Prickle1-Related Progressive Myoclonus Epilepsy With Ataxia
Summary
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 testing for a pregnancy 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 multigene panel that includes PRICKLE1 and other genes of interest (see Differential Diagnosis). Note: The genes included and the methods used in multigene panels vary by laboratory and are likely to change over time.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Table 1.
Molecular Genetic Testing Used in PRICKLE1-Related Progressive Myoclonus Epilepsy with Ataxia
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant Detectable by Method |
|---|---|---|
| PRICKLE1 | Sequence analysis 2 | See footnote 3 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.
- 2.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon 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 Characteristics
Clinical Description
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, a proband age 18 years had 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:
- Unverricht-Lundborg disease (EPM1) caused by mutation of CSTB
- Lafora disease (LD) caused by mutation of EPM2A and NHLRC1 (EPM2B)
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.
Action myoclonus – renal failure syndrome (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 frameshift 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).
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
- Consultation with a clinical geneticist and/or genetic counselor
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:
- Phenytoin [Eldridge et al 1983]
- Carbamezapine, oxycarbazepine [National Organization for Rare Disorders 1990]
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 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: There may not be clinical trials for this disorder.