Expanding the Phenotypic Horizon of VAC14 ‐Related Neurodegeneration

VAC14‐related neurodegeneration, characterized by lower‐limb onset dystonia, parkinsonism, and spasticity, is an increasingly recognized disorder within the Neurodegeneration with Brain Iron Accumulation (NBIA) group. ¹ We report two unrelated children with VAC14 variants presenting with intriguing phenomenology.

A 16‐year‐old Asian boy, born to third‐degree consanguineous parents, presented with gait difficulties starting with toe walking at 13 years, which gradually worsened, rendering him nonambulatory by the time of presentation. A progressive slowness in activities of daily living was also noted by his parents. There was no history of cognitive decline, seizures, vision or hearing impairment. On examination, he exhibited spastic diplegia with hamstring and tendoachilles contractures, parkinsonism (bradykinesia, facial hypomimia), spastic dysarthria, and a Mini‐Mental State Examination score of 26/30 (Video 1, segments A and B). Small‐amplitude, high‐frequency, quasirhythmic, jerky movements of the eyelids, jaw and lips were appreciated during eye and jaw closure, suggestive of action‐induced myoclonus (Video 1, segment C). Magnetic resonance imaging (MRI) brain showed T2 hyperintensities in striatum and T2 hypointensity with blooming in globus pallidi (anteroposterior gradient) and substantia nigra (Fig. 1). The initial differentials considered were NBIA disorders, likely Kufor‐Rakeb disease, COASY or PLA2G6‐associated neurodegeneration. Other investigations, including fundus and brainstem auditory evoked response, were unremarkable. Whole‐exome sequencing (WES) demonstrated a homozygous missense variant (c.1685C>T, p.Ala562Val) in exon 15 of the VAC14 (NM_018052.5) gene. The variant was likely pathogenic (PS3 [functional studies supportive of a damaging effect] + PM2 [extremely low frequency in controls]) as per the American College of Medical Genetics and Genomics (ACMG) criteria. ¹ The patient did not respond to levodopa and was initiated on supportive care with neurorehabilitation.

Video 1.

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Segment A—facial hypomimia with bradykinesia. Segment B—spastic dysarthria. Segment C—small‐amplitude, high‐frequency, quasirhythmic, jerky movements of the eyelids, jaw, and lips during eye and jaw closure, suggestive of action‐induced myoclonus.

Fig. 1.

Upper panel—magnetic resonance imaging (MRI) brain of case 1 (A–D) showing bilateral T2 striatal hyperintensities (A—yellow arrows), T2 hypointensity (blue arrows) in globus pallidus (A) and substantia nigra (B) with increased susceptibility (C—red arrows) on susceptibility weighted imaging (SWI), consistent with iron accumulation. Also note the ventriculomegaly (D). Middle panel—MRI brain of case 2 (E–H) showing bilateral T2 striatal hyperintensities (E—yellow arrows) with T2 hypointensity (blue arrows) in globus pallidus (F) and substantia nigra (G). Subtle white matter signal changes were also noted in bilateral centrum semiovale (H). Lower panel—pedigrees of case 1 and case 2.

Another 8‐year‐old Asian girl, born to second‐degree consanguineous parents with normal premorbid development, presented with gait difficulties characterized by toe walking and a progressively worsening forward‐stooped posture, starting at 2 years of age. By the age of 4 years, she developed slurring of speech, difficulty swallowing liquids, and trouble chewing food. There was no history of cognitive decline, seizures, vision or hearing impairment. Examination showed spastic diplegia with biceps, hamstrings, and tendoachilles contractures, foot dystonia, parkinsonism (facial hypomimia, hypokinesia, postural instability), and bulbar dysfunction (hypersalivation, dysarthria, dysphagia), whereas her cognitive abilities were relatively preserved (Video 2, segment A). Her gait was notable for truncal flexion dystonia accompanied by flexed, knock knees, and toe walking (Video 2, segments B and C). MRI brain demonstrated T2 hyperintensities in striatum and T2 hypointensity with increased susceptibility in anterior globus pallidi and substantia nigra (Fig. 1). Fundoscopy and audiological evaluation were noncontributory. Although camptocormia was the predominant phenotype in this case, our experience with the previous case exhibiting analogous MRI findings, amid a backdrop of spasticity‐parkinsonism, helped us narrow the differentials to VAC14. The child showed no response to levodopa and was managed with trihexyphenidyl and baclofen. WES identified a novel homozygous missense variant (c.2260C>G, p.His754Asp) in exon 19 of the VAC14 (NM_018052.5) gene. Segregation analysis identified heterozygous states in both parents. The variant was classified as a variant of uncertain significance (VUS) (PM2 [extremely low frequency in controls] + PP3 [damaging in silico predictions]) as per ACMG criteria.

Video 2.

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Segment A—facial hypomimia with hypokinesia. Segments B and C—truncal dystonia (dystonic emprosthotonus) with mixed dystonic‐spastic gait.

The VAC14 gene encodes a homodimeric scaffold protein that interacts with PIKFYVE (lipid kinase) and FIG4 (lipid phosphatase), forming a ternary complex, which regulates the turnover of signaling lipid phosphatidylinositol 3,5‐bisphosphate (PI[3,5]P2) within the endolysosomal membrane system. ¹ Altered PI(3,5)P2 levels can disrupt diverse cellular processes, including membrane trafficking, autophagy, and generation of intracellular transport vesicles through membrane fission/fusion. ² , ³

The phenotypic spectrum of VAC14‐related neurodegeneration encompasses juvenile‐onset dystonia‐parkinsonism, childhood‐onset striatonigral degeneration, and infantile‐onset Yunis‐Varon syndrome. ⁴ Both of our cases had variable age of onset, one in toddler years and the other in adolescence, but shared the common features of progressive spastic diplegia and parkinsonism. Baumann et al. highlighted that lower‐limb onset dystonia at a young age, with frequent speech involvement and spasticity, is the red flag for VAC14‐related disorders. ¹ However, our first case exhibited a novel finding of action‐induced eyelid and jaw myoclonus, mimicking Kufor‐Rakeb disease. Other clinical differentials considered for this phenomenology were facial myokymia and tremor. Interestingly, our second case with an early‐onset emprosthotonic posture with mixed dystonic‐spastic gait was also a unique observation. Notably, Bhowmick et al. reported dystonic opisthotonus in an adolescent girl with biallelic VAC14 variants, initially misdiagnosed as psychogenic. ⁵ Our cases did not exhibit the abrupt onset and rapid progression reported in early‐onset VAC14 cases. ⁶ Although our second patient had a missense homozygous VUS, the phenotypic overlap with the published cases, radiologic similarities, consanguineous parentage, and predictive in silico tools, all add to the evidence of this mutant allele. ¹ , ³ , ⁴ , ⁵ , ⁶ , ⁷

In VAC14, the presence of additional striatal hyperintensities with a characteristic susceptibility pattern (anteroposterior gradient) in globus pallidi could serve as a diagnostic clue for the clinicians. ⁸ COASY protein‐associated neurodegeneration (CoPAN) is the closest radiologic mimic of VAC14, with key differentiating points including T2 thalamic hyperintensities and marked diffusion restriction of deep gray matter structures in CoPAN.

Although treatment remains largely supportive, with no significant response to levodopa or anticholinergic medications, globus pallidus internus (GPi) deep brain stimulation led to substantial improvement at 6 months in an adolescent girl with dystonia‐parkinsonism phenotype. ³

In conclusion, we described two novel phenomenologies, action‐induced facial myoclonus and dystonic emprosthotonus, expanding the phenotypic spectrum of VAC14‐related neurodegeneration.

Author Roles

1. Research project: A. Conception, B. Organization, C. Execution.

2. Manuscript preparation: A. Writing of the first draft, B. Review and critique.

S.R.C.: 1A, 1B, 1C, 2A.

T.S.: 1B, 1C, 2A.

R.M.: 1B, 1C.

J.G.: 1A, 2B.

S.S.: 1A, 2B.

Disclosure

Ethical Compliance Statement: The authors confirm that the approval of an institutional review board/patient consent was not required for this work. We also confirm that the patient has given written informed consent for the publication of his video. 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: The authors declare that there are no conflicts of interest or funding relevant to this work.

Financial Disclosures for the previous 12 months: The authors declare that there are no additional disclosures to report.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.