Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Oct;30(10):3377-3393.
doi: 10.1111/ene.15969. Epub 2023 Jul 17.

Genotype-phenotype relations for episodic ataxia genes: MDSGene systematic review

Diana Angelika Olszewska  1 , Aakash Shetty  2 , Rajasumi Rajalingam  1 , Jon Rodriguez-Antiguedad  3 , Moath Hamed  4 , Jana Huang  1 , Marianthi Breza  5 , Ashar Rasheed  1 , Natascha Bahr  6 , Harutyan Madoev  6 , Ana Westenberger  6 , Joanne Trinh  6 , Katja Lohmann  6 , Christine Klein  6 , Connie Marras  1 , Olga Waln  7
Affiliations

Genotype-phenotype relations for episodic ataxia genes: MDSGene systematic review

Diana Angelika Olszewska et al. Eur J Neurol. 2023 Oct.

Abstract

Background: Most episodic ataxias (EA) are autosomal dominantly inherited and characterized by recurrent attacks of ataxia and other paroxysmal and non-paroxysmal features. EA is often caused by pathogenic variants in the CACNA1A, KCNA1, PDHA1, and SLC1A3 genes, listed as paroxysmal movement disorders (PxMD) by the MDS Task Force on the Nomenclature of Genetic Movement Disorders. Little is known about the genotype-phenotype correlation of the different genetic EA forms.

Methods: We performed a systematic review of the literature to identify individuals affected by an episodic movement disorder harboring pathogenic variants in one of the four genes. We applied the standardized MDSGene literature search and data extraction protocol to summarize the clinical and genetic features. All data are available via the MDSGene protocol and platform on the MDSGene website (https://www.mdsgene.org/).

Results: Information on 717 patients (CACNA1A: 491, KCNA1: 125, PDHA1: 90, and SLC1A3: 11) carrying 287 different pathogenic variants from 229 papers was identified and summarized. We show the profound phenotypic variability and overlap leading to the absence of frank genotype-phenotype correlation aside from a few key 'red flags'.

Conclusion: Given this overlap, a broad approach to genetic testing using a panel or whole exome or genome approach is most practical in most circumstances.

Keywords: CACNA1A; KCNA1; PDHA1; SLC1A3; episodic ataxia.

PubMed Disclaimer

References

REFERENCES

    1. Maksemous N, Sutherland HG, Smith RA, Haupt LM, Griffiths LR. Comprehensive exonic sequencing of known ataxia genes in episodic ataxia. Biomedicine. 2020;8(5):134.
    1. Marras C, Lang A, van de Warrenburg BP, et al. Nomenclature of genetic movement disorders: recommendations of the International Parkinson and Movement Disorder Society Task Force. Mov Disord. 2017;32(5):724-725.
    1. Lange LM, Gonzalez-Latapi P, Rajalingam R, et al. Nomenclature of genetic movement disorders: recommendations of the International Parkinson and Movement Disorder Society Task Force-an update. Mov Disord. 2022;37(5):905-935.
    1. Browne D, Gancher S, Nutt J, et al. Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1. Nat Genet. 1994;8:136-140.
    1. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell. 1996;87:543-552.

Publication types

Supplementary concepts