Altered homodimer formation and increased iron accumulation in VAC14-related disease: Case report and review of the literature.

BACKGROUND Pathogenic variants in the VAC14 component of PIKFYVE complex (VAC14) gene have been identified as a cause of a childhood-onset complex dystonia with striato-nigral degeneration. VAC14 is a scaffold protein relevant for the regulation of phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) and is known to form homodimers. METHODS Whole exome sequencing was performed in a 32-year-old patient with adolescence-onset complex dystonia and his unaffected mother. We established primary fibroblast cultures from the patient and used stably transfected SH-SY5Y cells overexpressing wildtype or mutant VAC14 to investigate the influence of VAC14 variants on the homodimer formation. Furthermore, the current literature on VAC14-related disorders was reviewed. RESULTS Our patient presented with progressive, complex dystonia with anarthria, dysphagia, sensorineural deafness, spasticity and nigral and pallidal iron deposition and striatal hyperintensities upon MRI. We identified two rare compound-heterozygous VAC14 variants (p.Leu648Phe and p.Arg623His), both located at the C-terminus in the predicted homodimerization domain. Enhanced VAC14 homodimer formation was observed for two missense variants (p.Leu648Phe and p.Ala562Val, a published mutation), but not for p.Arg623His, compared to wildtype VAC14. In contrast to previous reports, no enlarged vacuoles were detected in fibroblasts of our patient. CONCLUSIONS We report a novel patient with a VAC14-related disorder and provide first evidence of an enhanced VAC14 homodimerization as a possible disease mechanism. Due to the increased iron deposition and the clinical overlap, this disorder should be discussed as a new form of neurodegeneration with brain iron accumulation (NBIA). We suggest that VAC14 should be implemented in NBIA gene panels.