ATP1A3-Associated Paroxysmal Dystonia

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• ATP1A3 mutations are linked to diverse neurological syndromes with weak genotype-phenotype correlations and no established treatments.
• These mutations can present with extra-neural features, complicating diagnosis and management.

Observation:

• A patient with a novel, highly deleterious ATP1A3 mutation (c.1072G>T;p.Gly358Cys) exhibited recurrent paroxysmal dyskinesias.
• Clinical features included jaw-opening dystonia, developmental delay, ataxia, and hypotonia, triggered by various stimuli.
• Paroxysmal episodes were brief (5 min) and responsive to oxcarbazepine and clonazepam.

Findings:

• The identified ATP1A3 variant (CADD 28.8, REVEL 0.992) is absent in gnomAD v.4.1.0, indicating its rarity and potential pathogenicity.
• Oxcarbazepine and clonazepam demonstrated efficacy in reducing the frequency of paroxysmal episodes in this patient.

Implications:

• ATP1A3 mutations should be considered in patients presenting with paroxysmal non-epileptic neurological events, including those overlapping with paroxysmal non-kinesigenic dyskinesias.
• Multi-gene panel testing for ATP1A3 mutations and variant deleteriousness assessment are crucial for diagnosing non-classical phenotypes.
• Pharmacological interventions targeting voltage-gated sodium channels, such as oxcarbazepine, may offer therapeutic benefits.