| 11068522 | PRICKLE1-Related Progressive Myoclonus Epilepsy with Ataxia | PubMed Book Article |
CLINICAL CHARACTERISTICS: PRICKLE1-related progressive myoclonus epilepsy (PME) with ataxia is characterized by myoclonic seizures (lightning-like jerks), generalized convulsive seizures, varying degrees of neurologic decline especially manifest as ataxia, and normal intellectual abilities. Onset of symptoms is between ages five and ten years. Action myoclonus may affect the limbs or bulbar muscles, sometimes with spontaneous myoclonus of facial muscles. Marked dysarthria may occur. Seizures can be myoclonic or tonic-clonic and are often nocturnal.
DIAGNOSIS/TESTING: PRICKLE1-related PME with ataxia is suspected in individuals with characteristic clinical findings and confirmed by identification of biallelic pathogenic variants in PRICKLE1.
MANAGEMENT: Treatment of manifestations: Treatment of epilepsy involves antiepileptic drugs (AEDs) including valproic acid, clonazepam, zonisamide, piracetam, and levetiracetam. Ataxia may require assistive devices or eventually wheelchair. Consultation with a speech pathologist may be helpful. Surveillance: Routine follow-up to ensure effective seizure control and monitor for changes in symptoms. Agents/circumstances to avoid: Phenytoin, carbamezapine, and oxycarbazpine.
GENETIC COUNSELING: PRICKLE1-related PME with ataxia is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified. | 20301774 | 1993-12-01 |
| 598119478 | A homozygous mutation in human PRICKLE1 causes an autosomal-recessive progressive myoclonus epilepsy-ataxia syndrome. | Bassuk AG, etal., Am J Hum Genet. 2008 Nov;83(5):572-81. doi: 10.1016/j.ajhg.2008.10.003. Epub 2008 Oct 30. | Progressive myoclonus epilepsy (PME) is a syndrome characterized by myoclonic seizures (lightning-like jerks), generalized convulsive seizures, and varying degrees of neurological decline, especially ataxia and dementia. Previously, we characterized three pedigrees of individuals with PME and ataxia , where either clinical features or linkage mapping excluded known PME loci. This report identifies a mutation in PRICKLE1 (also known as RILP for REST/NRSF interacting LIM domain protein) in all three of these pedigrees. The identified PRICKLE1 mutation blocks the PRICKLE1 and REST interaction in vitro and disrupts the normal function of PRICKLE1 in an in vivo zebrafish overexpression system. PRICKLE1 is expressed in brain regions implicated in epilepsy and ataxia in mice and humans, and, to our knowledge, is the first molecule in the noncanonical WNT signaling pathway to be directly implicated in human epilepsy. | 18976727 | 2008-11-01 |
| 11063450 | Identification and characterization of novel rare mutations in the planar cell polarity gene PRICKLE1 in human neural tube defects. | Bosoi CM, etal., Hum Mutat. 2011 Dec;32(12):1371-5. doi: 10.1002/humu.21589. Epub 2011 Sep 23. | The planar cell polarity (PCP) pathway controls the process of convergent extension (CE) during gastrulation and neural tube closure, and has been implicated in the pathogenesis of neural tube defects (NTDs) in animal models and human cohorts. In this study, we analyzed the role of one core PCP gene PRICKLE1 in these malformations. We screened this gene in 810 unrelated NTD patients and identified seven rare missense heterozygous mutations that were absent in all controls analyzed and predicted to be functionally deleterious using bioinformatics. Functional validation of five PRICKLE1 variants in a zebrafish model demonstrated that one variant, p.Arg682Cys, antagonized the CE phenotype induced by the wild-type zebrafish prickle1a (zpk1a) in a dominant fashion. Our study demonstrates that PRICKLE1 could act as a predisposing factor to human NTDs and further expands our knowledge of the role of PCP genes in the pathogenesis of these malformations. | 21901791 | 2011-04-01 |
| 11250618 | Prickle1 mutation causes planar cell polarity and directional cell migration defects associated with cardiac outflow tract anomalies and other structural birth defects. | Gibbs BC, etal., Biol Open. 2016 Feb 16;5(3):323-35. doi: 10.1242/bio.015750. | Planar cell polarity (PCP) is controlled by a conserved pathway that regulates directional cell behavior. Here, we show that mutant mice harboring a newly described mutation termed Beetlejuice (Bj) in Prickle1 (Pk1), a PCP component, exhibit developmental phenot ypes involving cell polarity defects, including skeletal, cochlear and congenital cardiac anomalies. Bj mutants die neonatally with cardiac outflow tract (OFT) malalignment. This is associated with OFT shortening due to loss of polarized cell orientation and failure of second heart field cell intercalation mediating OFT lengthening. OFT myocardialization was disrupted with cardiomyocytes failing to align with the direction of cell invasion into the outflow cushions. The expression of genes mediating Wnt signaling was altered. Also noted were shortened but widened bile ducts and disruption in canonical Wnt signaling. Using an in vitro wound closure assay, we showed Bj mutant fibroblasts cannot establish polarized cell morphology or engage in directional cell migration, and their actin cytoskeleton failed to align with the direction of wound closure. Unexpectedly, Pk1 mutants exhibited primary and motile cilia defects. Given Bj mutant phenotypes are reminiscent of ciliopathies, these findings suggest Pk1 may also regulate ciliogenesis. Together these findings show Pk1 plays an essential role in regulating cell polarity and directional cell migration during development. | 26883626 | 1000-06-01 |
