DiagnosisClinical DiagnosisThe diagnosis of Unverricht-Lundborg disease (EPM1) is suspected in a previously healthy child age six to 15 years who manifests the following:Involuntary, action-activated myoclonic jerks and/or Generalized tonic-clonic seizures Photosensitive, generalized spike-and-wave and polyspike-and-wave paroxysms on EEG. The EEG is always abnormal, even before the onset of symptoms. The background activity is labile and may be slower than normal. Photosensitivity is marked. A gradual worsening of the neurologic symptoms (myoclonus and ataxia) Normal brain MRI Molecular Genetic TestingGene. CSTB is the only gene in which mutation is known to cause Unverricht-Lundborg disease [Pennacchio et al 1998]. Virtually all affected individuals have an unstable expansion of a 12-nucleotide (dodecamer) repeat 5'-CCC-CGC-CCC-GCG-3' (g.513685_513696) in the promoter region in at least one of the two altered CSTB alleles; the majority of individuals have two expanded repeats in the abnormal allele range.The expanded dodecamer repeat mutation accounts for approximately 90% of Unverricht-Lundborg disease alleles found throughout the world.About 99% of Finnish individuals have two expanded alleles. Allele sizes Normal alleles. 2-3 dodecamer repeats Full-penetrance alleles. ≥30 dodecamer repeats. The largest allele observed to date using Southern blotting is approximately 125 dodecamer repeats (see Table 2). Alleles of questionable significance Alleles of 12-17 dodecamer repeats g.513685_513696(12_17) have been observed, but individuals with alleles in this range have not undergone thorough clinical evaluation for signs and symptoms of EPM1. Alleles of 4-11 dodecamer repeats and 18-29 dodecamer repeats g.513685_513696(18_29) have not been reported. Clinical testing Targeted mutation analysis Testing for the common dodecamer repeat expansion mutation g.513685_513696(30_?125)Testing for five mutations c.10G>C (p.Gly4Arg), c.67-1G>C (splicing defect), c.169-2A>G (splicing defect), c.202C>T (p.Arg68*), and c.218_219delTC (p.Leu73fs*3) (see Table 1)Sequence analysis detects the five CSTB mutations in Table 1 as well as novel variants. Table 1. Summary of Molecular Genetic Testing Used in Unverricht-Lundborg DiseaseView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityCSTBTargeted mutation analysisg.513685_513696(30_?125)
(alleles with dodecamer repeat expansion 30 to ~125)99% 2
~90% 3Clinicalc.10G>C, c.67-1G>C, c.169-2A>G, c.202C>T, c.218_219delTC 4UnknownSequence analysisSequence variants 5Unknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 99% of disease alleles in Finnish individuals3. 90% of disease alleles worldwide4. Mutations included in the panel may vary among laboratories.5. Examples of 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.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyConfirming the diagnosis in a proband. When heterozygosity for the dodecamer expansion is found in an affected individual, it is appropriate to pursue molecular genetic testing for other CSTB mutations in the second allele either by targeted mutation analysis for a broader panel of mutations or by sequence analysis. 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 disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in CSTB.}

Natural HistoryIn over half of individuals with Unverricht-Lundborg disease (EPM1), the first symptom is involuntary myoclonic jerks [Kälviäinen et al 2008]. The myoclonic jerks are action activated and stimulus-sensitive and may be provoked by light, physical exertion, and stress. They occur predominantly in the proximal muscles of the extremities and are asynchronous; they may be focal or multifocal and may generalize to a series of myoclonic seizures or even status myoclonicus (continuous myoclonic jerks involving a semi-loss of consciousness).During the first five to ten years, the symptoms/myoclonic jerks characteristically progress and the individual may become severely incapacitated (wheelchair bound). Although the myoclonic jerks are disabling and resistant to therapy, the individual usually learns to tolerate them over time, provided that the psychosocial circumstances are good and depression is not too severe.In almost half of individuals, the presenting symptom is tonic-clonic seizures. There may also be absence, psychomotor, and/or focal motor seizures. Epileptic seizures, infrequent in the early stages of the disease, often increase in frequency during the ensuing three to seven years. Later they may cease entirely with appropriate antiepileptic drug treatment. In rare cases, tonic-clonic seizures do not occur.Neurologic findings initially seem normal; however, experienced observers usually note recurrent, almost imperceptible myoclonus, especially in response to photic stimuli or other stimuli (threat, clapping of hands, nose tapping, reflexes) or to action (movements made during neurologic examination) or to cognitive stimuli (task demanding cognitive and psychomotor processing). 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.The disease course is inevitably progressive; however, the rate of deterioration especially in terms of walking capacity seems to vary even within the same family. Generalized tonic-clonic seizures are usually controlled with treatment, but myoclonic jerks may become severe, appear in series, and inhibit normal activities [Magaudda et al 2006]. Myoclonic jerks may also be subcortical in origin and therefore difficult to control [Danner et al 2009]. The individual becomes depressed and progression ensues. Education is often interrupted because of emotional, social, and intellectual problems.In the past, life span was shortened; many individuals died eight to 15 years after the onset of disease, usually before age 30 years. With better pharmacologic, physiotherapeutic, and psychosocial supportive treatment, life expectancy appears to be normal [Kälviäinen et al 2008].

Genotype-Phenotype CorrelationsAll individuals with mutations in CSTB develop similar disease manifestations. No correlation exists between the length of the expanded dodecamer repeat and the age of onset or disease severity [Lalioti et al 1998]. Disease severity may vary among affected individuals within a family who have apparently similar repeat-size expansions.

Differential DiagnosisAt the onset of Unverricht-Lundborg disease (EPM1), juvenile myoclonic epilepsy (JME), which has a favorable outcome, should be considered as a diagnostic alternative. Individuals with JME have a normal neurologic examination and the background of the EEG is undisturbed. In case of progression, other forms of progressive myoclonus epilepsy, notably myoclonic epilepsy with ragged red fibers (MERRF), neuronal ceroid-lipofuscinoses, and Lafora disease, should be considered:In CSTB mutation-negative individuals with an EPM1-like phenotype, the following two disorders should be considered.An EPM1-like progressive myoclonus epilepsy-ataxia syndrome, previously linked to the EPM1B locus on chromosome 12 [Berkovic et al 2005], was recently identified to result from a missense mutation in PRICKLE1 [Bassuk et al 2008]. Children present with ataxia at four to five years of age and later develop a progressive myoclonus epilepsy phenotype with mild or absent cognitive decline. The myoclonus-renal failure syndrome (AMRF) has been identified to be caused by mutations in SCARB2/Limp2 [Berkovic et al 2008]. AMRF typically presents at ages 15 to 25 years either with neurologic symptoms (including tremor, action myoclonus, seizures, and ataxia) or with proteinuria that progresses to renal failure.

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Unverricht-Lundborg disease (EPM1), the following evaluations are recommended:Clinical evaluation including walking, coordination, handwriting, school performance, and emotional features is essential. Examination of myoclonus should include evaluation of myoclonus at rest, with action, and in response to stimuli. EEG should be evaluated before therapy is initiated as it is most characteristic before use of anticonvulsive medication. Treatment of ManifestationsSymptomatic pharmacologic and rehabilitative management are the mainstay of patient care [Kälviäinen et al 2008]: Valproic acid is the first drug of choice. It diminishes myoclonus and the frequency of generalized seizures. Clonazepam, the only drug approved by the Food and Drug Administration (FDA) for the treatment of myoclonic seizures, is used as add-on therapy [Shahwan et al 2005].High-dose piracetam has been formally studied and has been found useful in the treatment of myoclonus [Koskiniemi et al 1998]. Levetiracetam has been evaluated in several series and seems to be effective for both myoclonus and generalized seizures. Topiramate and zonisamide may also be used as add-on therapies.SurveillancePatients need lifelong clinical follow up and psychosocial support including evaluation of the drug treatment and comprehensive rehabilitation.Agents/Circumstances to AvoidPhenytoin should be avoided, since it has been found to have aggravating side effects on the associated neurologic symptoms or even deteriorating effects on the cerebellar degeneration [Eldridge et al 1983]. Sodium channel blockers (carbamazepine, oxcarbazepine, phenytoin) and GABAergic drugs (tiagabine, vigabatrin) as well as gabapentin and pregabalin should in general be avoided as they may aggravate myoclonus and myoclonic seizures [Medina et al 2005]. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationBrivaracetam, a SV2A ligand that differs from levetiracetam by its mechanism of action profile, has shown significant antiepileptic activity in experimental models of epilepsy and myoclonus. Brivaracetam has been granted orphan drug designation by the FDA (United States) for the treatment of symptomatic myoclonus, and by the EMEA (European Agency for the Evaluation of Medicinal Products; European Union) for the treatment of progressive myoclonic epilepsies. Brivaracetam is currently being investigated as an add-on treatment for Unverricht-Lundborg disease in adolescents and adults. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherVagus nerve stimulator therapy reduces seizures and significantly improves cerebellar function on neurologic examination [Smith et al 2000]. N-acetylcysteine has been tried with variable results [Edwards et al 2002].

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. Unverricht-Lundborg Disease: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCSTB21q22​.3Cystatin-BFinnish Disease DatabaseCSTBData 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 Unverricht-Lundborg Disease (View All in OMIM) View in own window 254800MYOCLONIC EPILEPSY OF UNVERRICHT AND LUNDBORG 601145CYSTATIN B; CSTBNormal allelic variants. CSTB consists of three exons, all of them coding, which span roughly 2.5 kb of genomic DNA. Northern blot analysis shows a single transcript of approximately 0.8 kb. One silent normal allelic variant in CSTB has been reported (Table 2). Pathologic allelic variants. Ten different mutations have been identified [Kagitani-Shimono et al 2002, de Haan et al 2004, Joensuu et al 2007]. Among the more than 150 apparently unrelated families studied to date, all but one affected individual had at least one CSTB allele with an unstable expansion of a 12-nucleotide (dodecamer; 5'-CCC-CGC-CCC-GCG-3') repeat unit. The majority of affected individuals have this mutation on both alleles. The expanded repeat is located 175 bp upstream from the translation initiation codon in the promoter region of CSTB. This mutation accounts for approximately 90% of Unverricht-Lundborg disease alleles found throughout the world, and 99% of affected Finnish individuals have two disease-causing dodecamer expansions.Nine mutations occur in the transcription unit of CSTB (Table 2). The c.67-1G>C, c.202C>T, and c.218_219delTC mutations have been observed in more than one affected individual; the remaining six have been identified in one individual each [Kagitani-Shimono et al 2002, de Haan et al 2004, Joensuu et al 2007]. The c.10G>C mutation is the only mutation reported that does not occur in a compound heterozygous form with the dodecamer repeat expansion mutation. Table 2. Selected CSTB Allelic VariantsView in own windowClass of
Variant AlleleDNA Nucleotide Change
(Alias ¹)Protein Amino Acid ChangeReference SequencesNormalg.431G>Tp.= ^{2U46692Pathologicg.513685_513696(30_?125) (dodecamer repeat in promoter region)--NT_011515​.11c.10G>Cp.Gly4ArgNM_000100​.2
NP_000091​.1c.67-1G>C--c.149G>Ap.Gly50Gluc.168G>Ap.= 3c.168+1_18del--c.169-2A>G--c.202C>Tp.Arg68*c.212A>Cp.Gln71Proc.218_219delTCp.Leu73Profs*3See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventions 2. p.(=) designates that protein has not been analyzed, but no change is expected3. May produce abnormal splicing [Kagitani-Shimono et al 2002]Normal gene product. Cystatin-B is an inhibitor of several papain-family cysteine proteases, cathepsins, which are lysosomal enzymes. Cystatin-B is a ubiquitously expressed 98-amino acid protein and has a molecular weight of 11 kd. Its physiologic function is unknown. Within cells, cystatin-B shows lysosomal, nuclear, and/or cytosolic localization [Alakurtti et al 2005]. Cstb-deficient knockout mice display a phenotype similar to the human disease with progressive ataxia and myoclonic seizures [Pennacchio et al 1998]. The mice show neuronal apoptosis (especially of cerebellar granule cells), atrophy, and gliosis as well as increased expression of apoptosis and glial activation genes [Pennacchio et al 1998, Lieuallen et al 2001, Shannon et al 2002]. In mice double-deficient for cystatin-B and one of its target proteases, cathepsin B, significantly reduced cerebellar granule cell apoptosis establishes cathepsin B as a contributor to the disease pathogenesis [Houseweart et al 2003]. Recently, impaired redox homeostasis was reported as a pathophysiologic mechanism in EPM1 whereby dysregulation of cystatin-B-cathepsin B signaling may serve as a critical mechanism coupling oxidative stress to neuronal degeneration and death [Lehtinen et al 2009]. In cerebellar granule neurons, oxidative stress induces the expression of cystatin-B. Cystatin-B knockout or knockdown sensitizes cerebellar granule neurons to oxidative stress-induced cell death, mediated by cathepsin B. Moreover, the cerebella of Cstb-deficient knockout mice show evidence of oxidative damage in vivo, reflected by depletion of antioxidants and increased lipid peroxidation [Lehtinen et al 2009]. Abnormal gene product. The major mutation, the dodecamer repeat g.513685_513696(30_?125) underlying Unverricht-Lundborg disease results in a significantly reduced amount of CSTB mRNA: 5%-10% of the expression found in controls [Joensuu et al 2007]. Consequently, cells of individuals with Unverricht-Lundborg disease display significantly reduced CSTB protein expression [Alakurtti et al 2005, Joensuu et al 2007] and reduced CSTB inhibitory activity [Rinne et al 2002]. Cathepsin activity is significantly increased [Rinne et al 2002]. The c.67-1G>C, c.168+1_18del, and c.169-2A>G mutations affect splice sites and predict splicing defects. The c.67-1G>C mutation results in skipping of exon 2 and predicts an in-frame deletion of 34 amino acids. The c.67-1G>C mutant mRNAs seem to be unstable [Joensuu et al 2007]. The c.168+1_18del mutation also results in aberrant splicing of CSTB with two different transcripts, but the consequence of the c.169-2A>G mutation as a putative splice site mutation has not been experimentally tested. The c.168G>A affects the last nucleotide of exon 2 and its consequence as a putative splice site mutation has not been experimentally tested. Mutations c.202C>T and c.218_219delTC predict truncated proteins of 68 and 74 amino acids, respectively. The c.202C>T (p.Arg68*) mutant transcript and protein are unstable [Alakurtti et al 2005, Joensuu et al 2007], implying reduced CSTB expression as the primary pathophysiologic mechanism. All three of the following missense mutant proteins fail to associate with lysosomes implying the physiologic importance of CSTB-lysosome association [Alakurtti et al 2005, Joensuu et al 2007]: The c.10G>C mutation results in the substitution of a highly conserved glycine to an arginine at amino acid position 4 (Gly4Arg), critical for cathepsin binding. The c.149G>A mutation results in the substitution of glycine to glutamic acid (p.Gly50Glu) [Joensuu et al 2007]. It affects the highly conserved QVVAG-motif in the first beta-hairpin loop important for the complex formation with cathepsins.The c.212A>C mutation results in the substitution of a glutamine at position 71 by a proline (p.Gln71Pro) [de Haan et al 2004]. The glutamine does not interact directly with target proteases, but is located proximal to the second hairpin loop, which also contributes to protease binding.}