Objective: To describe a case series of neuroacanthocytosis in three siblings from the same family with the same pathogenic VPS13A nonsense mutation, highlighting the marked phenotypic variability of this disorder.

Background: VPS13A disease (chorea-Acanthocytosis), a form of neuroacanthocytosis is caused by pathogenic loss of function mutations in the VPS13A gene. The disorder is characterised by a spectrum of movement disorders including chorea, dystonia, tics, orofacial choreic and dystonic movements, dysarthria, dysphagia, seizures and cognitive impairment[1]. There is significant phenotypic variability even within affected families.

Method: Retrospective case series

Results: Patient A presented at 23 years old with generalised tonic-clonic seizures and was diagnosed with epilepsy. By the age of 25 she developed significant cognitive impairment. MRI showed multiple white matter lesions compatible with demyelination. At 27 she developed orolingual dyskinesias and phonic tics. Following an episode of optic neuritis and CSF examination showed oligoclonal bands she was given a diagnosis of MS. Creatine kinase (CK) remained persistently elevated (>1000 IU/L). From the age of 30 she developed progressive dysarthria and dysphagia, and chorea affecting the limbs and trunk with irregular dystonic truncal movements (rubber man syndrome). She now has severe generalised chorea and is wheelchair-bound since age 45.

Patient B, her younger brother presented at age of 37 with vocal and motor tics and was diagnosed with chronic tic disorder. He had a several year history of generalised chorea, dysarthria, hand dystonia and self-mutilation with persistently raised CK. By age 43 he had worsening mobility and dysphagia.

Patient C, the youngest brother, presented at age 30 with suppressible involuntary jerking of the left leg and later developed bruxism and phonic tics. At age of 37 he developed generalised tonic-clonic seizures, oromandibular and limb chorea.

Conclusion: Here we highlight the variable presentation of three from a consanguineous family with the pathogenic loss-of-function nonsense variant NM_033305.3:c.428T>A (p.Leu143Ter). The three siblings presented at variable ages and disease severity. The white matter lesions in patient A have been attributed to MS, however white matter lesions have also been identified in patients with neuroacanthocytosis and could represent part of the genetic syndrome[2].

References: 1. Peikert K, Dobson-Stone C, Rampoldi L, Miltenberger-Miltenyi G, Neiman A, De Camilli P, et al. VPS13A Disease. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993 [cited 2026 Mar 12]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1387/
2. Nicholl DJ, Sutton I, Dotti MT, Supple SG, Danek A, Lawden M. White matter abnormalities on MRI in neuroacanthocytosis. J Neurol Neurosurg Psychiatry. 2004 Aug;75(8):1200–1.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/marked-intrafamilial-phenotypic-variability-in-vps13a-disease-a-case-series-of-three-siblings/