Clinical characteristics.

Progressive myoclonic epilepsy type 1(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 cognitively mostly within the normal range, but show emotional lability and depression. The epileptic seizures are usually well controlled by anti-seizure medication, but the myoclonic jerks are progressive, action activated, and treatment resistant, and can be severely disabling.

Diagnosis/testing.

The diagnosis of EPM1 is established in a proband with suggestive findings and either biallelic abnormal CCC-CGC-CCC-GCG dodecamer repeat expansions in CSTB or compound heterozygosity for a CSTB dodecamer repeat expansion and a CSTB sequence variant (i.e., single-nucleotide variant or indel) identified by molecular genetic testing.

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, brivaracetam, and perampanel appear 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. Once both CSTB pathogenic variants in a family are known, carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

The diagnosis of progressive myoclonic epilepsy type 1 (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
• Abnormal EEG (always abnormal, even before the onset of manifestations). The background activity is labile and may be slower than normal. Photosensitivity is marked.
• A gradual worsening of the neurologic manifestations (myoclonus and ataxia), difficulties running, playing sports, using stairs
• Normal brain MRI

Establishing the Diagnosis

The diagnosis of EPM1 disease is established in a proband with suggestive findings and either biallelic abnormal CCC-CGC-CCC-GCG dodecamer repeat expansions in CSTB or compound heterozygosity for a CSTB dodecamer repeat expansion and a CSTB sequence variant (i.e., single-nucleotide variant or indel) identified by molecular genetic testing (see Table 1).

Note: Pathogenic dodecamer repeat expansions in CSTB cannot be detected by sequence-based multigene panels, exome sequencing, or genome sequencing.

Repeat sizes

• Normal. 2 to 3 dodecamer repeats
• Uncertain significance. 12-17 dodecamer repeats (unstable, but not clinically characterized)
• Pathogenic (full penetrance). ≥30 dodecamer repeats

Note: The dodecamer repeat sequence is CCC-CGC-CCC-GCG. Repeats of 4-11 and 18-29 have not been observed.

Molecular genetic testing relies on targeted analysis to characterize the number of CSTB CCC-CGC-CCC-GCG dodecamer repeats (see Table 7).

Clinical Description

In more than half of individuals with progressive myoclonic epilepsy type 1 (EPM1) the first manifestation is involuntary myoclonic jerks [Kälviäinen et al 2008, Hyppönen et al 2015]. 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, if psychosocial support is good and depression not too severe.

In almost half of individuals, the first manifestation 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 anti-seizure medication. In rare cases, tonic-clonic seizures do not occur.

Neurologic findings initially appear 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.

Cognitive performance, especially memory, is mostly within the normal range. However, affected individuals may exhibit poor performance in time-limited tests dependent on motor functions.

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, Hyppönen et al 2015]. 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 is comparable to controls up to age 40 years, but is poorer over the long term. Death occurs mainly due to respiratory infections [R Kälviäinen, personal communication].

Genotype-Phenotype Correlations

Individuals with pathogenic variants in CSTB usually develop similar disease manifestations. There is evidence that correlation exists between the length of the expanded dodecamer repeat and the age of onset or disease severity [Hyppönen et al 2015]. However, disease severity also varies among affected individuals within a family with apparently similar repeat-size expansions.

Moreover, EPM1 resulting from compound heterozygosity for a dodecamer repeat expansion and a sequence variant (i.e., single-nucleotide variant or indel) often presents with earlier age of onset, more severe myoclonus, and seizures that may be drug resistant [Koskenkorva et al 2011, Canafoglia et al 2012]. It has been also suggested that compound heterozygosity causes a more severe EPM1 phenotype in affected males than females, but the numbers are small [Assenza et al 2017].

Recently, homozygous stop-codon and frameshift pathogenic variants in CSTB were associated with infantile-onset progressive disorders with unexplained severe developmental delay, microcephaly, and hypomyelination [Mancini et al 2016, O'Brien et al 2017).

Nomenclature

Progressive myoclonic epilepsy type 1 (EPM1) was originally referred to as Baltic myoclonus (or Baltic myoclonic epilepsy) and Mediterranean myoclonus. EPM1 is known to occur worldwide, and thus these toponyms are misleading and should no longer be used.

Prevalence

EPM1 has the highest incidence among the progressive myoclonic epilepsies (PMEs), a term that includes a large and varied group of diseases characterized by stimulus-sensitive myoclonus, epilepsy, and progressive neurologic deterioration.

EPM1 occurs worldwide. Prevalence is increased in certain populations:

• The North African countries of Tunisia, Algeria, and Morocco, where exact prevalence figures are not available
• Finland, where its prevalence (2:100,000) is higher than anywhere else in the world [R Kälviäinen, personal communication]. The incidence in Finland is estimated at 1:20,000 births.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with progressive myoclonic epilepsy type 1 (EPM1), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

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

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.

Mode of Inheritance

Progressive myoclonic epilepsy type 1 (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 (i.e., presumed to be carriers of one CSTB pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for a CSTB pathogenic variant and allow reliable recurrence risk assessment. (De novo variants are known to occur at a low but appreciable rate in autosomal recessive disorders [Jónsson et al 2017].)
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If each parent is known to be heterozygous for a CSTB pathogenic variant, each sib of an affected individual has at conception 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.
• A sib who inherits biallelic CSTB pathogenic variants is likely to have clinical manifestations similar to those of the proband; however, intrafamilial clinical variability may be observed (particularly if affected family members have compound heterozygous CSTB pathogenic variants; see Genotype-Phenotype Correlations).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

• Unless an individual's reproductive partner has EPM1 or is a carrier, offspring will be 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 certain populations (see Prevalence).

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

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the CSTB pathogenic variants in the family.

Carrier testing for the reproductive partners of a known carrier is possible. Primarily, targeted testing for the dodecamer repeat expansion should be done, and if it remains negative, sequencing of CSTB should be considered.

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/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

CSTB encodes cystatin B, an inhibitor of several papain-family cysteine proteases, cathepsins. Cystatin B interacts with histones and cathepsin L in the nucleus where it could regulate cathepsin L activity [Čeru 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 early microglial activation and inflammation, preceding clinical onset of myoclonus [Tegelberg et al 2012, Okuneva et al 2015, Okuneva et al 2016]. In addition, altered GABAergic signaling with subsequent loss of GABA inhibition have been reported in Cstb-deficient knockout mice, suggesting a mechanism for latent hyperexcitability resulting in myoclonus and seizures [Franceschetti et al 2007, Buzzi et al 2012, Joensuu et al 2014].

Impaired redox homeostasis has been reported as a pathophysiologic mechanism in Cstb-deficient knockout mice with cystatin-B-cathepsin B signaling dysregulation being a critical mechanism coupling oxidative stress to neuronal degeneration and death [Lehtinen et al 2009].

Mechanism of disease causation. Loss of function. Dodecamer repeat expansion results in a significantly reduced amount of CSTB mRNA: 5%-10% of the expression found in controls [Joensuu et al 2007]. Other disease-associated variants also result in loss of cystatin-B function and some are associated with total lack of intracellular cystatin B [Joensuu et al 2007, Joensuu et al 2008].

Methods to characterize CSTB CCC-CGC-CCC-GCG repeats. Due to the technical challenges of detecting and sizing CSTB CCC-CGC-CCC-GCG repeat expansions, multiple methods may be needed to rule out or detect CCC-CGC-CCC-GCG repeat expansion (see Table 7). Repeats in the normal range (2-3) are detected by traditional PCR. However, detection of apparent homozygosity for a normal repeat by traditional PCR does not rule out the presence of an expanded repeat, thus, testing by a specific PCR method for expansion detection or Southern blotting is required.

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

• 2 July 2020 (bp) Comprehensive update posted live
• 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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