Objective: We report a 33 year old male patient without functional protein due to compound heterozygosity for VPS13A deletions and discuss the molecular diagnostic difficulties in detecting deletions using several sequencing approaches. We provide a comprehensive neuropsychiatric clinical follow up from childhood over several years including diagnostic process.

Background: Chorea-acanthocytosis (ChAc; OMIM #200150) is a rare autosomal recessive condition caused by mutations in the vacuolar protein sorting 13A (VPS13A) gene encoding chorein, that is clinically characterized by hyperkinetic involuntary movements, specifically chorea and orolingual dystonia, presenting in early adulthood. Self-mutilating tongue- and lip-biting, severe flexion episodes of neck (“head drops”) and trunk (“clasping”) are also typical. ChAc often presents with psychiatric symptoms, but also with seizures, peripheral neuropathy and muscle wasting. Elevated serum creatine phosphokinase (CK) is a reliable indicator, in contrast to acanthocytosis on peripheral blood smear, which is not a consistent finding.

Method: We present the whole diagnostic process. We show the molecular diagnostic pitfalls in detecting deletions using only genomic DNA (gDNA) sequencing approaches and exemplify alternative methods such as RNA/cDNA sequencing or qRT-PCR analysis necessary to avoid false-negative results.

Results: With manifest acanthocytosis, massively elevated CK, compatible clinical findings and neuroimaging  as well as onset age, and with exclusion of relevant differential diagnoses, ChAc was seriously considered as the patient´s diagnosis. The further genetic analysis showed the heterozygosity for two VPS13A large deletions of 1168 and 1823 base pairs (bp) affecting, respectively, exons 8 and 9 and exon 13.

Conclusion: Detection at the genomic DNA level of deletions affecting the VPS13A gene can be technically challenging and might yield false-negative results, particularly when the deletions are of a heterozygous nature. Methodologically, information obtained from less-common approaches such as RNA analysis or qRT-PCR is necessary to detect, verify or rule out a deletion. With regard to the clinical presentation, screening for chorein levels is strongly recommended in each patient presenting with any form of movement disorder compatible with ChAc so that the correct diagnosis can be arrived at and used to inform subsequent counselling and treatment approaches.

References: Danek, A. (2004). Neuroacanthocytosis Syndromes. Dordrecht, The Netherlands: Springer. Hermann, A., & Walker, R. H. (2015). Diagnosis and Treatment of Chorea Syndromes. Current Neurology and Neuroscience Reports, 15(2), Walker, R. H., Jung, H. H., Dobson-Stone, C., Rampoldi, L., Sano, A., Tison, F., & Danek, A. (2007). Neurologic phenotypes associated with acanthocytosis. Neurology, 68(2),

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MDS Abstracts - https://www.mdsabstracts.org/abstract/case-report-chorea-acynthocytosis-with-two-compoud-heterozygous-vps13a-large-deletions/