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

Area of Science:

• Genetics
• Neurology
• Rare Diseases

Background:

• Episodic ataxias (EA) are typically autosomal dominant disorders characterized by recurrent ataxia attacks.
• Pathogenic variants in CACNA1A, KCNA1, PDHA1, and SLC1A3 genes are common causes of EA, classified as paroxysmal movement disorders (PxMD).
• Understanding genotype-phenotype correlations in genetic EA forms remains limited.

Approach:

• A systematic literature review was conducted using the MDSGene protocol.
• Data from 717 patients with pathogenic variants in the four key EA genes were extracted and analyzed.
• Clinical and genetic features were summarized to explore genotype-phenotype relationships.

Key Points:

• Analysis of 717 patients revealed 287 distinct pathogenic variants across CACNA1A, KCNA1, PDHA1, and SLC1A3 genes.
• Profound phenotypic variability and overlap were observed among different genetic forms of EA.
• A clear genotype-phenotype correlation is largely absent, with only a few specific 'red flags' identified.

Conclusions:

• The significant overlap in clinical presentation complicates specific genotype-phenotype correlations in episodic ataxias.
• A comprehensive genetic testing strategy, such as gene panels or whole exome/genome sequencing, is the most practical approach.
• This broad testing strategy aids in diagnosing the diverse spectrum of paroxysmal movement disorders associated with these genes.