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Unverricht-Lundborg Disease

, MD, PhD and , MD, PhD.

Author Information

Initial Posting: ; Last Update: November 26, 2014.

Estimated reading time: 17 minutes


Clinical 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.


EPM1 results from defective function of cystatin B, a cysteine protease inhibitor, as a consequence of mutation of CSTB. The diagnosis can be confirmed by identifying the common dodecamer repeat expansion or other pathogenic variants in CSTB.


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 appears to be 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 CSTB pathogenic variants in a family are known.


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
    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

Gene. CSTB is the only gene in which pathogenic variants are 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.

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.

Table 1.

Molecular Genetic Testing Used in Unverricht-Lundborg Disease

Gene 1MethodProportion of Probands with a Pathogenic Variant Detectable by Method
CSTBTargeted analysis for g.513685_513696(30_125) 299% 3
~90% 4
Targeted analysis for pathogenic variants 5, 6Unknown
Sequence analysis 7, 8Unknown

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants.


Alleles with dodecamer repeat expansion 30 to ~125


99% of disease alleles in Finnish individuals


90% of disease alleles worldwide


c.10G>C, c.67-1G>C, c.169-2A>G, c.202C>T, c.218_219delTC


Pathogenic variants included in a panel may vary by laboratory.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. 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.


Detects the five CSTB pathogenic variants noted in footnote 5 as well as novel variants.

Testing Strategy

Confirming the diagnosis in a proband

Clinical Characteristics

Clinical Description

In more than 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 about one third of affected individuals 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 support is good and depression 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 have normal cognition 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 appears 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 near normal [Kälviäinen et al 2008].

Genotype-Phenotype Correlations

Individuals with pathogenic variants in CSTB develop similar disease manifestations. There is preliminary evidence that correlation exists between the length of the expanded dodecamer repeat and the age of onset or disease severity [Author, personal communication]. However, disease severity also varies among affected individuals within a family with apparently similar repeat-size expansions. Moreover EPM1 resulting from compound heterozygous CSTB pathogenic variants (a dodecamer repeat expansion on one allele and a single nucleotide variant or indel variant on the other allele) presents with earlier age of onset, more severe myoclonus, and seizures that may be drug-resistant [Koskenkorva et al 2011, Canafoglia et al 2012]. The presence of variable phenotypes (even in siblings) suggests that interactions with other genetic factors influence the final disease presentation.


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 and varied group of diseases characterized by myoclonus, epilepsy, and progressive neurologic deterioration.


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

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

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 individuals with an EPM1-like phenotype in whom a CSTB pathogenic variant is not identified, the following four disorders should be considered.

  • An EPM1-like progressive myoclonus epilepsy-ataxia syndrome has been shown to result from a missense pathogenic variant in PRICKLE1 [Bassuk et al 2008]. Children present with ataxia at age four to five years and later develop a progressive myoclonus epilepsy phenotype with mild or absent cognitive decline.
  • Action myoclonus – renal failure syndrome (myoclonus-renal failure, AMRF) is caused by pathogenic variants in SCARB2 [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.
  • Progressive myoclonus epilepsy-6 (EPM6) is caused by homozygous pathogenic variants in GOSR2 [Corbett et al 2011, Boissé Lomax et al 2013]. EPM6 presents with early-onset ataxia (average age 2 years), followed by action myoclonus and seizures later in childhood. Independent ambulation is lost in the second decade and affected individuals develop scoliosis by adolescence. Cognition is not usually affected.
  • The disorder myoclonus epilepsy and ataxia due to pathogenic variants in the potassium channel (MEAK), caused by a recurrent de novo missense variant in KCNC1, resembles EPM1 at disease onset [Muona et al 2015]. MEAK presents between ages six and 15 years with myoclonus (sometimes reported as tremor). The later disease course is characterized by moderate to severe incapacitating myoclonus, infrequent tonic-clonic seizures, ataxia, and mild (if any) cognitive decline. The clinical course for MEAK is generally more severe than for EPM1.

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


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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
  • Examination of myoclonus including evaluation of myoclonus at rest, with action, and in response to stimuli
  • EEG evaluation before initiation of therapy, as it is most characteristic before use of anticonvulsive medication
  • Clinical genetics consultation

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.


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, as it has been found to have aggravating side effects on the associated neurologic symptoms, and may even accelerate 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

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

Brivaracetam, a SV2A ligand that differs from levetiracetam by its mechanism of action profile, has demonstrated 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 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.


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 CSTB pathogenic variant.
  • 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 of a CSTB pathogenic variant 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 pathogenic variant 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 (Heterozygote) Detection

Carrier testing is possible once the pathogenic variants have been identified in the family.

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

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.

Testing of asymptomatic individuals younger than age 18 years. 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 adult-onset disorders for which no treatment exists is not considered appropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.

In a family with an established diagnosis of EPM1, it is appropriate to consider testing of symptomatic individuals regardless of age.

For more information, see also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

Testing of at-risk asymptomatic adult relatives of individuals with EPM1 is possible after molecular genetic testing has identified the specific pathogenic variants in the family. Such testing should be performed in the context of formal genetic counseling. This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. Testing of asymptomatic at-risk individuals with nonspecific or equivocal symptoms is predictive testing, not diagnostic testing.

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 and Preimplantation Genetic Diagnosis

Once both CSTB pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for EPM1 are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.


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.

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

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
CSTB21q22​.3Cystatin-BCSTB databaseCSTBCSTB

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Unverricht-Lundborg Disease (View All in OMIM)


Gene structure. 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. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Fourteen different pathogenic variants have been identified [Kagitani-Shimono et al 2002, de Haan et al 2004, Joensuu et al 2007, Erdinc et al 2010, Canafoglia et al 2012, Pinto et al 2012].

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 pathogenic variant on both alleles. The expanded repeat is located 175 bp upstream from the translation initiation codon in the promoter region of CSTB. This pathogenic variant 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.

Thirteen pathogenic variants occur in the transcription unit of CSTB (Table 2). The c.67-1G>C, c.202C>T, c.168+2_168+21delinsAA, and c.218_219delTC pathogenic variants have been observed in more than one affected individual; the remaining nine have been identified in one individual each. The c.10G>C and c.66G>A pathogenic variants are the only two pathogenic variants reported in CSTB that do not occur in a compound heterozygous form with the dodecamer repeat expansion.

Table 2.

Selected CSTB Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
g.513685_513696(30_125) (dodecamer repeat in promoter region)--NT_011515​.11
c.168G>Ap.= 1, 2

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

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


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


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 has been reported to interact with histones and cathepsin L in the nucleus where it could regulate cathepsin L activity [Ceru et al 2010].

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 [Pennacchio et al 1998, Shannon et al 2002]. Analysis of timing of pathologic changes in the brains of Cstb-deficient knockout mice have revealed early and localized microglial activation as the first pathologic hallmark, followed by activation of astroglia in brain regions where neuron loss subsequently occurs [Tegelberg et al 2012]. These changes are most pronounced in the thalamocortical system. Microglial activation is accompanied by the presence of inflammatory markers and peripheral immune cells in the brains of Cstb-deficient mice, implying the contribution of neuroinflammation to disease pathogenesis [Okuneva et al 2015].

Impaired redox homeostasis has been 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]. 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].

There is growing evidence from studies in Cstb-deficient knockout mice for the role of altered GABAergic signaling with subsequent loss of GABA inhibition as a mechanism underlying the latent hyperexcitability resulting in myoclonus and seizures [Franceschetti et al 2007, Buzzi et al 2012, Joensuu et al 2014].

Abnormal gene product. The major pathogenic variant underlying Unverricht-Lundborg disease, the dodecamer repeat g.513685_513696(30_125), 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.66G>A pathogenic variant affects the last nucleotide of exon 1 and it has experimentally verified to alter splicing.
  • The c.67-1G>C, c.168+1_168+18del, and c.169-2A>G pathogenic variants affect splice sites and predict splicing defects.
  • The c.67-1G>C pathogenic variant results in skipping of exon 2 and predicts an in-frame deletion of 34 amino acids.
  • The c.67-1G>C mutated mRNAs appear to be unstable.
  • The c.168+1_168+18del pathogenic variant also results in aberrant splicing of CSTB with two different transcripts, but the consequence of the c.169-2A>G pathogenic variant as a putative splice site variant has not been experimentally tested.
  • The c.168+2_168+21delinsAA pathogenic variant is a complex intronic deletion/insertion that involves the donor splice site of intron 2 and is predicted to lead to an aberrant transcript.
  • The c.168G>A affects the last nucleotide of exon 2 and its consequence as a putative splice site variant has not been experimentally tested.
  • Pathogenic variants c.125C>A, c.136C>T, c.202C>T, and c.218_219delTC predict truncated proteins of 42, 46, 68, and 74 amino acids, respectively.
  • The c.202C>T (p.Arg68Ter) mutated 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 mutated 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 pathogenic variant results in the substitution of a highly conserved glycine to an arginine at amino acid position 4 (p.Gly4Arg), critical for cathepsin binding.
  • The c.149G>A pathogenic variant 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 pathogenic variant 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.


Literature Cited

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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

  • 26 November 2014 (me) Comprehensive update posted live
  • 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 live
  • 24 June 2004 (me) Review posted live
  • 6 February 2004 (ael) Original submission
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