Objective: To report a novel VAC14 variant linked to levodopa-responsive dystonia.

Background: VAC14 is essential for membrane trafficking, endosomal maturation and autophagy. Bi-allelic pathogenic variants cause Yunis-Varón syndrome, a severe congenital disorder, as well as childhood and juvenile onset striatonigral degeneration, which usually presents with abrupt-onset of dystonia-parkinsonism associated with progressive motor and language regression.

Method: We report a 24-year-old man with progressive generalized dystonia carrying a novel homozygous variant in VAC14. Brain MRI, DAT SPECT and genetic analysis were performed. Functional studies are ongoing in patient derived fibroblasts.

Results: Symptoms began at age 13 in the right lower limb and gradually involved the contralateral side and cervical region, remaining stable over the last 3–4 years. Examination showed a “yes-yes” head dystonic tremor, severe bilateral lower limb dystonia with milder trunk involvement, and intermittent rest dystonic tremor of the right upper. Symptoms improved with levodopa (1200 mg/die) and baclofen. Brain MRI showed pallidal T2 hypointensity; DaT SPECT was normal. Whole genome sequencing identified a homozygous c.1339C>G (p.L447V) VAC14 variant of unknown clinical significance, maternally inherited. The variant lies within a region of absence of heterozygosity on chromosome 16, suggesting uniparental disomy. The variant affects a conserved residue in the HEAT repeat 5 domain, is absent from population databases, and predicted deleterious (CADD Phred 23.6). Functional studies to assess possible cellular vacuolization, autophagy, and endolysosomal function are ongoing to confirm the variant’s pathogenicity.

Conclusion: To date, 25 cases of VAC14-related disorders have been reported, usually presenting with severe progressive neurodegeneration and basal ganglia MRI abnormalities. We describe a patient carrying a novel missense variant and presenting with a mild, non-regressive phenotype, associated with levodopa responsiveness. Notably, while most pathogenic variants cluster within the FIG4-binding domain, p.L447V lies in the HEAT repeat 5 domain, a similar location to that of other variants reported in another case with a milder dystonic phenotype. This case broadens the phenotypic spectrum of VAC14-related disorders and suggests that variant location may influence disease severity.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-novel-vac14-variant-associated-with-levodopa-responsive-generalized-dystonia/