Compound Heterozygous VPS13A Variants in a Patient with Neuroacanthocytosis: A Case Report and Review of the Literature

Abstract

Chorea-acanthocytosis (ChAc) is a rare autosomal recessive neurodegenerative disorder caused by pathogenic variants of the vacuolar protein sorting 13A (VPS13A). Only a few patients with ChAc have been reported to date, and the variant spectrum of VPS13A has not been completely elucidated. We describe the case of a 36-year-old woman who had been experiencing orofacial dyskinesia since age 30 years. In a genetic study using next-generation sequencing, 2 variants of VPS13A, the nonsense variant c.4411C>T (p.Arg1471Ter) and the splicing variant c.145-2A>T, were identified. The splicing variant c.145-2A>T was newly classified as a pathogenic variant through a literature review. Consequently, the patient was diagnosed with ChAc based on the typical clinical manifestations, laboratory findings, and imaging results.

Patient History

A 36-year-old woman visited the clinic with involuntary movements of her lips and tongue. She had been experiencing facial dyskinesia, lip-smacking, and progressive dysarthria since age 30 years. Her fluency had also worsened along with progressive stuttering. After a certain period, she developed gait disturbances because of involuntary flexion of her legs. She had been receiving antiepileptic drugs after episodes of generalized tonic-clonic seizures since age 31 years, and she still had intermittent partial seizures.

The patient had graduated from high school and worked as an accountant without intellectual problems, but progressive cognitive problems started in her fourth decade. None of her family members, including her parents, older sister, younger brother, and 2 daughters, showed similar neurological symptoms. Neurological examinations showed generalized chorea and dystonia in both legs. She also showed oromandibular dyskinesia with self-mutilation and vocal tics. Her deep tendon reflexes were decreased with impaired proprioception position sense. Laboratory tests revealed that her creatine kinase level was elevated to 3460 U/L, and acanthocytosis was noted in the peripheral blood smear. In addition, spikes were observed in the left T1, F7, and T3 electrodes on the electroencephalogram. The patient showed cognitive impairment (a score of 26/30 on the Korean-Mini Mental Status Examination and a clinical dementia rating of 0.5). Her brain magnetic resonance imaging showed atrophy of both caudate nuclei (FIGURE 1). Based on her clinical features, a gene panel sequencing test was conducted upon suspicion of ChAc or abetalipoproteinemia.

Clinical and Laboratory Information

We selected 29 dystonia-related genes for the target sequencing panel: ADCY5, ANO3, ATP1A3, ATP7B, CACNA1B, CIZ1, COL6A3, GCH1, GNAL, GNAO1, HPCA, KCTD17, SLC30A10, TAF1, TH, THAP1, TOR1A, KMT2B, MECR, MR1, PRKRA, PRRT2, RELN, SGCE, SLC19A3, SLC2A1, TUBB4A, VAC14, and VPS13A. All procedures were performed at Green Cross Laboratories (Yongin-si, Republic of Korea) using MiSeq Dx (Illumina, San Diego, CA). The average sequence depth of the target regions was 242.64×, and the percentage of target regions with at least 10× coverage was 99.9%. The interpretation of genetic variants was classified into 5 categories: pathogenic, likely pathogenic, uncertain significance, likely benign, and benign, according to the 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines.¹

Two variants were found in the vacuolar protein sorting 13A (VPS13A) gene (reference sequence: NM_033305.2). First, a nonsense variant, c.4411C>T (p.Arg1471Ter), with allele frequency 48%, was classified as a pathogenic variant according to the 2015 ACMG/AMP guidelines.¹ This nonsense variant has an extremely low incidence in the general population (0.00041% in gnomAD exome ALL) and has been described as pathogenic in the ClinVar database. The other, a splicing variant, c.145-2A>T (allele frequency 44%), developed in the consensus splice acceptor site and has shown a low minor allele frequency (0.0058% in gnomAD exome EAS). Other individuals with this variant have also shown a similar clinical course and laboratory findings (TABLE 1). Therefore, although we did not perform a functional test for this variant, we classified it as a pathogenic variant.

Discussion

Research has shown that ChAc (OMIM *60598) is a syndromic neurodegenerative disease with variable neurologic symptoms and acanthocytosis of peripheral blood.² The disease usually manifests in the third to fourth decade of life, and patients can show many movement disorders, including both hyperkinetic and hypokinetic movements. In addition, some patients may show cognitive impairment, personality changes, seizures, dysphagia, dysarthria, and increased levels of creatine kinase.^3,4

Studies have indicated that ChAc shows autosomal recessive inheritance and is caused by pathogenic variants of the VPS13A gene mutation. A previous in vitro study suggested that loss of VPS13A function caused a reduction in intracellular phosphatidylinositol-4-phosphate (PtdIns[4]) levels, and this alteration may play a role in the degeneration of neuronal processes.⁵ However, it remains unclear how the VPS13A pathogenic variants cause neurodegenerative disorders. Acanthocytosis is a representative feature of neuroacanthocytosis, also observed in our patient.⁶ Altered plasma membrane levels of PtdIns(4) may play a decisive role in red cell morphologic abnormalities through unconjugated membrane components of the spectrin/action cytoskeleton. Still, the basis for these alterations remains unclear.⁵ Previous studies have described variable percentages of acanthocytes ranging from 5% to 50%, but this variation does not seem relevant to the development of clinical features. Another laboratory biomarker, creatinine kinase, is generally elevated in patients with ChAc.⁷

Both of the variants found in our patient have been reported in Japanese patients diagnosed with ChAc.⁸ The nonsense variant c.4411C>T (p.Arg1471Ter) is a frequent pathogenic variant, and it is found in more than 50% of Japanese patients with ChAc. The splicing variant, c.145-2A>T, is rare, and it has only been reported in a 26-year-old female patient with an additional pathogenic large deletion variant, c.8211 + 1232_8472-245delinsTC (p.V2738Afs*5). Although further evidence of pathogenicity was not obtained,¹ the patient’s clinical manifestations suggested a novel pathogenic variant. In addition, another study reported a 39-year-old Korean female patient with a c.145-2A>T splicing variant who also showed hyperkinetic movement, including orolingual dyskinesia.⁹ The authors performed an RNA study and confirmed that this variant also induces aberrant splicing.⁹ Moreover, previously known variants in the consensus splicing acceptor site of VPS13A have been classified as pathogenic, and these null variants are known to cause disease.¹⁰ These 2 unrelated patients with c.145-2A>T and our patient showed similar clinical features and laboratory findings. Consequently, this variant can be newly classified as a pathogenic variant.

In conclusion, we present the findings for a patient showing 2 pathogenic variants of VPS13A. Reports describing VPS13A are very rare in Korea. Although the limitations of the next-generation sequencing method made it difficult to determine whether the location was cis or trans, we concluded that the 2 variants may be trans hetero-compound variants according to the clinical features and laboratory findings.

Abbreviations

Abbreviations
 
• ChAc

  chorea-acanthocytosis

 
• VPS13A

  vacuolar protein sorting 13A

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