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Unverricht-Lundborg Disease

, MD, PhD and , MD, PhD.

Author Information
, MD, PhD
Folkhalsan Institute of Genetics and Neuroscience Center
University of Helsinki
Helsinki, Finland
, MD, PhD
Kuopio Epilepsy Center
Kuopio University Hospital
Kuopio, Finland

Initial Posting: ; Last Update: June 18, 2009.

Summary

Disease characteristics. Unverricht-Lundborg disease (EPM1) is a neurodegenerative disorder characterized by onset from age six to 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.

Diagnosis/testing. EPM1 results from defective function of cystatin B, a cysteine protease inhibitor, as a consequence of mutations in CSTB. The diagnosis can be confirmed by identifying the common dodecamer repeat expansion mutation or other disease-causing mutations in CSTB.

Management. Treatment of manifestations: Symptomatic pharmacologic and rehabilitative management, including psychosocial support, are the mainstay of care; 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. Topiramate and zonisamide may also be used as add-on therapy.

Surveillance: Lifelong clinical follow up, including evaluation of drug treatment and rehabilitation.

Agents/circumstances to avoid: Phenytoin aggravates neurologic symptoms or even accelerates cerebellar degeneration; sodium channel blockers (carbamazepine, oxcarbazepine), GABAergic drugs (tiagabine, vigabatrin) and gabapentin and pregabalin may aggravate myoclonus and myoclonic seizures.

Genetic counseling. EPM1 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 pregnancies at increased risk are possible if both disease-causing mutations in a family are known.

Diagnosis

Clinical Diagnosis

The 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 Testing

Gene. 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

Table 1. Summary of Molecular Genetic Testing Used in Unverricht-Lundborg Disease

Gene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1
CSTBTargeted mutation analysisg.513685_513696(30_?125)
(alleles with dodecamer repeat expansion 30 to ~125)
99% 2
~90% 3
c.10G>C, c.67-1G>C, c.169-2A>G, c.202C>T, c.218_219delTC 4Unknown
Sequence analysisSequence variants 5Unknown

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. 99% of disease alleles in Finnish individuals

3. 90% of disease alleles worldwide

4. 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 Strategy

Confirming 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.

Clinical Description

Natural History

In 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 Correlations

All 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.

Nomenclature

Unverricht-Lundborg disease was previously called Baltic myoclonus or Baltic myoclonic epilepsy. These names should no longer be used because the condition occurs worldwide.

An identical disorder, found in individuals from the Mediterranean countries and called Mediterranean myoclonus, is now known to be EPM1. The term progressive myoclonus epilepsy (PME) covers a large group of various diseases characterized by myoclonus, epilepsy, and progressive neurologic deterioration.

Prevalence

EPM1 is the major cause of progressive myoclonus epilepsy in North America, but exact prevalence figures are not available.

EPM1 occurs worldwide, but its prevalence is increased in certain populations, e.g., in the Western Mediterranean (i.e., North African countries of Tunisia, Algeria, and Morocco) where exact prevalence figures are not available and in Finland where its prevalence of 1:25,000 is higher than anywhere else in the world. The incidence in Finland is estimated at 1:20,000 births.

A founder effect in EPM1 on Reunion Island is evident, as all but one EPM1 chromosome in 14 individuals homozygous for the dodecamer repeat expansion had the same haplotype [Moulard et al 2003].

Differential Diagnosis

At 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.

Management

Evaluations Following Initial Diagnosis

To 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 Manifestations

Symptomatic 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.

Surveillance

Patients need lifelong clinical follow up and psychosocial support including evaluation of the drug treatment and comprehensive rehabilitation.

Agents/Circumstances to Avoid

Phenytoin 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 Risk

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

Therapies Under Investigation

Brivaracetam, 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.

Other

Vagus 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].

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

Unverricht-Lundborg disease (EPM1) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are 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 risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband

  • Several individuals with Unverricht-Lundborg disease, both males and females, have produced children.
  • The offspring of an individual with Unverricht-Lundborg disease are obligate heterozygotes (carriers) for a disease-causing mutation in CSTB.
  • Because of the low carrier rate in the general population, the risk that an affected individual would have children with a carrier is extremely low except in genetic isolates.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing is possible once the disease-causing mutations have been identified in the family.

Carrier testing for the reproductive partners of a known carrier is possible.

Related Genetic Counseling Issues

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.

Testing of at-risk individuals during childhood. Because practically all affected individuals have their first symptoms before age 18 years, requests from parents for testing of asymptomatic at-risk individuals younger than age 18 years may arise. Consensus holds that asymptomatic individuals younger than age 18 years who are at risk for non-treatable disorders should not have testing. The principal arguments against testing asymptomatic individuals during childhood are that it removes their choice to know or not know this information, it raises the possibility of stigmatization within the family and in other social settings, and it could have serious educational and career implications. In addition, no preventive treatment is available.

Individuals younger than age 18 years who are symptomatic usually benefit from having a specific diagnosis established.

See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.

Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults for Unverricht-Lundborg disease is possible using the techniques described in Molecular Genetic Testing. Such testing is not useful in predicting whether symptoms will occur, or if they do, what the age of onset, severity, and type of symptoms, or rate of disease progression in asymptomatic individuals will be. When testing at-risk individuals for Unverricht-Lundborg disease, an affected family member should be tested first to confirm the molecular diagnosis in the family.

Testing for the disease-causing mutation in the absence of definite symptoms of the disease is predictive testing. At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pre-test interviews in which the motives for requesting the test, the individual's knowledge of Unverricht-Lundborg disease, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow up and evaluations.

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for Unverricht-Lundborg disease is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations 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.

  • National Library of Medicine Genetics Home Reference
  • 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
  • Epilepsy Foundation
    8301 Professional Place
    Landover MD 20785-7223
    Phone: 800-332-1000 (toll-free)
    Fax: 301-577-2684
    Email: info@efa.org

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. Unverricht-Lundborg Disease: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
CSTB21q22​.3Cystatin-BCSTB databaseCSTB

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 Unverricht-Lundborg Disease (View All in OMIM)

254800MYOCLONIC EPILEPSY OF UNVERRICHT AND LUNDBORG
601145CYSTATIN B; CSTB

Normal 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 Variants

Class of
Variant Allele
DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
Normalg.431G>Tp.= 2U46692
Pathologicg.513685_513696(30_?125) (dodecamer repeat in promoter region)--NT_011515​.11
c.10G>Cp.Gly4ArgNM_000100​.2
NP_000091​.1
c.67-1G>C--
c.149G>Ap.Gly50Glu
c.168G>Ap.= 3
c.168+1_18del--
c.169-2A>G--
c.202C>Tp.Arg68*
c.212A>Cp.Gln71Pro
c.218_219delTCp.Leu73Profs*3

Note on variant classification: Variants listed in the table have been provided by the author(s). 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.

1. Variant designation that does not conform to current naming conventions

2. p.(=) designates that protein has not been analyzed, but no change is expected

3. 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.

References

Literature Cited

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  13. Koskiniemi M, Van Vleymen B, Hakamies L, Lamusuo S, Taalas J. Piracetam relieves symptoms in progressive myoclonus epilepsy: a multicentre, randomised, double blind, crossover study comparing the efficacy and safety of three dosages of oral piracetam with placebo. J Neurol Neurosurg Psychiatry. 1998;64:344–8. [PMC free article: PMC2169975] [PubMed: 9527146]
  14. Lalioti MD, Scott HS, Genton P, Grid D, Ouazzani R, M'Rabet A, Ibrahim S, Gouider R, Dravet C, Chkili T, Bottani A, Buresi C, Malafosse A, Antonarakis SE. A PCR amplification method reveals instability of the dodecamer repeat in progressive myoclonus epilepsy (EPM1) and no correlation between the size of the repeat and age at onset. Am J Hum Genet. 1998;62:842–7. [PMC free article: PMC1377038] [PubMed: 9529356]
  15. Lehtinen MK, Tegelberg S, Schipper H, Su H, Zukor H, Manninen O, Kopra O, Joensuu T, Hakala P, Bonni A, Lehesjoki A-E. Cystatin B deficiency sensitizes neurons to oxidative stress in progressive myoclonus epilepsy, EPM1. J Neurosci. 2009;29:5910–5. [PMC free article: PMC2694495] [PubMed: 19420257]
  16. Lieuallen K, Pennacchio LA, Park M, Myers RM, Lennon GG. Cystatin B-deficient mice have increased expression of apoptosis and glial activation genes. Hum Mol Genet. 2001;10:1867–71. [PubMed: 11555622]
  17. Magaudda A, Ferlazzo E, Nguyen VH, Genton P. Unverricht-Lundborg disease, a condition with self-limited progression: long-term follow-up of 20 patients. Epilepsia. 2006;47:860–6. [PubMed: 16686650]
  18. Medina MT, Martinez-Juarez IE, Duron RM, Genton P, Guerrini R, Dravet C, Bureau M, Perez-Gosiengfiao KT, Amador C, Bailey JN, Chaves-Sell F, Delgado-Escueta AV. Treatment of myoclonic epilepsies of childhood, adolescence, and adulthood. Adv Neurol. 2005;95:307–23. [PubMed: 15508934]
  19. Moulard B, Darcel F, Mignard D, Jeanpierre M, Genton P, Cartault F, Yaouanq J, Roubertie A, Biraben A, Buresi C, Malafosse A. FOunder effect in patients with Unverricht-Lundborg disease on reunion island. Epilepsia. 2003;44:1357–60. [PubMed: 14510831]
  20. Pennacchio LA, Bouley DM, Higgins KM, Scott MP, Noebels JL, Myers RM. Progressive ataxia, myoclonic epilepsy and cerebellar apoptosis in cystatin B-deficient mice. Nat Genet. 1998;20:251–8. [PubMed: 9806543]
  21. Rinne R, Saukko P, Jarvinen M, Lehesjoki AE. Reduced cystatin B activity correlates with enhanced cathepsin activity in progressive myoclonus epilepsy. Ann Med. 2002;34:380–5. [PubMed: 12452481]
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Suggested Reading

  1. Joensuu T, Lehesjoki AE, Kopra O. Molecular background of EPM1-Unverricht-Lundborg disease. Epilepsia. 2008;49:557–63. [PubMed: 18028412]
  2. Noebels JL. The inherited epilepsies. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 230. Available online. Accessed 9-18-12.

Chapter Notes

Author History

Reetta Kälviäinen, MD, PhD (2007-present)
Marja-Leena Koskiniemi, MD, PhD; University of Helsinki (2004-2007)
Anna-Elina Lehesjoki, MD, PhD (2004-present)

Revision History

  • 18 June 2009 (me) Comprehensive update posted live
  • 18 September 2007 (cd) Revision: sequence analysis available on a clinical basis
  • 12 February 2007 (me) Comprehensive update posted to live Web site
  • 24 June 2004 (me) Review posted to live Web site
  • 6 February 2004 (ael) Original submission
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