Berkovic et al. (2005) reported a consanguineous Israeli Arab family in which 8 members had an early-onset form of progressive myoclonic epilepsy. Age at seizure onset was 7.3 years (range, 5 to 10 years). Five patients presented with ... Berkovic et al. (2005) reported a consanguineous Israeli Arab family in which 8 members had an early-onset form of progressive myoclonic epilepsy. Age at seizure onset was 7.3 years (range, 5 to 10 years). Five patients presented with myoclonic seizures, 1 with tonic-clonic seizures, and 2 with both. In 4 cases, the parents reported delayed walking in infancy with difficulty walking or running in childhood, consistent with ataxia, before the onset of seizures. Myoclonic seizures were aggravated by sunlight. The disorder was progressive, and 3 patients became wheelchair-bound. There was no significant progressive dementia; brain MRI of 1 patient was normal. The clinical phenotype of this family was similar to that of classic Unverricht-Lundborg disease, but differed by early age of onset and a slightly more severe course. Straussberg et al. (2005) described a consanguineous Israeli Arab family in which 3 sibs had early-onset ataxia, dysarthria, upward gaze palsy, extensor plantar reflexes, axonal sensory neuropathy, and normal cognition. Onset of progressive ataxia was noted around age 4 years. The 2 older sibs, ages 11 and 9 years, developed myoclonic and generalized tonic-clonic seizures that were photosensitive. The youngest had not developed seizures at age 4. Specific features of all patients included tremor, dysmetria, impaired vibration and position sense, and extensor plantar responses. Genetic analysis excluded known loci for autosomal recessive ataxia. El-Shanti et al. (2006) reported a consanguineous Jordanian family in which 4 sibs had onset of gait ataxia at age 15 months, followed by fine tremor progressing to coarse action tremor at age 4 years, and atonic seizures at about age 8 to 10 years. Brain MRI showed no evidence of cerebellar hypoplasia, and cognitive function was spared. The seizures and tremor were responsive to medication. El-Shanti et al. (2006) noted that none of the patients had frank myoclonic seizures, and concluded that the action tremor was related to appendicular ataxia rather than to action myoclonus. The tremor started with fine movement early in the disease process, worsened as the hand approached the target, and continued for a few seconds after the target was reached. However, the authors thought it was possible that the tremor was composed of 2 components consisting of ataxic tremor and action myoclonus. Bassuk et al. (2008) noted that affected members of the family reported by El-Shanti et al. (2006) had developed progressive myoclonic seizures, and that some patients had also developed upward gaze palsy.
In affected members of the families reported by Berkovic et al. (2005), Straussberg et al. (2005), and El-Shanti et al. (2006), Bassuk et al. (2008) identified the same homozygous mutation in the PRICKLE1 gene (R104Q; 608500.0001). The findings ... In affected members of the families reported by Berkovic et al. (2005), Straussberg et al. (2005), and El-Shanti et al. (2006), Bassuk et al. (2008) identified the same homozygous mutation in the PRICKLE1 gene (R104Q; 608500.0001). The findings were consistent with a founder effect. Tao et al. (2011) identified 2 different heterozygous mutations in the PRICKLE1 gene (R144H; 608500.0002 and Y472H; 608500.0003, respectively) in 2 unrelated patients with myoclonic epilepsy. One patient had a more severe phenotype with mild mental retardation. The authors noted that both homozygous (Bassuk et al., 2008) and heterozygous mutations can result in seizures, suggesting a dosage effect. Heterozygous mutations were also identified in the homologous PRICKLE2 gene (608501.0001-608501.0002) in different patients with myoclonic seizures (EPM5; 613832). Tao et al. (2011) concluded that PRICKLE signaling is important in seizure prevention, and presented 2 hypotheses: (1) that PRICKLE affects cell polarity and contributes to the development of a functional neural network and (2) that PRICKLE affects calcium signaling, which may play a role in seizure genesis if disrupted.
The diagnosis of progressive myoclonus epilepsy (PME) with ataxia is suspected in a child or adolescent who displays the following:...
DiagnosisClinical DiagnosisThe 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 seizuresVarying degrees of neurologic decline especially manifest as ataxiaNormal intellectual abilities Molecular Genetic Testing Gene. PRICKLE1 is the only gene in which mutations are known to cause PRICKLE1-related PME with ataxia.Table 1. Summary of Molecular Genetic Testing Used in PRICKLE1-Related Progressive Myoclonus Epilepsy with AtaxiaView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityPRICKLE1Sequence analysisSequence variants 2N/A 3Clinical 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. Five unrelated persons reported with PRICKLE1 mutations to date; three persons of Middle Eastern descent were homozygous for the p.Arg104Gln mutation; one subject was found with a heterozygous p.Arg144His mutation and one was heterozygous for p.Tyr472His [Tao et al 2011]. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a proband. When PME is clinically diagnosed, it is reasonable 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 be appropriate to consider PRICKLE1 molecular genetic testing. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the phenotype of PME with ataxia.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersNo phenotypes other than PRICKLE1-related PME with ataxia are known to be associated with mutations in PRICKLE1.
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. ...
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].
Until more individuals with PRICKLE1-related PME with ataxia are evaluated, genotype-phenotype correlations cannot be determined....
Genotype-Phenotype CorrelationsUntil more individuals with PRICKLE1-related PME with ataxia are evaluated, genotype-phenotype correlations cannot be determined.
When first evaluated, many individuals with 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....
Differential Diagnosis When first evaluated, many individuals with 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 mutations in CSTB. Inheritance is autosomal recessive. Symptomatic pharmacologic and rehabilitative management, including psychosocial support, are the mainstay of care for those with Unverricht-Lundborg disease; valproic acid, the first drug of choice, diminishes myoclonus and the frequency of generalized seizures; clonazepam, approved by FDA for the treatment of myoclonic seizures, is an add-on therapy; high-dose piracetam is used to treat myoclonus; levetiracetam seems effective for both myoclonus and generalized seizures. Of note, phenytoin aggravates the associated neurologic symptoms or even accelerates cerebellar degeneration; sodium channel blockers (carbamazepine, oxcarbazepine, and phenytoin) and GABAergic drugs (tiagabine and vigabatrin), as well as gabapentin and pregabalin, may aggravate myoclonus and myoclonic seizures.Lafora disease (LD) 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 two mutations in one of the two genes known to be associated with LD: EPM2A or NHLRC1 (EPM2B). Antiepileptic drugs (AEDs) are effective against generalized seizures; however, as with other forms of PME, it is best for individuals with LD to avoid phenytoin, and possibly carbamazepine, oxcarbazepine, and lamotrigine. Inheritance is autosomal recessive. Progressive myoclonic epilepsy 4 with or without renal failure (EPM4), associated with mutations in SCARB2. Five unrelated subjects with mutations in SCARB2 have been identified. SCARB2 mutations included homozygous splice site variants and frame shifts as well as heterozygous splice site variants and missense mutations [Dibbens et al 2009]. A sixth individual with EPM4 was recently described with a novel 1 base pair deletion in SCARB2 [Hopfner et al 2011].Progressive myoclonic epilepsy 5 (EPM5), associated with mutations in PRICKLE2. PRICKLE2 mutations included one subject with two mutations: p.[Arg148His; Val153Ile], one subject homozygous for p.Val605Phe and one with a homozygous deletion of the entire PRICKLE2 gene [Tao et al 2011].Progressive myoclonic epilepsy 6 (EMP6), associated with mutations in GOSR2. Six subjects from five unrelated families with a mutation in GOSR2 have been identified. All subjects affected with GOSR2 were homozygous for a p.Gly144Trp mutation [Corbett et al 2011].To view the OMIM summary (phenotypic series table) on progressive myoclonic epilepsy, click here. Ataxia. Other individuals with PRICKLE1-related PME with ataxia display varying degrees of ataxia as the primary symptom 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the level of severity of PRICKLE1-related progressive myoclonus epilepsy (PME) with ataxia, the following evaluations should be performed:...
Management Evaluations Following Initial DiagnosisTo establish the level of severity of PRICKLE1-related progressive myoclonus epilepsy (PME) with ataxia, the following evaluations should be performed:Clinical evaluationNeurologic examination for evidence of ataxia, including speech, walking, coordination, and handwritingEvaluation of school performance and emotional status EEG Brain MRI Genetics consultationTreatment 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.SurveillanceCheck-ups should be performed every three to four months to ensure effective seizure control and monitor for changes in symptoms.Agents/Circumstances to AvoidDrugs to avoid:Phenytoin [Eldridge et al 1983]Carbamezapine, oxycarbazepine [National Organization for Rare Disorders 1990]Evaluation of Relatives at RiskSee 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDPRICKLE112q12Prickle-like protein 1PRICKLE1 homepage - Mendelian genesPRICKLE1Data 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) View in own window 608500PRICKLE-LIKE 1; PRICKLE1 612437EPILEPSY, PROGRESSIVE MYOCLONIC 1B; EPM1BNormal allelic variants. PRICKLE1 consists of eight exons spanning roughly 3.3 kb of genomic DNA. All exons are coding with the exception of exon 1 being fully non-coding. Pathologic allelic variants. In addition to the homozygous p.Arg104Gln mutation described in this review [Bassuk et al 2008], two more pathologic variants have been reported [Table 2] [Tao et al 2011].Table 2. Selected PRICKLE1 Pathologic Allelic Variants View in own windowDNA Nucleotide Change Protein Amino Acid Change Reference Sequencesc.311G>Ap.Arg104GlnNM_153026.2 NP_694571.2c.431G>Ap.Arg144Hisc.1414T>Cp.Tyr472HisSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).Normal gene product. Human prickle-like protein 1 is 831 amino acids in length and contains conserved PET (named after the Drosophilaprickle-espinas-testin proteins) and LIM (named after the C ElegansLin11 and Mec3 proteins) domains extending from residues 13-181 and 126-312, 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 gene product is under investigation.