Objective: To describe a new missense variant found in a 67 years old woman with progressive ataxia causing a phenotype compatible with SCA 6.
Background: CACNA1A is the calcium voltage-gated channel subunit alpha1 A (19p13.13). Its mutations have been related to spinocerebellar ataxia (SCA) type 6 among others. SCA 6 is an uncommon dominantly inherited neurological disorder. It is characterized by late-onset and slowly progressive gait ataxia and in some cases parkinsonism, dystonia, depression, fatigue, and cognitive impairment.
Molecular mechanisms of SCA6 are trinucleotide (CAG) repeat expansions in the CACNA1A gene (21-29 expansions), but there are two previous reports of missense mutations causing this disease. [1,2]
Method: 67 years old woman, second of 4 healthy siblings and mother of one healthy son. No familial history of neurological disorders but migraines (non-hemiplegic) in her sister, her mother and herself. Her father and mother died from non-neurological causes at age >80. She refers slowly progressive instability since she was 60, in the last 2 years dysarthria, parkinsonism and recurrent falls. MRI has no relevant findings, normal 123-I Ioflupane SPECT and altered (123)I-metaiodobenzylguanidine (MIBG). She has been treated with levodopa up to 1 gr/day with no effect. SCA1, 2, 3, 6, 7 and Huntington genetic screening was performed.
Results: PCR amplification showed no pathologic expansion associated to SCA 1,2,3,7; TP-PCR was performed to detect CAG repeats seen in SCA 2 and 7. Clinic exome was performed and showed a novel heterozygous variant in exon 45 of the CACNA1A gene, c.6481C>G; (p.Arg2161Gly). This variant was not reported in online databases and classification from in silico prediction bioinformatic tools were contradictory, thus this change was classified as variant of uncertain significance.
Conclusion: Diagnosis of SCA require a high suspicion degree, the manifestation of ataxia combined with other movement disorders can be confusing and misleading to complex diagnosis. Up to date there is no cure for SCA6. Riluzole has shown some benefit in clinical trials IIA. Acetazolamide, although no trials have been published, may have some effect in episodic ataxia caused by CACNA1A mutations, thus it is logical to try in this disease. Physiotherapy remains one of the of the treatments with more evidence of reducing SARA scale scores.
References:  Q. Yue. The American Journal of Human Genetics. 61 (1997) 1078–1087.  I. Alonso. Arch Neurol. 60 (2003) 610–614.
To cite this abstract in AMA style:J.P Romero, J. Herreros, S. Santillán, Y. Moreno, A. Andújar. A Novel CACNA1A Nonsense Variant [c.6481C>G; (p.Arg2161Gly)] Causing Spino Cerebellar Ataxia Type 6 (SCA6) [abstract]. Mov Disord. 2020; 35 (suppl 1). https://www.mdsabstracts.org/abstract/a-novel-cacna1a-nonsense-variant-c-6481cg-p-arg2161gly-causing-spino-cerebellar-ataxia-type-6-sca6/. Accessed December 11, 2023.
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