Identification of two compound heterozygous <i>VPS13A</i> large deletions in chorea‐acanthocytosis only by protein and quantitative DNA analysis

Spieler, Derek; Velayos‐Baeza, Antonio; Mühlbäck, Alžbeta; Castrop, Florian; Maegerlein, Christian; Slotta‐Huspenina, Julia; Bader, Benedikt; Haslinger, Bernhard; Danek, Adrian

doi:10.1002/mgg3.1179

Cited by 6 publications

(4 citation statements)

References 35 publications

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“…FASTQ files were analyzed using the Integrated Genome Browser human genome 38 (GRCH38) 38 . For case 6, VPS13A DNA, RNA, and protein were analyzed as previously described, using relevant oligonucleotides 39 . VPS13A mutations in cases 1, 20,40 4, 41 and 5 2 were documented as previously reported, adjusting the nomenclature to current standards.…”

Section: Methodsmentioning

confidence: 99%

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An Autopsy Series of Seven Cases of VPS13A Disease (Chorea‐Acanthocytosis)

Ditzel,

Walker,

Nirenberg

et al. 2023

Movement Disorders

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BackgroundVacuolar protein sorting 13 homolog A (VPS13A) disease, historically known as chorea‐acanthocytosis, is a rare neurodegenerative disorder caused by biallelic mutations in VPS13A, usually resulting in reduced or absent levels of its protein product, VPS13A. VPS13A localizes to contact sites between subcellular organelles, consistent with its recently identified role in lipid transfer between membranes. Mutations are associated with neuronal loss in the striatum, most prominently in the caudate nucleus, and associated marked astrogliosis. There are no other known disease‐specific cellular changes (eg, protein aggregation), but autopsy reports to date have been limited, often lacking genetic or biochemical diagnostic confirmation.ObjectiveThe goal of this study was to characterize neuropathological findings in the brains of seven patients with VPS13A disease (chorea‐acanthocytosis).MethodsIn this study, we collected brain tissues and clinical data from seven cases of VPS13A for neuropathological analysis. The clinical diagnosis was confirmed by the presence of VPS13A mutations and/or immunoblot showing the loss or reduction of VPS13A protein. Tissues underwent routine, special, and immunohistochemical staining focused on neurodegeneration. Electron microscopy was performed in one case.ResultsGross examination showed severe striatal atrophy. Microscopically, there was neuronal loss and astrogliosis in affected regions. Luxol fast blue staining showed variable lipid accumulation with diverse morphology, which was further characterized by electron microscopy. In some cases, rare degenerating p62‐ and ubiquitin‐positive cells were present in affected regions. Calcifications were present in four cases, being extensive in one.ConclusionsWe present the largest autopsy series of biochemically and genetically confirmed VPS13A disease and identify novel histopathological findings implicating abnormal lipid accumulation. © 2023 International Parkinson and Movement Disorder Society.

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Section: Methodsmentioning

confidence: 99%

“…38 For case 6, VPS13A DNA, RNA, and protein were analyzed as previously described, using relevant oligonucleotides. 39 VPS13A mutations in cases 1, 20,40 4, 41 and 5 2 were documented as previously reported, adjusting the nomenclature to current standards. Cases 2 and 7 were diagnosed only by VPS13A Western blot analysis.…”

Section: Genetic Analysismentioning

confidence: 99%

An Autopsy Series of Seven Cases of VPS13A Disease (Chorea‐Acanthocytosis)

Ditzel,

Walker,

Nirenberg

et al. 2023

Movement Disorders

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“…Two recent reports describe separate patients with ChAc found to have compound heterozygous VPS13A deletions [14, 15]. Perhaps exome sequencing in our patient missed an additional VPS13A variant allele.…”

Section: Discussionmentioning

confidence: 62%

Heterozygous VPS13A and PARK2 Mutations in a Patient with Parkinsonism and Seizures

Mitchell¹,

Albin²,

Dauer³

et al. 2021

Case Rep Neurol

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Neuroacanthocytosis (NA) is a diverse group of disorders in which nervous system abnormalities co-occur with irregularly shaped red blood cells called acanthocytes. Chorea-acanthocytosis is the most common of these syndromes and is an autosomal recessive disease caused by mutations in the <i>vacuolar protein sorting 13A</i> (VPS13A) gene. We report a case of early onset parkinsonism and seizures in a 43-year-old male with a family history of NA. Neurologic examinations showed cognitive impairment and marked parkinsonian signs. MRI showed bilateral basal ganglia gliosis. He was found to have a novel heterozygous mutation in the VPS13A gene, in addition a heterozygous mutation in the PARK2 gene. His clinical picture was atypical for typical chorea-acanthocytosis (ChAc). The compound heterozygous mutations of VPS13A and PARK2 provide the most plausible explanation for this patient’s clinical symptoms. This case adds to the phenotypic diversity of ChAc. More research is needed to fully understand the roles of epistatic interactions on phenotypic expression of neurodegenerative diseases.

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“…VPS13A mutations dysregulate chorein protein to promote actin polymerization, thus leading to cell membrane rupture and echinocytosis [21]. VPS13A mutations may involve frameshift mutations, large deletions/repeats, small insertions/deletions, splice site mutations, nonsense mutations, or missense mutations, all increasing the complexity of ChAc diagnosis [22,23].…”

Section: Discussionmentioning

confidence: 99%

Chorea-echinocytosis caused by two novel compound heterozygous mutations in the VPS13A gene: a case report and literature review

Li,

Wang,

et al. 2023

Preprint

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Chorea-acanthocytosis (ChAc) is a rare neurodegenerative disease caused by mutations in the VPS13A gene (vacuolar proteinsorting protein 13). Here we report a case of ChAc caused by two new compound heterozygous mutation in the VPS13A. A 36-year-old female presented with orolingual dystonia, dysarthria and mental symptom. A diagnosis of ChAc was established based on typical clinical symptoms, neuroimaging features, acanthocytosis in the peripheral blood smears. Then, whole-exome sequencing of the proband family members determined two novel mutations in VPS13A, including c.4242 + 1G > T (exon36, NM_033305) and c.9270_9274dupCAGAC (exon36, NM_033305). Two novel compound heterozygous mutations in VPS13A cause ChAc, which deepens current understanding about the pathogenesis of ChAC.

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Identification of two compound heterozygous VPS13A large deletions in chorea‐acanthocytosis only by protein and quantitative DNA analysis

Cited by 6 publications

References 35 publications

An Autopsy Series of Seven Cases of VPS13A Disease (Chorea‐Acanthocytosis)

An Autopsy Series of Seven Cases of VPS13A Disease (Chorea‐Acanthocytosis)

Heterozygous VPS13A and PARK2 Mutations in a Patient with Parkinsonism and Seizures

Chorea-echinocytosis caused by two novel compound heterozygous mutations in the VPS13A gene: a case report and literature review

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