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PRICKLE1-Related Progressive Myoclonus Epilepsy with Ataxia

Synonym: EPM1B

, MD and , MD, PhD.

Author Information
, MD
Department of Pediatrics
University of Iowa
Iowa City, Iowa
, MD, PhD
Department of Pediatrics and Neurology
University of Iowa
Iowa City, Iowa

Initial Posting: ; Last Update: April 10, 2014.

Summary

Disease 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.

Diagnosis

The diagnosis of progressive myoclonus epilepsy (PME) with ataxia is suspected in a child or adolescent who displays the following:

  • Myoclonic seizures (lightning-like jerks)
  • Generalized convulsive seizures
  • Varying degrees of neurologic decline especially manifest as ataxia
  • Normal intellectual abilities

The diagnosis of PME with ataxia is confirmed by identification of biallelic pathogenic variants in PRICKLE1 (see Table 1).

One approach to genetic testing when progressive myoclonus epilepsy is clinically diagnosed is to perform molecular genetic testing for Unverricht-Lundborg disease and Lafora disease first because both are more common than PRICKLE1-related PME with ataxia. If those diagnoses can be ruled out, it may then be appropriate to consider PRICKLE1 molecular genetic testing.

An alternative approach to genetic testing is use of a multi-gene panel that includes PRICKLE1 and other genes of interest (see Differential Diagnosis). Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

Table 1. Summary of Molecular Genetic Testing Used in PRICKLE1-Related Progressive Myoclonus Epilepsy with Ataxia

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by this Method
PRICKLE1Sequence analysis 2See footnote 3

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3. To date five unrelated persons have been reported with PRICKLE1 pathogenic variants: three of Middle Eastern descent were homozygous for the pathogenic variant p.Arg104Gln; one individual was heterozygous the pathogenic variant p.Arg144His; and one individual was heterozygous for the pathogenic variant p.Tyr472His [Tao et al 2011].

Clinical Description

Natural History

In PRICKLE1-related progressive myoclonus epilepsy (PME) with ataxia, ataxia begins in general between ages four and five years, with PME emerging later. Individuals reported onset of symptoms of myoclonus and seizures between ages five and ten years. Difficulty walking prior to onset of myoclonus and seizures was reported but not documented. Some individuals in the preliminary study of this disorder exhibited early-onset ataxia, followed later by myoclonus and seizures, whereas in others ataxia was followed by florid progressive myoclonic epilepsy.

In many forms of PME, cognitive decline is severe and generally occurs early; however, in this disorder, intellect is generally preserved. Brain magnetic resonance imaging (MRI) yielded unremarkable results in all affected individuals tested.

In one family, the 18-year-old index case had onset of ataxia at age 15 months, followed by hand tremor at age four years that became coarse and jerky by age ten years [El-Shanti et al 2006]. Atonic seizures began at age ten years.

Action myoclonus may affect the limbs or bulbar muscles, sometimes with spontaneous myoclonus of facial muscles. In one family the myoclonic jerks were worse in the sun [El-Shanti et al 2006].

Marked dysarthria may occur and upgaze palsy has been described [Straussberg et al 2005].

Tendon reflexes may be decreased, suggesting peripheral neuropathy. Babinski reflexes have been reported.

Seizures can be myoclonic or tonic-clonic and are often nocturnal. Electroencephalography (EEG) reveals generalized spike-wave or polyspike-wave discharges and sometimes photosensitivity.

One individual died at age 17 years from disease complications (falls and infection); another person in the same family is alive at age 40 years [El-Shanti et al 2006].

Genotype-Phenotype Correlations

Until more individuals with PRICKLE1-related PME with ataxia are evaluated, genotype-phenotype correlations cannot be determined.

Penetrance

Complete penetrance was observed in the original families studied.

Nomenclature

The term progressive myoclonus epilepsy covers a large and varied group of diseases characterized by myoclonus, generalized tonic-clonic seizures, and progressive neurologic deterioration. The other well-known forms of PME are the autosomal recessive disorders:

Before mutation of PRICKLE1 was identified as the cause of this form of PME with ataxia, the disorder was referred to as EPM1B because of its similarity to Unverricht-Lundberg disease (EPM1).

Prevalence

Prevalence for PRICKLE1-related PME with ataxia is not known. To date, three large families of Middle Eastern descent and two other, unrelated individuals have been reported with this rare form of PME.

Differential Diagnosis

When first evaluated, many individuals with PRICKLE1-related progressive myoclonus epilepsy (PME) with ataxia have progressive myoclonic epilepsy that most closely resembles Unverricht-Lundborg disease. Similar diagnoses such as Lafora disease, neuronal ceroid-lipofuscinoses, sialidosis, and myoclonic epilepsy with ragged red fibers (MERRF) should be considered.

Unverricht-Lundborg disease (EPM1) is a neurodegenerative disorder characterized by onset between ages six and 15 years, stimulus-sensitive myoclonus, and tonic-clonic epileptic seizures. Some years after the onset, ataxia, incoordination, intentional tremor, and dysarthria develop. Individuals with EPM1 are mentally alert but show emotional lability, depression, and mild decline in intellectual performance over time. EPM1 results from defective function of cystatin B, a cysteine protease inhibitor, as a consequence of mutation of CSTB. Inheritance is autosomal recessive.

Progressive myoclonus epilepsy, Lafora type is characterized by fragmentary, symmetric, or generalized myoclonus and/or generalized tonic-clonic seizures, visual hallucinations (occipital seizures), and progressive neurologic degeneration including cognitive and/or behavioral deterioration, dysarthria, and ataxia beginning in previously healthy adolescents between ages 12 and 17 years. The frequency and intractability of seizures increase over time. Status epilepticus is common. Emotional disturbance and confusion are common at or soon after onset of seizures and are followed by dementia. Dysarthria and ataxia appear early; spasticity late. Most affected individuals die within ten years of onset, usually from status epilepticus or from complications related to nervous system degeneration. Diagnosis is usually based on clinical and EEG findings and detection of biallelic pathogenic variants in one of the two genes known to be associated with LD: EPM2A or NHLRC1 (EPM2B). Inheritance is autosomal recessive.

Progressive myoclonic epilepsy 4 with or without renal failure (EPM4) is associated with mutation of SCARB2. The biallelic SCARB2 pathogenic variants identified in five unrelated individuals include homozygous splice site and frame shift variants as well as compound heterozygous splice site and missense variants [Dibbens et al 2009]. A sixth individual was described with a previously unknown single base-pair deletion in SCARB2 [Hopfner et al 2011]. Inheritance is autosomal recessive.

Progressive myoclonic epilepsy 5 (EPM5) is associated with mutation of PRICKLE2. The PRICKLE2 pathogenic variants in three individuals were: two pathogenic variants, p.[Arg148His; Val153Ile], in one; homozygosity for p.Val605Phe in one; and homozygous deletion of PRICKLE2 in one [Tao et al 2011]. Inheritance is autosomal recessive.

Progressive myoclonic epilepsy 6 (EMP6) is associated with mutation of GOSR2. Six persons from five unrelated families were identified to be homozygous for the pathogenic variant p.Gly144Trp [Corbett et al 2011]. Inheritance is autosomal recessive.

See Epilepsy, Progressive Myoclonic: OMIM Phenotypic Series, to view genes associated with this phenotype in OMIM.

Ataxia. Other individuals with PRICKLE1-related PME with ataxia display varying degrees of ataxia as the primary finding before signs of PME become evident. Consequently, a preliminary diagnosis of “ataxia” would be common. Individuals initially displaying only ataxia should be periodically examined to determine if they have developed any form of PME similar to the type described in this review (See Hereditary Ataxia Overview.)

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PRICKLE1-related progressive myoclonus epilepsy (PME) with ataxia, the following evaluations should be performed:

  • Clinical evaluation
  • Neurologic examination for evidence of ataxia, including speech, walking, coordination, and handwriting
  • Evaluation of school performance and emotional status
  • EEG
  • Brain MRI
  • Medical genetics consultation

Treatment of Manifestations

Treatment of epilepsy involves antiepileptic drugs including valproic acid, clonazepam, zonisamide, piracetam, and levetiracetam. Valproate was particularly helpful in one family [El-Shanti et al 2006].

Ataxia may require assistive devices or eventually wheelchair.

Consultation with a speech pathologist may be helpful.

Prevention of Secondary Complications

Valproate levels are affected by a number of drugs. Serum valproate concentration should be closely monitored to ensure proper levels. If consistent side effects such as nausea, vomiting, hair loss, or tremor are reported, consider switching to an extended-release formulation which allows for more stable serum levels.

Surveillance

Follow-up evaluations should be performed every three to four months to ensure effective seizure control and monitor for changes in clinical findings.

Agents/Circumstances to Avoid

Avoid the following:

Evaluation of Relatives at Risk

It is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from institution of treatment and preventive measures. If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.

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

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

PRICKLE1-related progressive myoclonus epilepsy (PME) with ataxia is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one mutant allele).
  • To date, heterozygotes (carriers) appear asymptomatic.

Sibs of a proband

  • 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.
  • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

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 of a proband. Sibs of the proband’s parents are at a 50% risk of being carriers; first cousins of the proband are at a 25% risk of being carriers.

Carrier Detection

Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified.

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, clarification of carrier status, and discussion of the availability of prenatal 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 carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the PRICKLE1 pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variants have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Epilepsy Society (AES)
    342 North Main Street
    West Hartford CT 06117-2507
    Phone: 860-586-7505
    Fax: 860-586-7550
    Email: info@aesnet.org
  • Ataxia UK
    Lincoln House
    1-3 Brixton Road
    London SW9 6DE
    United Kingdom
    Phone: 0845 644 0606 (helpline); 020 7582 1444 (office); +44 (0) 20 7582 1444 (from abroad)
    Email: helpline@ataxia.org.uk; office@ataxia.org.uk
  • Epilepsy Foundation
    8301 Professional Place
    Landover MD 20785-7223
    Phone: 800-332-1000 (toll-free)
    Fax: 301-577-2684
    Email: info@efa.org
  • euro-ATAXIA (European Federation of Hereditary Ataxias)
    Ataxia UK
    9 Winchester House
    Kennington Park
    London SW9 6EJ
    United Kingdom
    Phone: +44 (0) 207 582 1444
    Email: marco.meinders@euro-ataxia.eu
  • International Network of Ataxia Friends (INTERNAF)
    Email: internaf-owner@yahoogroups.com
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
    Email: naf@ataxia.org
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. PRICKLE1-Related Progressive Myoclonus Epilepsy with Ataxia: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
PRICKLE112q12Prickle-like protein 1PRICKLE1 homepage - Mendelian genesPRICKLE1

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for PRICKLE1-Related Progressive Myoclonus Epilepsy with Ataxia (View All in OMIM)

608500PRICKLE, DROSOPHILA, HOMOLOG OF, 1; PRICKLE1
612437EPILEPSY, PROGRESSIVE MYOCLONIC 1B; EPM1B

Gene structure. PRICKLE1 consists of eight exons spanning roughly 3.3 kb of genomic DNA. All exons are coding with the exception of exon 1, which is fully non-coding. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Three pathogenic variants have been reported: p.Arg104Gln [Bassuk et al 2008], p.Arg144His, and p.Tyr472His [Tao et al 2011] (see Table 2).

Table 2. Selected PRICKLE1 Pathogenic Allelic Variants

DNA Nucleotide Change Protein Amino Acid Change Reference Sequences
c.311G>Ap.Arg104GlnNM_153026​.2
NP_694571​.2
c.431G>Ap.Arg144His
c.1414T>Cp.Tyr472His

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. Human prickle-like protein 1 is 831 amino acids in length and contains conserved PET (named after the Drosophila prickle-espinas-testin proteins) and LIM (named after the C Elegans Lin11 and Mec3 proteins) domains extending from residues 13 to 181 and 126 to 312, respectively. These domains are required for protein-protein interactions, including binding between the proteins disheveled (encoded by DAAM1) and prickle-like protein 1.

Abnormal gene product. The function and cause of the abnormal prickle-like protein 1 is under investigation.

References

Literature Cited

  1. Bassuk AG, Wallace RH, Buhr A, Buller AR, Afawi Z, Shimojo M, Miyata S, Chen S, Gonzalez-Alegre P, Griesbach HL, Wu S, Nashelsky M, Vladar EK, Antic D, Ferguson PJ, Cirak S, Voit T, Scott MP, Axelrod JD, Gurnett C, Daoud AS, Kivity S, Neufeld MY, Mazarib A, Straussberg R, Walid S, Korczyn AD, Slusarski DC, Berkovic SF, El-Shanti HI. A homozygous mutation in human PRICKLE1 causes an autosomal-recessive progressive myoclonus epilepsy-ataxia syndrome. Am J Hum Genet. 2008;83:572–81. [PMC free article: PMC2668041] [PubMed: 18976727]
  2. Corbett MA, Schwake M, Bahlo M, Dibbens LM, Lin M, Gandolfo LC, Vears DF, O'Sullivan JD, Robertson T, Bayly MA, Gardner AE, Vlaar AM, Korenke GC, Bloem BR, de Coo IF, Verhagen JM, Lehesjoki AE, Gecz J, Berkovic SF. A mutation in the Golgi Qb-SNARE gene GOSR2 causes progressive myoclonus epilepsy with early ataxia. Am J Hum Genet. 2011;88:657–63. [PMC free article: PMC3146720] [PubMed: 21549339]
  3. Dibbens LM, Michelucci R, Gambardella A, Andermann F, Rubboli G, Bayly MA, Joensuu T, Vears DF, Franceschetti S, Canafoglia L, Wallace R, Bassuk AG, Power DA, Tassinari CA, Andermann E, Lehesjoki AE, Berkovic SF. SCARB2 mutations in progressive myoclonus epilepsy (PME) without renal failure. Ann Neurol. 2009;66:532–6. [PubMed: 19847901]
  4. Eldridge R, Iivanainen M, Stern R, Koerber T, Wilder BJ. "Baltic" myoclonus epilepsy: hereditary disorder of childhood made worse by phenytoin. Lancet. 1983;2:838–42. [PubMed: 6137660]
  5. El-Shanti H, Daoud A, Sadoon AA, Leal SM, Chen S, Lee K, Spiegel R. A distinct autosomal recessive ataxia maps to chromosome 12 in an inbred family from Jordan. Brain Dev. 2006;28:353–7. [PubMed: 16376507]
  6. Hopfner F, Schormair B, Knauf F, Berthele A, Tölle TR, Baron R, Maier C, Treede RD, Binder A, Sommer C, Maihöfner C, Kunz W, Zimprich F, Heemann U, Pfeufer A, Näbauer M, Kääb S, Nowak B, Gieger C, Lichtner P, Trenkwalder C, Oexle K, Winkelmann J. Novel SCARB2 mutation in action myoclonus-renal failure syndrome and evaluation of SCARB2 mutations in isolated AMRF features. BMC Neurol. 2011;11:134. [PMC free article: PMC3222607] [PubMed: 22032306]
  7. National Organization for Rare Disorders. Progressive Myoclonus Epilepsy. Available online. 1990. Accessed 4-4-14.
  8. Straussberg R, Basel-Vanagaite L, Kivity S, Dabby R, Cirak S, Nurnberg P, Voit T, Mahajnah M, Inbar D, Saifi GM, Lupski JR, Delague V, Megarbane A, Richter A, Leshinsky E, Berkovic SF. An autosomal recessive cerebellar ataxia syndrome with upward gaze palsy, neuropathy, and seizures. Neurology. 2005;64:142–4. [PubMed: 15642921]
  9. Tao H, Manak JR, Sowers L, Mei X, Kiyonari H, Abe T, Dahdaleh NS, Yang T, Wu S, Chen S, Fox MH, Gurnett C, Montine T, Bird T, Shaffer LG, Rosenfeld JA, McConnell J, Madan-Khetarpal S, Berry-Kravis E, Griesbach H, Saneto RP, Scott MP, Antic D, Reed J, Boland R, Ehaideb SN, El-Shanti H, Mahajan VB, Ferguson PJ, Axelrod JD, Lehesjoki AE, Fritzsch B, Slusarski DC, Wemmie J, Ueno N, Bassuk AG. Mutations in prickle orthologs cause seizures in flies, mice, and humans. Am J Hum Genet. 2011;88:138–49. [PMC free article: PMC3035715] [PubMed: 21276947]

Chapter Notes

Revision History

  • 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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