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Genetic Testing

Genetic Testing for

Unverricht-Lundborg Disease (EPM1)

and Spectrum of Disease



Mayank Verma M.D., Ph.D. and Brianne Dentel M.D., Ph.D.


Unverricht-Lundborg Disease (ULD) is caused by mutations in the cystatin B gene (CSTB). Complete loss of CSTB on the other hand leads to developmental epileptic encephalopathy (DEE). The spectrum of ULD disease is based on the amount of expression of the gene cystatin B (CSTB).


The 5’- flanking region of the CSTB gene contains a dodecamer repeat that contains normally 2-3 repeats but can spontaneously expand (Lafrenière et al., 1997, Lalioti et al., 1997). A large expansion causes a significant decrease in the expression of CSTB. While carriers with one allele with the CSTB dodecamer repeat expansion are not affected, two alleles of this dodecamer repeat expansion cause a sufficient decrease in the expression of the protein (~10% of normal). This results in the Classical ULD phenotype which leads to disease onset between 6-15 years of age with intractable myoclonus, difficult to treat seizures, and neurodegeneration (Joensuu et al., 2008, Kälviäinen et al., 2008, Joensuu et al., 2007). Additionally, there are individuals who have compound heterozygous mutations in CSTB where one allele is affected by the expansion repeat, and the other is affected by a loss of function or null mutation (Canafoglia et al., 2012). These individuals typically have even less CSTB (around 5% of normal), an earlier onset of symptoms, and more severe phenotypes of ULD (Koskenkorva et al., 2011).


It is now standard of care to evaluate for genetic epilepsies with genetic “Epilepsy panels”. These panels are performed using next-generation sequencing technology (NGS) and provide full-gene sequencing and deletion/duplication analysis. While the CSTB gene is included in many of these commercial panels, they lack the ability to detect the dodecamer repeat. This repeat expansion is also not detected with advanced techniques such as whole exome sequencing (WES) or whole genome sequencing (WGS). In addition, if a variant of unknown significance (VUS) or pathogenic mutation is found in one allele, it may be disregarded as not being disease causative as ULD is an autosomal recessive disease. Therefore, a high index of suspicion and knowledge of ULD is required to send out specific testing for the dodecamer repeat expansion. Unfortunately, many of these individuals are either missed or have great delays in diagnosis because of the lack of repeat expansion testing.

The following offer testing for the specific CSTB repeat expansion analysis:


Mayo Clinic



Charleston Area Medical Center


Medical Genetics Center


CANAFOGLIA, L., GENNARO, E., CAPOVILLA, G., GOBBI, G., BONI, A., BECCARIA, F., VIRI, M., MICHELUCCI, R., AGAZZI, P., ASSERETO, S., COVIELLO, D. A., DI STEFANO, M., ROSSI SEBASTIANO, D., FRANCESCHETTI, S. & ZARA, F. 2012. Electroclinical presentation and genotype-phenotype relationships in patients with Unverricht-Lundborg disease carrying compound heterozygous CSTB point and indel mutations. Epilepsia, 53, 2120-7.

JOENSUU, T., KURONEN, M., ALAKURTTI, K., TEGELBERG, S., HAKALA, P., AALTO, A., HUOPANIEMI, L., AULA, N., MICHELLUCCI, R., ERIKSSON, K. & LEHESJOKI, A. E. 2007. Cystatin B: mutation detection, alternative splicing and expression in progressive myclonus epilepsy of Unverricht-Lundborg type (EPM1) patients. Eur J Hum Genet, 15, 185-93.


JOENSUU, T., LEHESJOKI, A.-E. & KOPRA, O. 2008. Molecular background of EPM1—Unverricht–Lundborg disease. Epilepsia, 49, 557-563.


KÄLVIÄINEN, R., KHYUPPENEN, J., KOSKENKORVA, P., ERIKSSON, K., VANNINEN, R. & MERVAALA, E. 2008. Clinical picture of EPM1-Unverricht-Lundborg disease. Epilepsia, 49, 549-56.


KOSKENKORVA, P., HYPPÖNEN, J., AIKIÄ, M., MERVAALA, E., KIVIRANTA, T., ERIKSSON, K., LEHESJOKI, A. E., VANNINEN, R. & KÄLVIÄINEN, R. 2011. Severer phenotype in Unverricht-Lundborg disease (EPM1) patients compound heterozygous for the dodecamer repeat expansion and the c.202C>T mutation in the CSTB gene. Neurodegener Dis, 8, 515-22.


LAFRENIÈRE, R. G., ROCHEFORT, D. L., CHRÉTIEN, N., ROMMENS, J. M., COCHIUS, J. I., KÄLVIÄINEN, R., NOUSIAINEN, U., PATRY, G., FARRELL, K., SÖDERFELDT, B., FEDERICO, A., HALE, B. R., COSSIO, O. H., SØRENSEN, T., POULIOT, M. A., KMIEC, T., ULDALL, P., JANSZKY, J., PRANZATELLI, M. R., ANDERMANN, F., ANDERMANN, E. & ROULEAU, G. A. 1997. Unstable insertion in the 5' flanking region of the cystatin B gene is the most common mutation in progressive myoclonus epilepsy type 1, EPM1. Nat Genet, 15, 298-302.


LALIOTI, M. D., SCOTT, H. S., BURESI, C., ROSSIER, C., BOTTANI, A., MORRIS, M. A., MALAFOSSE, A. & ANTONARAKIS, S. E. 1997. Dodecamer repeat expansion in cystatin B gene in progressive myoclonus epilepsy. Nature, 386, 847-51.

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