Progressive Myoclonic Epilepsy Type 1
Summary
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 antiseizure medications, 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.
Diagnosis
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).
Table 1.
Molecular Genetic Testing Used in Progressive Myoclonic Epilepsy Type 1
| Gene 1 | Method 2, 3 | Proportion of Probands with a Pathogenic Variant Detectable by Method |
|---|---|---|
| CSTB | Targeted analysis for the dodecamer expansion | ~90% 4, 5 |
| Sequence analysis 6 | ~10% 4 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Table 7 for specific methods to characterize the number of dodecamer (CCC-CGC-CCC-GCG) repeats in CSTB.
- 3.
Sequence-based multigene panels, exome sequencing, and genome sequencing cannot detect pathogenic repeat expansions in this gene.
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or 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.
- 5.
Lalioti et al [1997], Joensuu et al [2008]
- 6.
~99% in Finnish individuals [Joensuu et al 2008]
Clinical Characteristics
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 antiepileptic drug treatment. 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.
Differential Diagnosis
At the onset of progressive myoclonic epilepsy type 1 (EPM1), juvenile myoclonic epilepsy (JME) (OMIM PS254770) – which has a more favorable outcome – should be considered as a diagnostic alternative. Individuals with JME have a normal neurologic examination and undisturbed background of the EEG.
Other disorders to consider in the differential diagnosis of EPM1 are summarized in Table 2.
Table 2.
Genes of Interest in the Differential Diagnosis of Progressive Myoclonic Epilepsy Type 1
| Gene(s) | Disorder | MOI | Clinical Characteristics of Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/EPM1 | Distinguishing from EPM1 | |||
| EPM2A NHLRC1 | PME, Lafora type | AR |
|
|
| GOSR2 | EPM6 (OMIM 614018) | AR |
| Earlier onset; scoliosis (develops by adolescence) |
| KCNC1 | EPM7 (OMIM 616187) | AD |
| EPM7 & EPM1 have a remarkably similar clinical presentation. EPM7 may have a somewhat more severe progression than EPM1 in its early phases. |
| MT-TF MT-TI MT-TK MT-TL1 MT-TP | MERRF | Mat |
|
|
| SCARB2 | Action myoclonus - renal failure syndrome | AR | Typically presents at ages 15-25 yrs; may present w/neurologic symptoms (e.g., tremor, action myoclonus, seizures, ataxia) 2 | May present w/proteinuria that progresses to renal failure |
AD = autosomal dominant; AR = autosomal recessive; Mat = maternal; MERRF = myoclonic epilepsy with ragged red fibers; MOI = mode of inheritance; PME = progressive myoclonic epilepsy; RRF = ragged red fibers
- 1.
Muona et al [2015]
- 2.
Action myoclonus - renal failure syndrome typically comprises a continuum of two major (and ultimately fatal) manifestations: progressive myoclonic epilepsy and renal failure; however, in some instances, the kidneys are not involved. Neurologic manifestations can appear before, simultaneously, or after the renal manifestations.
Management
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.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with EPM1
| System/Concern | Evaluation | Comment |
|---|---|---|
| Neurologic | Neurologic assessment of myoclonus, incl myoclonus at rest, w/action, & in response to stimuli | Use standardized UMRS. |
| Seizure type & frequency | Obtain baseline EEG before initiation of antiseizure therapy (when EEG is most characteristic). | |
| Cerebellar motor dysfunction (gait & postural ataxia, dysmetria, dysdiadochokinesis, tremor, dysarthria, nystagmus, saccades & smooth pursuit) | Use standardized scale to establish baseline for ataxia (SARA, ICARS, or BARS). | |
| Musculoskeletal / Activities of daily living | By physical medicine & rehabilitation/OT/PT | To assess gross motor & fine motor skills, gait, ambulation, need for adaptive devices, need for ongoing PT/OT |
| Speech | For those w/dysarthria: speech & language eval | Consider referral to speech & language pathologist. |
| Cognitive | Neuropsychologist | Cognitive eval to establish baseline |
| Psychiatric | Psychiatrist | Evaluate as needed for depression & supportive therapy. |
| Development / School performance | Developmental assessment |
|
| Genetic counseling | By genetics professionals 1 | To inform affected individuals & their families about the nature, MOI, & implications of EPM1 to facilitate medical & personal decision making |
| Family support/ resources | Assess:
| To facilitate peer support for patients & families |
BARS = Brief Ataxia Rating Scale; ICARS = International Cooperative Ataxia Rating Scale; MOI = mode of inheritance; OT = occupational therapist/therapy; PT = physical therapist/therapy; SARA = Scale for the Assessment and Rating of Ataxia; UMRS = Unified Myoclonus Rating Scale
- 1.
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Treatment of Manifestations
Table 4.
Treatment of Manifestations in Individuals with EPM1
| Manifestation/Concern | Treatment | Considerations/Other | |
|---|---|---|---|
| Myoclonus | Pharmacologic | Valproic acid | First drug of choice; diminishes myoclonus & frequency of generalized seizures |
| Clonazepam | FDA-approved for treatment of myoclonic seizures; used as add-on therapy 1 | ||
| High-dose piracetam | Useful in treatment of myoclonus 2 | ||
| Levetiracetam, brivaracetam, 3 perampanel 4 | Appears effective for both myoclonus & generalized seizures | ||
| Topiramate & zonisamide | May be used as add-on therapies | ||
| N-acetylcysteine | Variable results 5 | ||
| Vagus nerve stimulation | Reduces seizures & significantly improves cerebellar function on neurologic exam 6 | ||
| Other | Avoid extreme stimuli (lights, noises, stress). | ||
| Seizures | Antiseizure medication | ||
| Activities of daily living | PT/OT |
| |
| Developmental delay / Intellectual disability | See Developmental Delay / Intellectual Disability Management Issues. | ||
| Dysarthria | Speech & language therapy | Consider alternative communication methods as needed (e.g., writing pads & digital devices). | |
| Dysphagia | Feeding therapy programs to improve nutrition & dysphagia & reduce aspiration risk |
| |
| Weight | Nutrition assessment |
| |
| Family support/resources | Psychotherapy, peer support | ||
ADL = activities of daily living; OT = occupational therapy; PEG = percutaneous endoscopic gastrostomy; PT = physical therapy
- 1.
Shahwan et al [2005]
- 2.
Koskiniemi et al [1998]
- 3.
Kälviäinen et al [2016]
- 4.
Crespel et al [2017]
- 5.
Edwards et al [2002]
- 6.
Smith et al [2000]
Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for school-age individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:
- Individualized education plan (IEP) services:
- An IEP provides specially designed instruction and related services to children who qualify.
- IEP services will be reviewed annually to determine whether any changes are needed.
- As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
- PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
- As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
- A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
- Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
- Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Surveillance
Table 5.
Recommended Surveillance for Individuals with EPM1
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Myoclonus | Severity of myoclonus using UMRS | At least annually |
| Seizures | Seizure type & frequency | |
| Cerebellar involvement | Clinical eval | Per symptom progression |
| Dysarthria | Need for alternative communication method or speech therapy | |
| Dysphagia | Assess aspiration risk & feeding methods | |
| Weight / Nutritional status |
| |
| Activities of daily living | Clinically to evaluate rehabilitation plan | At least annually |
| School performance | Interview | |
| Cognitive / Psychiatric | Evaluate mood, signs of psychosis, & cognitive complaints to identify need for pharmacologic & psychotherapeutic interventions. | Per symptom progression & development of psychiatric symptoms |
| Family support/resources | Interview | Annually |
BMI = body mass index; UMRS = Unified Myoclonus Rating Scale
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
See 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