year‐old patient with an NBIA pattern harboring a homozygous, nonsense SLC27A3 variant. Methods SLC27A3 variants were identified using whole exome sequencing (WES). Their impact on protein function was assessed in patient fibroblasts using Western blot analysis, aerobic metabolism analysis, and fatty acid trafficking assays. Results The patient presented with progressive ataxia, neuropathy, optic atrophy, cognitive deterioration, mood disorder, and brain iron accumulation. WES unraveled the homozygous c.1138C>T, p.(Arg380Ter) variant in the SLC27A3 gene. Functional studies showed that proband's variants eliminate protein expression, severely impair mitochondrial respiration, and disrupt lipid turnover. Conclusion Our results suggest that SLC27A3 biallelic nonsense variant may represent a novel cause of NBIA.