PRICKLE1 – Progressive Myoclonus Epilepsy

Progressive myoclonus epilepsy (PME) is defined by action myoclonus, generalized seizures, and progressive neurological decline. The planar cell polarity protein PRICKLE1 has been implicated in noncanonical WNT signaling and neural development and is now linked to autosomal recessive progressive myoclonus epilepsy.

In a cohort of three unrelated pedigrees, homozygous PRICKLE1 variants c.310C>T (p.Arg104Trp) and c.311G>A (p.Arg104Gln) were identified in individuals presenting with myoclonus, ataxia, and dementia; these variants co-segregated with disease in all affected family members and were absent in unaffected relatives (PMID:18976727).

A single-family study reported an autosomal dominant c.251G>A (p.Arg84Gln) PRICKLE1 variant in a mother and two siblings with PME, ataxia, and cognitive decline; the variant was also found in two unaffected sisters, indicating incomplete penetrance (PMID:31035234).

Functional assays demonstrated that c.310C>T (p.Arg104Trp) disrupts PRICKLE1–REST interaction in vitro and induces PME-like motor deficits in zebrafish embryos, recapitulating human phenotypes and supporting a loss-of-function mechanism (PMID:18976727).

Sequencing of PRICKLE1 in PME cases negative for SCARB2 mutations found no additional pathogenic alleles, reinforcing gene specificity and excluding broad phenocopies (PMID:19847901).

Together, these data establish PRICKLE1 as a moderate-strength PME gene: autosomal recessive inheritance is supported by segregation in multiple families and functional concordance, while rare autosomal dominant alleles exhibit incomplete penetrance. PRICKLE1 should be included in diagnostic panels for AR PME, especially in patients with early-onset myoclonus, ataxia, and cognitive decline. Key Take-home: PRICKLE1 mutations drive autosomal recessive progressive myoclonus epilepsy with strong functional validation, while variable penetrance in dominant cases warrants comprehensive genetic analysis.

References

• American Journal of Human Genetics • 2008 • A homozygous mutation in human PRICKLE1 causes an autosomal-recessive progressive myoclonus epilepsy-ataxia syndrome PMID:18976727
• Seizure • 2019 • A very rare form of autosomal dominant progressive myoclonus epilepsy caused by a novel variant in the PRICKLE1 gene PMID:31035234
• Annals of Neurology • 2009 • SCARB2 mutations in progressive myoclonus epilepsy (PME) without renal failure PMID:19847901

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