# Novel VAC14 Variants Identified in a Patient with Striatonigral Degeneration and Prolonged Survival

Silvestre Cuinat, Christèle Dubourg, Gaël Nicolas, Jean-Madeleine de Sainte

Agathe, Sylvie Odent, Laurent Pasquier, Audrey Riou

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Silvestre Cuinat, Christèle Dubourg, Gaël Nicolas, Jean-Madeleine de Sainte Agathe, Sylvie Odent, et al.. Novel VAC14 Variants Identified in a Patient with Striatonigral Degeneration and Prolonged Survival. Movement Disorders Clinical Practice, 2025, 10.1002/mdc3.70152. hal-05097906

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# Novel VAC14 Variants Identified in a Patient with Striatonigral Degeneration and Prolonged Survival

Silvestre Cuinat, MD,<fnref n="1" />,* Christèle Dubourg, MD, PhD,²,³ Gaël Nicolas, MD, PhD,⁴,⁵ Jean-Madeleine de Sainte Agathe, MD,⁵,⁶

Sylvie Odent, MD, PhD,<fnref n="1" />,³,⁷ Laurent Pasquier, MD, PhD,<fnref n="1" />,⁷ and Audrey Riou, MD<fnref n="1" />,⁸

Neurodegeneration with Brain Iron Accumulation (NBIA, [MIM:PS234200]) are Mendelian disorders, associated with excessive iron deposition in the brain, particularly in globi pallidi, with extrapyramidal, pyramidal, cognitive, psychiatric symptoms, and early death. To date, >10 genes are associated with NBIA.

Recently, biallelic pathogenic variants in *VAC14* were reported in children with striatonigral degeneration<fnref n="1" /> and NBIA.² Since then, 17 patients from 13 different families have been identified.<fnref n="1" />⁻⁸

We report here a 37-year-old patient with rapid striatonigral degeneration, which started at the age of 2 years, followed by a clinical stabilization, while his sister died at 20 from the same disease. We identified two novel variants in *VAC14* by trio-based genome sequencing.

A 37-year-old (y.o) male, second child born from unrelated parents with unremarkable family history, had a normal initial neurodevelopment. He presented with ambulation difficulties from age 2, walking on his toes, then quickly lost his ability to walk and speak. At 14 y.o, he suffered from severe motor disability requiring an electric wheelchair. Neurological examination showed tetraspasticity, extrapyramidal hypertonia, generalized dystonia, but preserved cognition. Dysphagia required a gastrostomy tube. Increased auditory evoked potentials suggested brainstem involvement. At 37, his condition appeared to have been stable for several years (Fig. 1A–C). He could read and communicate through a computer. He developed vertical gaze palsy. At 14 y.o, brain MRI suggested bilateral abnormalities of medial globi pallidi (GPm) and striatum. At 20 and 33 y.o, these abnormalities were evident, with cerebral peduncles and putamen T2-FLAIR hyperintensities, GPm T2-FLAIR hypointensities, and pallidal T₂*

hypointensity suggesting metal deposits. The ventricles were slightly enlarged, associated with cortico-subcortical, cerebellar and putaminal atrophy, with a slight evolution over the past 17 years (Fig. 1D–M).

His sister had a similar history. After an initially normal neurodevelopment, she also presented with progressive spastic paraparesis, followed by language regression. At the age of 7, she lost her ability to speak. Her intellectual functions were preserved. She died at 20, following inhalation pneumopathy.

After a negative exome sequencing, genome sequencing was performed on the proband and his unaffected parents (Supplemental Methods). Two *VAC14* (NM_018052.5) variants in compound heterozygous state were identified: chr16(GRCh38):70698720T>C c.1753A>G p.(Met585Val) inherited from the father, and chr16 (GRCh38):70698834T>C c.1662-23A>G p.? inherited from the mother, both rare in general population (1 and 0 individuals in gnomADv4.1.0, respectively). The p.(Met585Val) missense variant was predicted as deleterious (REVEL = 0.48; CADD = 23). The intronic variant c.1662-23A>G was predicted to disrupt the nearby 3'splice site of intron 14 (SpliceAI), as confirmed by a *VAC14* transcript analysis: RT-PCR revealed an intronic retention of the last 143-nucleotides of intron 14 (r.1662-143_1662-1) resulting in a frameshift p.Arg554Serfs*55 and supporting a loss-of-function effect. Both variants have therefore been reclassified as likely pathogenic.

Thus, the two siblings had a *VAC14*-related neurodegeneration manifested by early motor and language regression with progressive spastic tetraparesis, and absence of intellectual impairment. While the elder sister died at 20 y.o, the proband aged 37 is the oldest patient reported to date, with a

<footnote n="1">¹Service de Génétique Clinique, CRMR anomalies du développement CLAD-Ouest, CRDI (Centre de Référence Déficiences Intellectuelles de Causes Rares), CHU Rennes, Rennes, France; ²Laboratoire de Génétique Moléculaire, Hôpital Pontchailou, CHU Rennes, Rennes, France; ³CNRS, INSERM UMR 6290, ERL U1305, F-35000, Université de Rennes, IGDR, Rennes, France; ⁴Department of Genetics, Univ Rouen Normandie, Normandie Univ, Inserm U1245 and CHU Rouen, Rouen, France; ⁵LBM SeqOIA, Paris, France; ⁶Département de Génétique Médicale, Hôpital Pitié-Salpêtrière, AP-HP, Sorbonne Université, Paris, France; ⁷FHU GenOMedS, ERN ITHACA, CHU Rennes, Rennes, France; ⁸Service de Neurologie, CHU Rennes, Rennes, France</footnote>

<footnote>*Correspondence to: Silvestre Cuinat, Centre de Recherche en Neurosciences de Lyon, 95 Bd Pinel, 69,500 Bron, France; E-mail: silvestre.cuinat@inserm.fr</footnote>

<footnote>**Keywords:** dystonia, neurodegeneration with brain iron accumulation, spastic tetraplegia, striatonigral degeneration, *VAC14*. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Received 20 February 2025; revised 2 May 2025; accepted 9 May 2025.
Published online 00 Month 2025 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mdc3.70152</footnote>
<figure><img src="image_3.png" /><figcaption>**Figure 1.** Clinical and radiological features of the proband. (A–C) Pictures of the proband at 37 years of age. Note orofacial dystonia resulting in a chronic subluxation of the jaw (A, B), high forehead, bitemporal narrowing, thin upper lip, hypoplastic nasal wings, slightly low-set ears (B), severe hyperflexion of the wrists, mallet fingers (C). (D–M) Brain MRI of the patient at the age of 20 (D–H) and 37 years (I–M), showing GPm “comet tail” hyposignal on T2-FLAIR (red arrows; E, F, J), T2 (red arrows; G, K), T₂* (red arrows; H), T1 sequences (red arrows; D, I), and T2-SWI (M), hyperintensities of putamen on T2-FLAIR sequences (red and yellow stars; E, F, J), T2-FLAIR hyperintensities (Figure legend continues on next page.)</figcaption></figure>
noticeable stabilization of the disease over several years, and an
MRI pattern suggestive of NBIA.

VAC14 biallelic pathogenic variants are now reported in 19 patients from 14 different families. After a normal neurodevelopment, motor and language regression occurs before 5 y.o in 70% of cases.<sup>1,5</sup> Later-onset forms manifest as progressive generalized dystonia in childhood or adolescence, with or without spasticity.<sup>2,4,6-8</sup> Over the disease progression, motor disability worsens, while intellectual capacities are preserved in most cases (16/19). Clinical and radiological features are summarized in Tables S1 and S2.

We noted singular elements in our patients’ history: they presented a very rapid motor and language deterioration, but while most patients enter the disease with dystonia, both showed pyramidal syndrome in the foreground, evoking hereditary spastic paraplegia. A vertical gaze ophtalmoplegia was lately observed in the proband, possibly due to the mesencephalic involvement as reported previously.⁶ A moderate frontal cortico-subcortical atrophy was observed, not reported before, perhaps due to the lack of neuroradiological descriptions in adult patients. The prolonged survival and clinical stability of the proband is also remarkable, since only 3/17 patients have been reported in adulthood.<sup>4-6</sup>

Despite a typical NBIA pattern, the symptoms could be better explained by neuronal death and cavitation, as suggested by T2-FLAIR hyperintensities of putamen and cerebral peduncles. Indeed, the ferromagnetic artifact is observed in 37% patients (7/19), who appear older (mean age 16 y.o [range: 9–29]) and with a longer disease course (mean 7 years [0–18]), compared with those presenting only a lesional pattern in basal ganglia (mean age 2.1 y.o [1–3]; mean duration 0.8 years [0–2]). This suggests that neuronal cell death may precedes iron accumulation (Table S2), as supported by neuropathology of young siblings showing neurodegeneration with vacuolization, but no iron deposition,⁹ and Vac14-hypomorphic mouse model showing extensive spongiform neurodegeneration.¹⁰ However, the clinical improvement after GPi-DBS in one patient with VAC14-NBIA² would also suggest a neuronal dysfunction, rather than a pure, irreversible lesional process.

A total of 19 different variants are now identified, mostly mis-
sense changes aggregating in the VAC14 dimerization domain
(Fig. 1N). Genotype–phenotype correlation is difficult to estab-
lish, but the only patient with congenital presentation carried the
only nonsense variant reported.³ Complete VAC14 biallelic loss-
of-function has never been reported in humans, suggesting a
lethality of this condition as reported in mice,¹⁰ and raising the
hypothesis of a correlation between clinical severity and residual
VAC14 amount.

In conclusion, we describe siblings with *VAC14*-related disorder, carrying two novel pathogenic variants. The proband, oldest patient reported so far, had a 35-year history of disease progression, with surprising clinical stabilization, prolonged survival and no cognitive impairment, bringing a novel perspective for prognosis.

Author Roles

(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.

S.C.: 1A, 1B, 1C, 2A, 2B, 3A.

C.D.: 1A, 1B, 1C, 2C, 3B.

G.N.: 1A, 1B, 1C, 2C, 3B.

J.M.S.A.: 1A, 1B, 1C, 2C, 3B.

S.O.: 1B, 1C, 2C, 3B.

L.P.: 1A, 1B, 1C, 2C, 3B.

A.R.: 1A, 1B, 1C, 2C, 3A, 3B.

Acknowledgments

The authors would like to acknowledge the patient and his fam-
ily for their collaboration, and Emmanuelle Lecommandeur for
her careful proofreading.

Disclosures

**Ethical Compliance Statement:** Genetic analyses were subject to informed consent by the families following a specialized genetic consultation in Rennes UMC, in accordance with French guidelines, bioethics laws and the General Data Protection Regulation (RGPD), framed by the National Commission for Information Technology and Civil Liberties (CNIL). A specific consent for the publication of the patient's photographs was obtained. 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 Conflicts of Interest:** The authors have no funding nor conflicts of interest to declare in the context of this work.

**Financial Disclosures for the Previous 12 Months:** All authors declare no financial or non-financial competing interests.

(Figure legend continued from previous page.)

of cerebral peduncles and posterior limbs of internal capsules suggesting pyramidal damage (yellow stars; E, F, J), striatum atrophy on T1 sequence (D, I), evolutive cortico-subcortical atrophy, particularly in the frontal region, with ventricular enlargement (D, I), and cerebellar atrophy (L). Note the stability of the lesions over 17 years, apart from the progression of the cortico-subcortical atrophy. (N) Genetic findings of individuals with VAC14 variants. A schematic view of VAC14 exon sequence (NM_16120.3), its Metadome missense tolerance landscape (https://stuart.radboudumc.nl/metadome/) and the variants identified in the literature. The amino acid numbering and the protein domains are based on PeCan Data of Proteinpaint. The red arrows indicate the variants identified in the family described here.
# Data Availability Statement

The data that support the findings of this study are in the supplemental data section. ■

# References

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2. de Gusmao CM, Stone S, Waugh JL, Yang E, Lenk GM, Rodan LH. VAC14 gene-related parkinsonism-dystonia with response to deep brain stimulation. *Mov Disord Clin Pract* 2019;6:494-497.

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4. Taghavi S, Chaouni R, Tafakhori A, et al. A clinical and molecular genetic study of 50 families with autosomal recessive parkinsonism revealed known and novel gene mutations. *Mol Neurobiol* 2018;55:3477-3489.

5. Lyon GJ, Marchi E, Ekstein J, et al. VAC14 syndrome in two siblings with retinitis pigmentosa and neurodegeneration with brain iron accumulation. *Cold Spring Harb Mol Case Stud* 2019;5:a003715.

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7. Bhowmick SS, Mahajan SK, Shah V, Kashyap K. Unmistakable truncal dystonia mistaken as psychogenic: a case report of VAC14-related neurodegeneration. *Movement Disord Clin Pract* 2023;10:S15-S20.

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# Supporting Information

Supporting information may be found in the online version of this article.

**Data S1** Supplemental methods: Detailed method of genetic investigation in the proband and his parents.

**Table S1** Summary of clinical and neuroradiological characteristics in patients with VAC14-related disorders, in this study and in literature

**Table S2.** Detailed clinical and neuroradiological characteristics in patients with VAC14-related disorders, in this study and in literature