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)P) 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.