Objective: To describe clinical and genetic findings in a patient with focal adult-onset primary cranial dystonia and chorea, and a mutation in CACNA1B (also referred to as ‘DYT23’ dystonia).

Background: Disordered striatal calcium signalling is important in the pathophysiology of primary dystonia. (1) HPCA mutations that were recently identified as a cause of ‘DYT2’-like phenotype. (2) In 2015, a mutation in CACNA1B was reported in a in a single Dutch family with myoclonus-dystonia family as the likely cause of disease. (3) This was considered a plausible candidate gene, and fitted well with the well-described calcium homeostasis hypothesis of genetic dystonia. However, a subsequent large study later in the same year (4) found that this variant was found at comparable frequencies in normal controls, thus calling the pathogenicity of this specific mutation into question. There is no subsequent second report of CACNA1B mutation in a patient with primary dystonia.

Methods: Clinical- Case Report. Genetics- Targeted gene sequencing.

Results: A 52-year old man presented with blepharospasm and mild cervical dystonia of 3 years’ duration, and chorea in both upper limbs. Birth and developmental history was normal, and family history was negative for similar complaints. No other cause of secondary dystonia was found, and complete metabolic testing for dystonia was negative. MRI Brain was normal. Genetic Findings: A heterozygous missense variation in exon 6 of the CACNA1B gene (chr9:140811749G>A; Depth: 106x) that results in the amino acid substitution of Lysine for Glutamic acid at codon 278 (p.Glu278Lys; ENST00000371372) was detected. The observed variation lay in the ion transport domain of CACNA1B protein. The Glu278Lys variant is not reported in the 1000 genomes database and has a minor allele frequency of 0.006% and 0.03% in ExAC and our internal databases respectively. The in-silico predictions of the variant are damaging by LRT and MutationTaster2. The mutation was later validated by Sanger sequencing. Further, the mutation was shown to be absent in two asymptomatic siblings.

Conclusions: We report a patient with primary adult-onset focal craniocervical dystonia/chorea and a ‘likely pathogenic’ CACNA1B mutation, thus adding to the first (and only existent) report of dystonia in a Dutch family due to mutations in this gene by Groen et al in 2015. Further genetic studies of CACNA1B and confirmation of our findings by other independent groups will reveal the true significance of mutations in this gene in patients with primary dystonia.

References: 1. Domingo A, Erro R, Lohmann K.Novel Dystonia Genes: Clues on Disease Mechanisms and the Complexities of High-Throughput Sequencing. Mov Disord. 2016 Apr;31(4):471-7. 2. Charlesworth G, Angelova PR, Bartolomé-Robledo F, Ryten M, Trabzuni D, Stamelou M, Abramov AY, Bhatia KP, Wood NW. Mutations in HPCA cause autosomal-recessive primary isolated dystonia. Am J Hum Genet. 2015 Apr 2;96(4):657-65. doi: 10.1016/j.ajhg.2015.02.007. Epub 2015 Mar 19. 3. Groen JL, Andrade A, Ritz K, Jalalzadeh H, Haagmans M, Bradley TE, Jongejan A, Verbeek DS, Nürnberg P, Denome S, Hennekam RC, Lipscombe D, Baas F, Tijssen MA. CACNA1B mutation is linked to unique myoclonus-dystonia syndrome. Hum Mol Genet. 2015 Feb 15;24(4):987-93. 4. Mencacci NE, R’bibo L, Bandres-Ciga S, Carecchio M, Zorzi G, Nardocci N, Garavaglia B, Batla A, Bhatia KP, Pittman AM, Hardy J, Weissbach A, Klein C, Gasser T, Lohmann E, Wood NW. 4. The CACNA1B R1389H variant is not associated with myoclonus-dystonia in a large European multicentric cohort. Hum Mol Genet. 2015 Sep 15;24(18):5326-9.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/does-dyt23-exist-report-of-a-second-family-with-adult-onset-focal-dystonia-and-a-cacna1ab-mutation-causative-or-coincidental/