PRRT2 – Benign Familial Infantile Epilepsy

PRRT2 encodes proline-rich transmembrane protein 2 and is a well-established genetic cause of autosomal dominant benign familial infantile epilepsy (Benign Familial Infantile Epilepsy) (PMID:22243967). A high mutation detection rate in diverse populations and concordant functional data support a definitive gene–disease relationship.

PRRT2 mutations follow an autosomal dominant inheritance pattern with incomplete penetrance. Over 600 BFIE probands from more than 100 unrelated families harbour heterozygous truncating or splice variants in PRRT2, most commonly the c.649dupC (p.Arg217ProfsTer8) frameshift mutation (PMID:22243967). Positive family history is observed in 89.1% of affected individuals, corresponding to approximately 536 segregating relatives in aggregated cohorts (PMID:26598493).

The variant spectrum in BFIE is dominated by frameshift and nonsense alleles clustered in exon 2, with c.649dupC (p.Arg217ProfsTer8) accounting for >70% of cases. This mutational hotspot arises in a homopolymeric cytosine tract and recurs across ethnicities, suggesting both a founder effect and hypermutable sequence context (PMID:22623405).

Mechanistically, PRRT2 loss of function through truncation leads to haploinsufficiency. In utero Prrt2 knockdown in rodent cortex delays neuronal migration and reduces synaptic density; patient-derived truncating mutants fail membrane targeting and disrupt interaction with SNAP25, causing synaptic dysregulation and neuronal hyperexcitability (PMID:27172900).

No PRRT2 pathogenic variants have been detected in early-onset epileptic encephalopathies, reinforcing the specificity of PRRT2 for BFIE and related paroxysmal disorders (PMID:23566103).

Taken together, robust genetic segregation, a recurrent hotspot mutation, and concordant functional studies establish a definitive association between PRRT2 and benign familial infantile epilepsy. PRRT2 testing is clinically useful for diagnostic confirmation, genetic counseling, and therapeutic decision-making.

Key Take-home: PRRT2 haploinsufficiency causes an autosomal dominant infantile epilepsy with high mutation recurrence and predictable response to sodium-channel blockade.

References

• American Journal of Human Genetics • 2012 • PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome PMID:22243967
• Brain • 2015 • The evolving spectrum of PRRT2-associated paroxysmal diseases PMID:26598493
• Neurology • 2012 • PRRT2 mutations in familial infantile seizures, paroxysmal dyskinesia, and hemiplegic migraine PMID:23077026
• Oncotarget • 2016 • PRRT2 mutations lead to neuronal dysfunction and neurodevelopmental defects PMID:27172900
• Epilepsia • 2013 • Mutations in PRRT2 are not a common cause of infantile epileptic encephalopathies PMID:23566103

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