Early Onset Dystonia, Parkinsonism, and Spasticity in Siblings with <scp> <i>VAC14</i> </scp> ‐Associated Neurodegeneration: A Case Report and Literature Review

The scaffold protein VAC14 complexes with PIKFYVE and FIG4, and regulates the biosynthesis of phosphatidylinositol 3,5-bisphosphate, a phosphoinositide essential for intracellular vesicle trafficking within the endolysosomal pathway.1 Children with VAC14 gene variants typically experience childhood onset striatonigral degeneration (OMIM #617054) without a significant prior developmental delay. Here, we describe the clinical phenotype, imaging findings and genotype of siblings with biallelic compound heterozygous variants in VAC14 gene. Patient 1: A seven-year-old boy, presented to neurology clinic at 2 years of age for the evaluation of gait instability and toe-walking. Born at 36 weeks of gestation due to maternal preeclampsia, he experienced neonatal jaundice that was managed with phototherapy. He had feeding difficulties throughout infancy and early childhood. He walked at 15 months with a clumsy gait, could not use cutlery, and had an expressive language delay. He developed progressive spasticity and dystonia around 2 years of age. His mobility progressively declined with a need for wheelchair assistance from 4 years of age. At age 7, he was non-verbal because of anarthria and received gastrostomy tube feeding due to persistent drooling and swallowing difficulties. Anthropometry and neurological assessment revealed normocephaly, normal fundus, hypomimia, bradykinesia, oromandibular, cervical and limbs dystonia, spastic paraparesis, hyperreflexia and extensor plantar responses. Video 1 shows parkinsonism features with scissoring gait and toe walking due to severe foot dystonia. Brain MRI (Fig. 1A–D) revealed T2 hyperintensities in the bilateral ventral medulla, thalami and globus pallidi with mineralization on susceptibility-weighted images (SWI). Younger sibling of patient 1, was brought for the evaluation of toe walking from 18 months of age. He was born at 36 weeks due to maternal preeclampsia and his early development was normal until 18 months when he began to exhibit frequent falls, toe walking, and speech delay. Global developmental delay was observed from 2 years of age; however, his cognitive skills were relatively preserved. He developed progressive spasticity, dystonia, sialorrhea, and dysphagia, necessitating the placement of a gastrostomy tube for nutritional support. His facial features and neurological assessment findings resembled his sibling (Video 2) and his neuroimaging findings were identical to his sibling. Molecular testing identified a maternally inherited likely pathogenic variant seq[GRCh37] del(16)(q22.1), chr16:g.70680744_70778584del encompassing exons 13–19 of VAC14 and a paternally inherited missense variant of uncertain significance c.542G>A (p.Arg181Gln) in the exon 5 of VAC14 gene (NM_018052.3). The VAC14 gene is an excellent phenotypic fit for the clinical presentation of our patients. Therefore, the variant c.542G>A has been reclassified as likely pathogenic (PP4, PM3, PM2, PP3). Targeted genetic testing in the sibling also revealed same biallelic variants in VAC14 gene. The siblings were managed with baclofen, trihexiphenidyl, gabapentin, botulinum toxin injections, orthotic devices, and physical therapy following which a minimal response was observed. Pathogenic variants in VAC14 gene results in childhood-onset striatonigral degeneration.1, 2 To date, there are 18 reported cases of VAC14-associated neurodegeneration from 14 distinct families (Table S1). The typical clinical course includes normal early development followed by regression of motor milestones from around 2 years of age. The onset of regression of motor skills is marked by toe-walking, followed by generalized dystonia, and, in some cases, associated parkinsonism and spasticity. One of our patients had mild delay in motor milestones while his younger sibling had normal motor milestones until 18 months of age. Expressive language delay related to anarthria was observed in both siblings. Infantile-onset developmental delay has been reported previously.3-5 Although onset of symptoms in childhood is typical, three patients had onset of symptoms from adolescence.6-8 Additional reported symptoms include dysarthria, dysphagia, sensorineural hearing loss, and sialorrhea. Most patients have preserved cognitive function. Individuals with nonsense or truncating variants in a compound heterozygous state with a missense variant have been reported previously.2, 9 The typical age at onset in these individuals ranged from birth to 3.5y and the phenotypic severity varied from Yunis-Varon syndrome to generalized dystonia and Parkinsonism with regression of developmental skills. Rapid progression and death were reported in siblings with compound heterozygous variants c.1271 G>T (p.Trp424Leu) and c.1096 + 1 G>C in VAC14 gene.2 Vac-14 null mice was found to have a severe phenotype with perinatal-lethal vacuolar degeneration in contrast to mice model with Vac-14 recessive substitution.9 Our patients have a deletion on chromosome 16 which encompasses the 3′ end of the VAC14 gene, including exons 13–19 and would be predicted to undergo nonsense mediated decay. However, functional studies were not performed for confirmation. Interestingly, our patients have symmetric signal changes involving bilateral ventral medulla, globus pallidi and thalami, a finding that has not been frequently reported. Faint mineralization was seen in the bilateral globus pallidi. Thalamic volume loss and brainstem signal changes have been described previously.4, 10 “Comet tail sign,” a pattern of iron accumulation reported previously was not observed in our patients.7 Though the exact mechanisms are not fully understood, it may be related to disrupted iron homeostasis in basal ganglia structures where VAC14 is expressed or due to dysfunctional autophagy. In summary, patients with VAC14-associated striatonigral degeneration typically have disease onset in early childhood with regression of motor skills, relative preservation of cognition and progressive extrapyramidal symptoms. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. RL: 1A, 1B, 1C, 3A SY: 1A, 1B, 1C, 3A WKL: 1C, 3B PK: 1C, 3B AD: 1C, 3B SV: 1C, 3B JR: 1C, 3B SB: 1C, 3B NSYL: AF: 1C, 3B GMI: 1C, 3B CG: 1A, 1B, 1C, 3B RL and SY drafted the initial manuscript. PK prepared the neuroimages. WKL, AD, SV, JR, SB, NL, AF, GMI, and CG revised the manuscript. All authors reviewed and approved the final manuscript. Ethical Compliance Statement: The institutional review board or ethics committee approval was not necessary for this report. Declaration of patient consent: Informed written consent was obtained from the parent. Affirmation that all authors have read and complied with the Journal's Ethical Publication Guidelines: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflict of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: AD has received personal compensation for serving as an Expert Witness for the CMPA, Integra and Connect Care. AF has stock ownership in Inbrain Pharma and has received payments as consultant and/or speaker from Abbvie, Abbott, Boston Scientific, Ceregate, Dompé Farmaceutici, Inbrain Neuroelectronics, Ipsen, Medtronic, Iota, Syneos Health, Merz, Sunovion, Paladin Labs, UCB, Sunovion. He received research support from Abbvie, Boston Scientific, Medtronic, Praxis, ES and receives royalties from Springer. GMI is an advisory board member in Synergia, consultant in LivaNova, Medtronic and Synergia and advisory board member in Pediatric Epilepsy Surgery Alliance. CG received consulting fees from Medtronic Inc and Ipsen, participated as an advisor on the advisory board meetings Medtronic Inc. The data that support the findings of this study are available from the corresponding author upon reasonable request. Supplemental TABLE S1. Summary of phenotype, imaging findings and genotype in patients with variants in VAC14 gene Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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