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Myoclonus improvement after seizures in progressive myoclonic epilepsy type 7: a case report

Abstract

Background

Progressive Myoclonic Epilepsy (PME) is a group of rare diseases that are difficult to differentiate from one another based on phenotypical characteristics.

Case report

We report a case of PME type 7 due to a pathogenic variant in KCNC1 with myoclonus improvement after epileptic seizures.

Discussion

Myoclonus improvement after seizures may be a clue to the diagnosis of Progressive Myoclonic Epilepsy type 7.

Peer Review reports

Background

Progressive Myoclonic Epilepsies (PMEs) are a group of rare and severe conditions characterized by action myoclonus, refractory epilepsy, ataxia and dementia. Most diseases in this group have an autosomal recessive pattern of inheritance [1, 2]. PMEs usually present in late childhood or adolescence. Patients commonly become wheelchair-bound and have a reduced life expectancy.

Progressive Myoclonic Epilepsy type 7, also known as myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK), is associated with the recurrent c.959G > A (p.Arg320His) variant in KCNC1 and stands out for , relatively easily treatable epilepsy without severe cognitive impairment and autosomal dominant inheritance associated with de novo variants [1, 2]. Other variants in EPM7 have been reported to cause epileptic encephalopathy [3].

Case Report

A 29-year-old woman presented at the age of 10 with upper limb abnormal jerky movements. These movements were triggered by action and worsened in the morning. After two months, she started focal epileptic seizures with left limb tonic postures that progressed to generalized tonic-clonic seizures in most occurrences. Her mean seizure frequency was around 2 to 5 seizures a month and tonic-clonic seizures lasted up to 5 min at most, followed by 30 to 60 min of somnolence.

Interestingly, involuntary movements worsened during the menstrual period and improved after each generalized tonic-clonic seizure (Video). The improvement lasted from 5 to 7 days after each seizure. Improvement in myoclonus was not seen with fever and the patient did not consume alcohol.

Following the myoclonus and seizures onset in early adolescence, progressive impairment in gait and balance was observed. By the age of 21, the patient was wheelchair-bound.

Seizures were controlled with valproate. The patient has been seizure-free since the age of 15. Before presenting at our outpatient clinic, she was on carbamazepine which wasn’t effective. No other anti-seizure drugs had been used before valproate and piracetam (which we discontinued posteriorly due to somnolence).

The patient’s early development was marked by a delay in walking and language (she walked without support at the age of three and spoke more elaborated phrases around four years of age). Her medical history was remarkable only for insulin-dependent diabetes mellitus. Her family history was unremarkable.

By the age of 29, the patient achieved a highschool degree. She recently scored 25/30 on Mini Mental State Examination. Neurological examination revealed severe generalized action myoclonus, global ataxia, and dysarthria (Video). Brain MRI showed mild cerebellar atrophy (Fig. 1). Electroencephalogram disclosed generalized spike and spike-wave paroxysms. Whole exome sequencing identified a previously described missense variant c.959G > A (p.Arg320His) in KCNC1 [4, 5]. This variant is classified as pathogenic according to ACMG criteria [6] and was reported to cause Myoclonic Epilepsy Type 7 (OMIM#616,187). Unfortunately, parental testing could not be performed for segregation analysis.

Fig. 1
figure 1

Family pedigree (A): the patient’s parents were unaffected first-degree cousins. Brain MRI (B) showed mild cerebellar atrophy

Discussion

Next-Generation Sequencing (NGS) technology has uncovered rare genetic causes in unsolved PME cases, including established and novel PME-related genes, with a diagnostic yield of over 80% in PME, underlining its status as one of the best genetically defined epilepsy syndromes [7].

The potassium channel subfamily Kv3 consists of four subunits which are encoded by KCNC1, KCNC2, KCNC3, and KCNC4. Pathogenic variants in KCNC3 are associated with spinocerebellar ataxia type 13, whereas KCNC2 and KCNC4 have not been associated with human disease up to this moment [8]. Regarding KCNC1, a study conducted in 2016 found that 16 out of 84 clinically confirmed Progressive Myoclonic Epilepsy (PME) cases without clear genetic etiology had a monoallelic missense variant in the KCNC1 gene, c.959G > A (p.Arg320His), 13 of whom were unrelated [9]. The authors suggested the name MEAK (Myoclonus Epilepsy and Ataxia due to potassium channel mutation) for the condition, corresponding to the PME type 7.

The phenotype described in PME type 7 consists of normal early development with myoclonus as the first symptom (onset at 6 to 14 years), which becomes progressively worse affecting the gait and resulting in patients being wheelchair-bound by adolescence or early adulthood in most cases. Tonic-clonic seizures may be present but are not frequent. Mild cognitive decline occurs in some cases after seizure onset. Magnetic resonance may be normal or show cerebellar atrophy [9, 10]. Exacerbation during menses was reported [5]. High fever is reported to transiently (from hours to days) improve gait and myoclonus in PME type 7 patients [5]. Our patient, however, did not report improvement with fever. Alcohol and pregnancy were also reported to improve the condition of these patients [5]. The patient in this report did not consume alcohol.

Compared to other types of PME, the type 7 has a somewhat similar presentation to Unverricht-Lundborg disease (PME type 1), but with more severe disease progression [2, 10]. To the best of our knowledge, there are no reports describing improvement of myoclonus after seizures in this condition.

Seizures may reduce post-ictal neuronal activity by several mechanisms. Increased calcium entry during depolarization activates a calcium-dependent membrane potassium conductance that allows potassium efflux and membrane hyperpolarization [11, 12]. Extracellular calcium levels also change markedly after paroxysmal neuronal firing. Seizures result in a decline in extracellular calcium activity of approximately 50% [13]. This decrease may impair synaptic transmission because synaptic vesicle fusion and neurotransmitter release are dependent on the entrance of extracellular calcium [14, 15]. Seizure discharges also produce recurrent GABAergic synaptic inhibition via inhibitory interneurons [16, 17], thus reducing excitatory output. Neuromodulators, such as endocannabinoids, adenosine, and neuropeptide Y (NPY) are synthesized and released from neurons following membrane depolarization and inhibit neuronal activity. We hypothesize that the post-seizure inhibition of neuronal activity caused by the aforementioned factors may result in myoclonus improvement in the patient reported here. The deficiency in potassium channel activity may lead to an increase in other compensatory mechanisms responsible for the termination of seizures, but further studies are needed to confirm this hypothesis.

The current therapeutic approach to PMEs remains palliative, to control seizures and myoclonus, and improve patients’ quality of life and independence. Literature is scarce concerning pharmacological options in PMEs, mostly composed of reports and small observational studies [18]. Valproic acid (VPA) is the most reported drug in PMEs. It is described as the drug of choice, alone or in combination with clonazepam, due to its high effectiveness on myoclonus, seizures, and photosensitivity [18].

The PMEs, despite having similar phenotypic features overall, form a very heterogeneous group of conditions, each having a different genetic background and disease-causing mechanism. This makes a single therapeutic approach to all forms unlikely, but also opens up the possibility for personalized therapeutic approaches. Currently, there are several experimental studies in animal and cellular models that aim to correct the main disease-causing mechanism, such as enzyme replacement therapies for Sialidosis and Gaucher’s disease type III, and gene replacement therapy for Lafora disease [2].

This case describes a patient with PME type 7 and illustrates a novel interesting clinical phenomenon myoclonus improvement after seizures in a rare form of progressive myoclonic epilepsy. This adds to the literature as a possible clinical phenomenon that may help clinicians to raise suspicion of Progressive Myoclonic Epilepsy type 7.

Data availability

The dataset generated during the current study is available from the corresponding author on reasonable request. The detailed information regarding the identified variant is available in the ClinVar repository under the Variation ID 162519.

References

  1. Malek N, Stewart W, Greene J. The progressive myoclonic epilepsies. Pract Neurol. 2015;15(3):164–71.

    Article  PubMed  Google Scholar 

  2. Orsini A, Valetto A, Bertini V, Esposito M, Carli N, Minassian BA, et al. The best evidence for progressive myoclonic epilepsy: a pathway to precision therapy. Seizure. 2019;71:247–57.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Cameron JM, Maljevic S, Nair U, Aung YH, Cogné B, Bézieau S, et al. Encephalopathies with KCNC1 variants: genotype-phenotype-functional correlations. Ann Clin Transl Neurol. 2019;6(7):1263–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Barot N, Margiotta M, Nei M, Skidmore C. Progressive myoclonic epilepsy: myoclonic epilepsy and ataxia due to KCNC1 mutation (MEAK): a case report and review of the literature. Epileptic Disord. 2020;22(5):654–8.

    Article  PubMed  Google Scholar 

  5. Oliver KL, Franceschetti S, Milligan CJ, Muona M, Mandelstam SA, Canafoglia L, et al. Myoclonus epilepsy and ataxia due to KCNC1 mutation: analysis of 20 cases and K + channel properties. Ann Neurol. 2017;81(5):677–89.

    Article  CAS  PubMed  Google Scholar 

  6. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a Joint Consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Canafoglia L, Franceschetti S, Gambardella A, Striano P, Giallonardo AT, Tinuper P et al. Progressive Myoclonus epilepsies: Diagnostic Yield with Next-Generation sequencing in previously Unsolved cases. Neurol Genet. 2021;7(6).

  8. Park J, Koko M, Hedrich UBS, Hermann A, Cremer K, Haberlandt E, et al. KCNC1-related disorders: new de novo variants expand the phenotypic spectrum. Ann Clin Transl Neurol. 2019;6(7):1319–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Nascimento FA, Andrade DM. Myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK) is caused by heterozygous KCNC1 mutations. Epileptic Disord. 2016;18(S2):S135–8.

    Article  Google Scholar 

  10. Muona M, Berkovic SF, Dibbens LM, Oliver KL, Maljevic S, Bayly MA, et al. A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. Nat Genet. 2015;47(1):39–46.

    Article  CAS  PubMed  Google Scholar 

  11. Timofeev I, Grenier F, Steriade M. Contribution of intrinsic neuronal factors in the generation of cortically driven electrographic seizures. J Neurophysiol. 2004;92(2):1133–43.

    Article  CAS  PubMed  Google Scholar 

  12. Alger BE, Nicoll RA. Epileptiform burst afterhyperolarization: calcium-dependent potassium potential in hippocampal CA1 pyramidal cells. Science. 1980;210(4474):1122–4.

    Article  CAS  PubMed  Google Scholar 

  13. Heinemann U, Lux HD, Gutnick MJ. Extracellular free calcium and potassium during paroxsmal activity in the cerebral cortex of the cat. Exp Brain Res. 1977;27(3–4):237–43.

    CAS  PubMed  Google Scholar 

  14. Cohen JE, Fields RD. Extracellular calcium depletion in synaptic transmission. Neuroscientist. 2004;10(1):12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. King RD, Wiest MC, Montague PR. Extracellular calcium depletion as a mechanism of short-term synaptic depression. J Neurophysiol. 2001;85(5):1952–9.

    Article  CAS  PubMed  Google Scholar 

  16. Dorn T, Witte OW. Refractory periods following interictal spikes in acute experimentally induced epileptic foci. Electroencephalogr Clin Neurophysiol. 1995;94(1):80–5.

    Article  CAS  PubMed  Google Scholar 

  17. Kostopoulos G, Avoli M, Gloor P. Participation of cortical recurrent inhibition in the genesis of spike and wave discharges in feline generalized penicillin epilepsy. Brain Res. 1983;267(1):101–12.

    Article  CAS  PubMed  Google Scholar 

  18. Ferlazzo E, Trenite DKN, de Haan GJ, Felix Nitschke F, Ahonen S, Gasparini S, et al. Update on Pharmacological Treatment of Progressive Myoclonus Epilepsies. Curr Pharm Des. 2017;23(37):5662–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors

Contributions

PLGSBL, TGG and PRN were responsible for the conceptualization of this report. All authors were engaged in data collection, literature review and early manuscript draft. PBN, ARBP, FF and FK were responsible for manuscript revision. The final version of the article was written by TGG, PRN and PLGSBL.

Corresponding author

Correspondence to Thiago Gonçalves Guimarães.

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G S B Lima, P.L., Nobrega, P.R., Freua, F. et al. Myoclonus improvement after seizures in progressive myoclonic epilepsy type 7: a case report. BMC Neurol 24, 169 (2024). https://doi.org/10.1186/s12883-024-03625-z

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