PRRT2 – Infantile Convulsions and Choreoathetosis (ICCA)

Paroxysmal kinesigenic dyskinesia with infantile convulsions (ICCA) is an autosomal dominant disorder characterised by brief choreoathetotic movements and afebrile seizures in infancy. Mutations in PRRT2 (HGNC:30500) have been established as the predominant genetic cause of ICCA, identified in 24 of 25 well-characterised families and in 28 of 78 additional pedigrees ((PMID:22832103)). High penetrance is evidenced by segregation of truncating variants across multiple kindreds.

Genetic analyses across cohorts have uncovered over 70 distinct PRRT2 variants in 1444 patients with paroxysmal disorders, with the frameshift hotspot c.649dup (p.Arg217ProfsTer8) accounting for 78.5% of cases ((PMID:26598493)). The majority of pathogenic alleles are truncating, consistent with a loss-of-function mechanism.

Inheritance is autosomal dominant with incomplete penetrance; segregation was demonstrated in multiple multigenerational families, totaling at least 24 affected relatives with co-segregating PRRT2 variants ((PMID:22832103)). Affected individuals typically present with infantile onset seizures (mean age 5–7 months) and later develop kinesigenic dyskinesias in childhood.

Functional studies support haploinsufficiency as the mechanism of pathogenicity. Truncating PRRT2 mutants undergo nonsense-mediated mRNA decay and/or mislocalization from the neuronal membrane to cytoplasm ((PMID:25457817)), while knockdown of Prrt2 in rodent cortex impairs neuronal migration and reduces synaptic density ((PMID:27172900)).

No significant conflicting evidence has been reported. Comprehensive clinical and molecular concordance across large cohorts and cellular models underpins a definitive disease association.

Genetic testing for PRRT2 mutations is recommended to confirm ICCA diagnosis and guide early initiation of sodium channel blockers such as carbamazepine, which yields rapid and sustained symptom control.

Key Take-home: PRRT2 truncating mutations cause autosomal dominant ICCA via haploinsufficiency, making genetic screening critical for diagnosis and targeted therapy.

References

• Cell reports • 2012 • Mutations in the gene PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions. PMID:22832103
• Brain • 2015 • The evolving spectrum of PRRT2-associated paroxysmal diseases. PMID:26598493
• Parkinsonism & related disorders • 2014 • PRRT2 truncated mutations lead to nonsense-mediated mRNA decay in Paroxysmal Kinesigenic Dyskinesia. PMID:25457817
• Oncotarget • 2016 • PRRT2 mutations lead to neuronal dysfunction and neurodevelopmental defects. PMID:27172900

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