Clinical characteristics.

Individuals with biallelic PRICKLE1-related disorders typically present with progressive myoclonus epilepsy (PME) with ataxia characterized by myoclonic seizures (lightning-like jerks), generalized convulsive seizures, varying degrees of neurologic regression mainly presenting with ataxia, and mild cognitive impairment or normal cognition. Onset of symptoms is between ages five and ten years. Action myoclonus may affect the limbs or bulbar muscles, while spontaneous myoclonus may occasionally involve facial muscles. Dysarthria may also be an early feature of this condition. The main seizure types are myoclonic or tonic-clonic with frequent nocturnal occurrence.

Individuals with heterozygous PRICKLE1 pathogenic variants have presented with non-PME seizures (isolated myoclonic seizures, juvenile myoclonic epilepsy), myoclonic epilepsy, developmental delay, intellectual disability, autism spectrum disorder, and/or central nervous system malformations.

Diagnosis/testing.

The diagnosis of a PRICKLE1-related disorder is established in a proband with suggestive findings and biallelic or heterozygous pathogenic variant(s) in PRICKLE1 identified by molecular genetic testing.

Management.

Treatment of manifestations: Occupational therapy, psychomotricity/physical therapy, and speech therapy for ataxia and neurodevelopmental impairment; adaptive devices as needed to maintain or improve independence in mobility and feeding; anti-seizure medications as needed, such as valproic acid, clonazepam, zonisamide, and levetiracetam.

Surveillance: Neurologic examination every six months; developmental assessment and evaluation of school performance and emotional status every six to 12 months as needed based on age.

Agents/circumstances to avoid: Phenytoin, carbamezapine, oxycarbazpine, gabapentin, pregabalin, tiagabine, and vigabatrin may worsen myoclonic seizures.

Genetic counseling.

PRICKLE1-related PME with ataxia is associated with biallelic homozygous or compound heterozygous PRICKLE1 pathogenic variants and inherited in an autosomal recessive manner. PRICKLE1-related phenotypes associated with a heterozygous PRICKLE1 pathogenic variant are inherited in an autosomal dominant manner.

• Autosomal recessive inheritance. If both parents of a proband with PRICKLE1-related PME with ataxia are known to be heterozygous for a PRICKLE1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial PRICKLE1 pathogenic variants.
• Autosomal dominant inheritance. An individual with an autosomal dominant PRICKLE1-related disorder may have the disorder as the result of a de novo pathogenic variant or a pathogenic variant inherited from a parent. Each child of an individual with a heterozygous PRICKLE1 pathogenic variant has a 50% chance of inheriting the pathogenic variant.

Once the PRICKLE1 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for PRICKLE1-related disorders are possible.

Suggestive Findings

PRICKLE1-related progressive myoclonus epilepsy (PME) with ataxia should be suspected in a child or adolescent with the following:

• Myoclonic seizures (lightning-like jerks)
• Generalized convulsive seizures
• Varying degrees of cognitive decline and motor impairment especially presenting with ataxia
• Family history consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Autosomal dominant transmission or absence of a known family history does not preclude the diagnosis.

Heterozygous PRICKLE1-related disorders should be considered in individuals with any combination of the following features:

• Seizures
• Developmental delay / intellectual disability
• Autism spectrum disorder
• Central nervous system malformations

Establishing the Diagnosis

The diagnosis of a PRICKLE1-related disorder is established in a proband with suggestive findings and biallelic or heterozygous pathogenic (or likely pathogenic) variant(s) in PRICKLE1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

The current preferred approach to genetic testing is use of a multigene panel including PRICKLE1 and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

An alternative approach to genetic testing in an individual with PME is to perform molecular genetic testing for Unverricht-Lundborg disease and Lafora disease first because both are more common than PRICKLE1-related disorders. If pathogenic variants are not identified, PRICKLE1 sequence analysis may be considered.

Clinical Description

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Prevalence

Prevalence for PRICKLE1-related PME with ataxia is not known. To date, four large families of Middle Eastern descent and a few other, unrelated individuals with PRICKLE1-related PME have been reported [Algahtani et al 2019].

Fewer than 50 individuals have been described with heterozygous PRICKLE1-related disorders, including nonsyndromic epilepsy, autism, and central nervous system malformations [Mastrangelo et al 2018].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a PRICKLE1-related disorder, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Agents/Circumstances to Avoid

Avoid the following drugs, which could worsen myoclonic seizures:

• Phenytoin [Eldridge et al 1983]
• Carbamezapine and oxycarbazepine [National Organization for Rare Disorders 1990]
• Gabapentin, pregabalin, tiagabine, and vigabatrin [National Institute for Health and Care Excellence 2016]

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual to identify as early as possible those who would benefit from institution of treatment and preventive measures.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: No clinical trials are currently ongoing for PRICKLE1-related disorders.

Mode of Inheritance

PRICKLE1-related progressive myoclonus epilepsy (PME) with ataxia is associated with biallelic homozygous or compound heterozygous PRICKLE1 pathogenic variants and inherited in an autosomal recessive manner.

PRICKLE1-related phenotypes associated with heterozygous PRICKLE1 pathogenic variants (e.g., non-PME seizures, myoclonic epilepsy with neurodevelopmental features, polyneuropathy, and central nervous system malformations) are inherited in an autosomal dominant manner.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an individual with PRICKLE1-related PME with ataxia are presumed to be heterozygous for a PRICKLE1 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a PRICKLE1 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.

Sibs of a proband

• If both parents of a proband with PRICKLE1-related PME with ataxia are known to be heterozygous for a PRICKLE1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial PRICKLE1 pathogenic variants.
• To date, the heterozygous sibs of individuals with PRICKLE1-related PME with ataxia have been asymptomatic. However, further data are needed to determine if the pathogenic variants associated with PRICKLE1-related PME with ataxia can also be associated with manifestations in heterozygous individuals.

Offspring of a proband. Because of the early onset and rapid deterioration, individuals with PRICKLE1-related PME with ataxia typically do not reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for a PRICKLE1 pathogenic variant.

Heterozygote detection. Heterozygote testing for at-risk relatives requires prior identification of the PRICKLE1 pathogenic variants in the family.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• An individual with an autosomal dominant PRICKLE1-related disorder may have the disorder as the result of a de novo pathogenic variant or a pathogenic variant inherited from a parent.
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with an autosomal dominant PRICKLE1-related disorder may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents: if a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.

Because reduced penetrance has been suggested in autosomal dominant PRICKLE1-related disorders [Algahtani et al 2019], sibs who inherit a PRICKLE1 pathogenic variant may or may not be affected.

• If the PRICKLE1 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the PRICKLE1 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for an autosomal dominant PRICKLE1-related disorder because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with a heterozygous PRICKLE1 pathogenic variant has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the PRICKLE1 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.

Prenatal Testing and Preimplantation Genetic Testing

Once the PRICKLE1 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for PRICKLE1-related disorders are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

PRICKLE1 encodes a nuclear membrane receptor called prickle homolog 1 (Pk). This protein is likely a regulator of the Wnt noncanonic planar cell polarity (PCP) pathway, implicated in the nuclear trafficking of the transcription repressors REST (RE-1 silencing transcription factor) / NRSF (neuron-restrictive silencer factor) and REST4. The Wnt/PCP pathway is crucial in the regulation of gastrulation movements and neurulation and Pk is thought to be essential for organ formation and proper function of the primary cilia. Primary cilia are hair-like structures protruding from the cell surface that sense and transduce many extracellular signals to influence processes, such as cell proliferation and polarity and neuronal growth during embryonic development [Liu et al 2013].

Mechanism of disease causation. PRICKLE1-related epileptogenesis may be correlated with: (1) impairment of calcium-mediated signaling in different brain regions, especially the cortex, thalamus, and hippocampus; (2) impairment of microtubule-associated vesicle transport of neurotransmitter; and (3) dysregulation of neurite outgrowth and neuronal connectivity [Mastrangelo et al 2018].

The alterations of neuronal signaling and networking cascades in which PRICKLE1 is involved may result in dysfunction of RE-1 silencing transcription factor or ubiquitin-specific peptidase 9 X-linked, which may contribute to cognitive decline [Mastrangelo et al 2018].

Author Notes

Mario Mastrangelo, MD, PhD
Caterina Caputi, MD
Dario Esposito, MD
Vincenzo Leuzzi, MD

Unit of Child Neurology and Psychiatry
Department of Human Neuroscience
Sapienza Università di Roma
Referring Center for Rare and Complex Neurologic and Neurometabolic Pediatric Diseases

Department of Human Neuroscience web page

Unit of Child Neurology and Psychiatry web page

Acknowledgments

We acknowledge the patient association Il sorriso di Titto-ONLUS for its continuous support in our clinical, research, and educational work.

Author History

Alexander G Bassuk, MD, PhD; University of Iowa (2009-2022)
Caterina Caputi, MD (2022-present)
Dario Esposito, MD (2022-present)
Mark H Fox, MD; University of Iowa (2009-2022)
Vincenzo Leuzzi, MD (2022-present)
Mario Mastrangelo, MD, PhD (2022-present)

Revision History

• 21 April 2022 (sw) Comprehensive update posted live
• 10 April 2014 (me) Comprehensive update posted live
• 10 January 2013 (cd) Revision: prenatal diagnosis available
• 8 December 2011 (me) Comprehensive update posted live
• 8 September 2009 (et) Review posted live
• 25 March 2009 (ab) Original submission

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