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VAC14 Gene‐Related Parkinsonism‐Dystonia With Response to Deep Brain Stimulation

The patient was born in a Middle Eastern country from consanguineous parents. Her past medical and family histories were unremarkable. At 12 years of age, she developed focal dystonia of her left hand, which generalized over 2.5 years (Video 1). She developed bradykinesia and freezing of gait, with intact cognition. Medical treatment was ineffective. MRI of the brain demonstrated restricted diffusion of the bilateral corpus striatum, and T2 hypointensity with increased susceptibility of the globus pallidus and SN consistent with abnormal mineralization (Fig. 1). A clinically available gene panel evaluating diseases in the spectrum of neurodegeneration with brain iron accumulation (NBIA) was nondiagnostic. A chromosomal microarray returned with a duplication at 16p13.11 and multiple areas of homozygosity comprising 3% of the genome. The duplication was thought to be an incidental finding, given mismatch between patient and typical phenotype. Upon reviewing the areas of homozygosity, the VAC14 gene stood out as a potential candidate based on previous reports. Sequencing of the VAC14 gene identified a homozygous missense variant of unknown significance (p.Lys651Glu, c.1951A > G). The variant has not been previously described in publicly available databases (gnomAD, Exome Variant Server, or 1000 Genomes) and involves a highly conserved amino acid in the protein C-terminal dimerization domain, where previous pathogenic mutations have been located. The alteration is nonconservative from a positively charged amino acid to a negatively charged one. In-silico analysis with Mutation Taster predicted it to be disease causing, but Align GVGD and SIFT predicted the variant to be benign and tolerated. The patient’s skin fibroblasts were analyzed for abnormal endolysosomal morphology, associated with loss of VAC14 function. Patient cells as well as control human fibroblasts were cultured at equal density in full media for 24 hours. Fields of the cells were imaged and scored for the presence of visible perinuclear vacuoles. Cell culture experiments using primary fibroblasts were carried out. Briefly, all images were live cells captured using a Leica DMIRB inverted fluorescence microscope (Leica Microsystems, Wetzlar, Germany). Transfections were carried out using Liofectamine 3000 (Thermo Fisher Scientific, Waltham, MA). The patient’s fibroblasts demonstrated evidence of abnormal vacuolization in 76 2% of cells. In a second experiment, normal VAC14 transfected into patient cells rescued the vacuoles, whereas green fluorescent protein (GFP) alone did not (Fig. 2). At 15 years old, the patient underwent GPi-DBS, based on literature supporting benefit of pallidal stimulation in early-onset dystonia and brain iron accumulation syndromes. On initial examination, she had fluctuating tone without rigidity, 1+ hypomimia, 3+ symmetric bradykinesia, and generalized dystonia. There was no resting, postural, or kinetic tremor. She endorsed fatigue, constipation, and joint pain. There was no cognitive change, dysautonomia or rapid eye movement sleep behavior disturbance. After 6 months of DBS, there was improvement in facial animation, 2+ bradykinesia, and recovery of ambulatory capacity. She required five steps to recover from the pull test, with spontaneous retropulsion. Freezing of gait was noted upon turns. Dystonia was much improved.