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 Table of Contents  
CASE SERIES
Year : 2022  |  Volume : 2  |  Issue : 1  |  Page : 7-11

Three Indian siblings affected with progressive myoclonic epilepsy due to unverricht–Lundborg disease


Department of Pediatrics, Pediatric Neurology Unit, Bharati Vidyapeeth Deemed University Medical College, Pune, Maharashtra, India

Date of Submission30-Jan-2022
Date of Decision02-Feb-2022
Date of Acceptance02-Feb-2022
Date of Web Publication25-Feb-2022

Correspondence Address:
Dr. Kavita Srivastava
Department of Pediatrics, Eighth Floor, Bharati Hospital, Katraj, Pune - 411 043, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ipcares.ipcares_205_21

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  Abstract 

Background: Progressive myoclonus epilepsy (PME) is a group of heterogeneous genetic disorders characterized by action myoclonus, epileptic seizures, and progressive neurologic deterioration with onset of symptoms in adolescence and adulthood. Unverricht–Lundborg disease (ULD) is the most common type of PME in high-income countries; however, it is under-reported from India due to challenges in clinical recognition and establishment of diagnosis due to lack of availability of genetic studies. Clinical Description: We herewith report three siblings (two girls and a boy) born out of a third-degree consanguineous marriage, with onset of “difficult-to-treat” seizures since early adolescence, with concurrent action myoclonus and ataxia. All three had a waxing and waning course. Electroencephalography exhibited generalized spike-wave and polyspike-wave discharges with photosensitivity while neuroimaging was normal. Management and Outcome: The possibility of PME was considered in view of the clinical phenotype and strong family history. Following detailed elicitation of history, focused physical examination, and rational investigative work-up specific molecular genetic testing were planned for ULD. This showed homozygous expansion of dodecamer (set of 12 nucleotides) repeat in the cystatin B gene in all the three affected siblings. The parents were heterozygous carriers. Genetic counseling was undertaken and anticonvulsant drugs (ACDs) modified accordingly. The definitive diagnosis helped in accurate prognostication and management to improve the quality of life of all three siblings. Conclusion: Clinicians should consider a specific epilepsy syndrome in patients with onset of symptoms in adolescence. ULD is a type of PME with a relatively better course of illness. Establishing the diagnosis has implications on the extent of investigative workup, choice of ACD, and prognosis.

Keywords: Action myoclonus, generalized epilepsy, progressive myoclonic epilepsy, Unverricht–Lundborg disease


How to cite this article:
Srivastava K, Thakor BM, Roy S, Rajadhyaksha S, Datar C. Three Indian siblings affected with progressive myoclonic epilepsy due to unverricht–Lundborg disease. Indian Pediatr Case Rep 2022;2:7-11

How to cite this URL:
Srivastava K, Thakor BM, Roy S, Rajadhyaksha S, Datar C. Three Indian siblings affected with progressive myoclonic epilepsy due to unverricht–Lundborg disease. Indian Pediatr Case Rep [serial online] 2022 [cited 2022 May 27];2:7-11. Available from: http://www.ipcares.org/text.asp?2022/2/1/7/338478

As a clinician, it is very important to know the difference between epilepsy and epilepsy syndrome. Epilepsy is a common neurological condition that is characterized by an enduring predisposition to generate recurrent seizures. In contrast, an epilepsy syndrome refers to a cluster of features occurring together, including age at onset, seizure type, triggers, remission (wherever applicable), and electroencephalogram (EEG) findings. These have etiologic and prognostic implications.[1] The epilepsy syndromes with onset in adolescence include genetic generalized epilepsies (GGEs) and progressive myoclonus epilepsies (PMEs).

GGE usually has their onset around adolescence, is characterized by generalized seizures (i.e., generalized tonic–clonic, myoclonic, absence, etc.), and display generalized epileptiform discharges on EEG. These include Juvenile myoclonic epilepsy (JME), Juvenile absence epilepsy, and epilepsy with generalized tonic–clonic seizures (GTCS) on awakening. On the other hand, PME is a group of rare, autosomal recessive disorders, characterized by action myoclonus (mostly drug-resistant), epileptic seizures with abnormal EEG background activity, progressive neurologic deterioration, and reduced life expectancy in most. These account for about 1% of childhood epilepsies.[2]

The PME spectrum includes heterogeneous entities; Unverricht–Lundborg disease (ULD), Lafora body disease (LBD), neuronal ceroid lipofuscinosis (NCL), myoclonic epilepsy with ragged red fibers (MERRF), Gaucher's disease, and sialidosis.[2] Understandably, individual workup is exhaustive, challenging, and expensive. A study from India on the spectrum of PME observed that an etiologic diagnosis was not reached in most cases, primarily due to the prohibitive cost of genetic studies.[3]

ULD is the most common type of PME. Typical clinical manifestations include stimulus-induced myoclonic seizures (i.e., triggered by movement, stress, and sensory stimuli), GTCS, ataxia, and mild cognitive decline. At the onset, these symptoms may mimic GGE, resulting in misdiagnosis. ULD is endemic in several Baltic countries, the highest point prevalence being 1.91/100,000 persons in Finland.[4] An important reason for under-reporting in underdeveloped countries is unavailability of diagnostic facilities locally.

In this case series, we describe an Indian family with three siblings affected with ULD, in which the diagnosis was possible only after we collaborated with an international institute for genetic studies. At the same time, we would also like to emphasize that even in this era of sophisticated investigations, the value of a systematic clinical approach to narrow down the differential diagnoses and choose the most appropriate test for confirmation of diagnosis cannot be underscored.


  Clinical Description Top


The index child, a 17-year-old girl, was referred to us for GTCS that was present since she was 10 years old. These occurred every 2–3 months despite having received multiple combinations of anticonvulsant drugs (ACDs) since the onset; these included valproate, oxcarbazepine, levetiracetam, clonazepam, topiramate, lamotrigine, lacosamide, and even a short course of steroids. Review of the available investigations showed generalized spike-wave and polyspike-wave discharges on her EEG and a normal magnetic resonance imaging (MRI) of the brain.

After the first GTCS, she developed unusual jerky movements of her arms and legs that occurred while attempting any movements. These worsened when performing voluntary activities such as getting up from the chair, or climbing onto the bed, and also, under emotional duress (e.g., during her examinations), or on exposure to bright light and loud sounds. The child was sure that these differed from her seizures in terms of duration (these lasted for few seconds) and nature and occurred irrespective of whichever ACD she was on. Initially, she could control or mask them to a certain extent, but they had become progressively disabling. In fact, the severity increased to such an extent that she had frequent falls, was unable to sit in the classroom, and had to drop out of school. However, she was still able to perform her activities of daily living, independently. On probing further, it became apparent that the jerks had a waxing and waning course, i.e., there were periods of worsening (lasting for weeks to months) followed by improvement. In addition, she described feeling imbalanced while walking (that we ascribed to ataxia) and tremors which also increased during voluntary movements. There was no dysphagia, dysarthria, or any visual or auditory hallucinations. Her academic performance had been satisfactory while she was still attending school. The parents did not feel that she was exhibiting any memory loss. Features of mild cognitive decline and morning drowsiness were ascribed to the multiple ACD.

The girl was born of a 3rd-degree consanguineous marriage. The antenatal and perinatal history was normal. Her development in the initial years was parallel to her peers. The detailed three-generation pedigree is presented in [Figure 1]. There was a significant family history of similar complaints in her younger sister and brother.
Figure 1: Three-generation pedigree chart of the family

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The affected sister was 5 years younger than the index child. The onset of her GTCS was at 11 years of age, occurring twice a month in the initial 2 years. She had been prescribed valproate, lamotrigine, zonisamide, and clonazepam without significant abatement till the 3rd year which lasted for a year. However, after that, the frequency increased substantially, causing her to drop out of school. The parents noted a mild cognitive decline whenever there were very frequent GTCS. She also had severe action myoclonus, bradykinesia, ataxia, and tremors.

The youngest brother (whose twin sister was unaffected) had his first GTCS at the age of 11 years, was seizure free for a year (during which period action myoclonus was noted), and currently has very frequent GTCS, for which he is on levetiracetam, clonazepam, and valproate. He does not have ataxia, tremors, or cognitive decline. The child is attending school, though he has frequent absenteeism due to the seizures. The clinical details of the three siblings, including medications and clinical course, are presented in [Table 1].
Table 1: Clinical details of three Indian siblings with Unverricht–Lundborg disease

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On examination of the index case, her heart rate, respiratory rate, blood pressure, and body mass index were normal. There was no dysmorphism or neurocutaneous markers, but her facies appeared mask-like. She was unable to climb onto the patient bed for examination and had hesitancy in walking due to the fear of fall. Her muscle bulk, tone, power, and reflexes were normal. Myoclonus was observed which increased in amplitude and frequency on attempting movements. She also had bradykinesia, mild ataxia, and tremulousness. The respiratory, cardiovascular, and abdominal examinations were normal. The ophthalmological evaluation revealed normal vision without oculomotor apraxia (excluding Gaucher's disease). The fundus examination did not detect a cherry-red spot, retinitis pigmentosa, or optic atrophy, the presence of which would have indicated Gaucher's disease, MERRF, and NCL, respectively.

We investigated all the siblings, as per protocol. Each of them had similar EEG findings; generalized spike-wave and polyspike-wave discharges with photosensitivity [Figure 2] and [Figure 3]. The MRI (epilepsy protocol) of the index case and younger sister were normal.
Figure 2: Electroencephalogram in awake state showing frequent multifocal and generalized spike and polyspike-wave discharges

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Figure 3: Electroencephalogram showing generalized high-amplitude spike-polyspike–slow-wave discharge (photoparoxysmal response) during photic stimulation at frequency of 15 Hz

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Based on the clinical phenotype of the family, we considered both JME and PME. JME seemed less likely in view of the spectrum and severity of their symptoms (action myoclonus, ataxia, and tremors) and drug refractoriness. The likelihood of the PME spectrum seemed higher. We decided to review all the available clinical information and see which one seemed most suitable to avoid wasting resources and time on a battery of investigations to rule out all the other PME.

The probability of ULD was highest in view of the waxing–waning course, absence of significant cognitive decline, and a normal brain MRI. Since genetic testing was unavailable in any center in India, we collaborated with investigators based in Finland, and samples of the whole family were sent to look for expansion of dodecamer repeats in the cystatin B (CSTB) gene on polymerase chain reaction (PCR). This was detected in all the three affected siblings, and the parents were found to be heterozygous carriers of the same. The final diagnosis of all three siblings was ULD.


  Management and Outcome Top


All the three siblings were managed on varying combinations of broad-spectrum ACD that included sodium valproate, lamotrigine, clonazepam, and topiramate. Despite medications, there was a fluctuating course wherein the myoclonus and/or GTCS worsened periodically to a degree that interfered with activities of daily living. None of the drugs were effective in controlling the action myoclonus during the “worse periods.”

Formal assessment of intelligence quotient could not be done. However, the parents noted that the sisters showed mild cognitive decline. Till the last follow-up, the brother was attending school during the good periods. Both the sisters had to drop out of school due to disabling myoclonus. The index case is recently married and contemplating pregnancy. Her medications were modified and antenatal follow-up was planned with our obstetric colleagues.

The establishment of diagnosis helped in prognostication of the affected individuals and family. They were counseled regarding the relatively better prognosis in terms of possibility of disease stabilization after a few years. This is in contrast to other disorders included in PMEs, which have a uniformly fatal outcome, such as NCL and LBD.


  Discussion Top


Epilepsy syndromes are distinctive syndromes that can be differentiated according to the typical age of onset (as in this case series), specific EEG characteristics, seizure semiology, and other nonseizure-related characteristics, such as cognitive affection and drug responsiveness. Classification of a specific epilepsy syndrome has implications on the extent of investigative workup, choice of ACD, and prognosis.

The two close differentials considered in this family were JME and PME. ULD shares features of both PME (refractory myoclonus, ataxia, tremors) and GGE (no evidence of progressive neurological deterioration, cognitive decline, etc.). The most characteristic feature which differentiates it from both GGE and other forms of PME is the waxing and waning periods – alternating periods of relative quiescence interspersed with periods of refractory seizures.[5] In ULD, the ataxia, tremors, and cognitive disturbances are much milder and appear later and stabilize after a few years.[6]

A step-wise approach encompassing detailed elicitation of history and examination can help reach a diagnosis and prevent unnecessary and invasive investigations, which are likely to have poor yield. Some of the PMEs have clinical indicators which can help in narrowing down the differentials: visual hallucinations (LBD); myopathy, neuropathy, and cardiomyopathy (MERRF); visual impairment, optic atrophy, or cherry-red spot (NCL/sialidosis); oculomotor apraxia or hematological manifestations (Gaucher's), etc.[7] Hence, elicitation of a detailed history and performance of a thorough examination provides direction to the planning of further investigations that include: bone marrow examination (Gaucher's disease), skin biopsy (Lafora disease), CSF lactate and muscle biopsy (MERRF), and genetic studies (NCL, ULD, etc.).

ULD is caused by mutations in the CSTB gene mapped to chromosome 21q22.3. This gene regulates the production of CSTB, a protein that reduces the activity of lysosomal cathepsins (enzymes that break down proteins). Deficiency of CSTB predisposes neurons to oxidative stress, causing neuronal death.[8] The mutation is an unstable dodecamer repeat CCC-CGC-CCC-GCG expansion in the promoter region. Two to three dodecamer repeats are normal, 12–17 repeats are unstable without clinical manifestations, while more than 30 dodecamer repeats are pathogenic. Genetic testing is by Southern blot or PCR (as was done for this family). The mutation may be missed in exome sequencing studies.[6] Carrier testing is recommended for the spouse of affected individuals in communities with high frequency of consanguinity. Antenatal targeted testing for the dodecamer repeat expansion is available.[8]

Broad-spectrum ACDs such as valproate, levetiracetam, topiramate, zonisamide, clonazepam, and piracetam have shown variable response in seizure control.[9] Recent studies report the efficacy of brivaracetam and perampanel for both myoclonus and generalized seizures.[10],[11] Narrow spectrum drugs such as phenytoin, carbamazepine, and oxcarbazepine should be avoided as they may exacerbate myoclonic seizures.

ULD is a PME with a relatively better course with respect to other PME: The myoclonus worsens for 5–10 years and then stabilizes, and epilepsy may also remit after 10–15 years with abatement of EEG changes.[12] In the past, life expectancy was only 8–15 years after the symptoms began. However, recently with newer supportive treatments, individuals with milder forms can live into their seventies.[12]



Acknowledgments

We thank Dr. Anna - Elina Lehesjoki and Dr. Tarja Joensuu of Biomedicum Helsinki, Folkhalsan Research Center, University of Helsinki, Finland, for conducting the genetic studies.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE commission for classification and terminology. Epilepsia 2017;58:512-21.  Back to cited text no. 1
    
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Kälviäinen R. Progressive myoclonus epilepsies. Semin Neurol 2015;35:293-9.  Back to cited text no. 2
    
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Satishchandra P, Sinha S. Progressive myoclonic epilepsy. Neurol India 2010;58:514-22.  Back to cited text no. 3
[PUBMED]  [Full text]  
4.
Sipilä JO, Hyppönen J, Kytö V, et al. Unverricht-Lundborg disease (EPM1) in Finland: A nationwide population-based study. Neurology 2020;95:e3117-23.  Back to cited text no. 4
    
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Kälviäinen R, Khyuppenen J, Koskenkorva P, et al. Clinical picture of EPM1-Unverricht-Lundborg disease. Epilepsia 2008;49:549-56.  Back to cited text no. 5
    
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Lehesjoki AE, Kälviäinen R. Progressive myoclonic epilepsy type 1. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993-2021; 2004. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1142/8. [Last updated on 2020 Jul 02].  Back to cited text no. 6
    
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Shahwan A, Farrell M, Delanty N. Progressive myoclonic epilepsies: A review of genetic and therapeutic aspects. Lancet Neurol 2005;4:239-48.  Back to cited text no. 7
    
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Lehtinen MK, Tegelberg S, Schipper H, et al. Cystatin B deficiency sensitizes neurons to oxidative stress in progressive myoclonus epilepsy, EPM1. J Neurosci 2009;29:5910-5.  Back to cited text no. 8
    
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Lasek-Bal A, Lukasik M, Żak A, et al. Unverricht-Lundborg disease: Clinical course and seizure management based on the experience of Polish centers. Seizure 2019;69:87-91.  Back to cited text no. 9
    
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Kälviäinen R, Genton P, Andermann E, et al. Brivaracetam in Unverricht-Lundborg disease (EPM1): Results from two randomized, double-blind, placebo-controlled studies. Epilepsia 2016;57:210-21.  Back to cited text no. 10
    
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Crespel A, Gelisse P, Tang NP, et al. Perampanel in 12 patients with Unverricht-Lundborg disease. Epilepsia 2017;58:543-7.  Back to cited text no. 11
    
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Magaudda A, Ferlazzo E, Nguyen VH, et al. Unverricht-Lundborg disease, a condition with self-limited progression: Long-term follow-up of 20 patients. Epilepsia 2006;47:860-6.  Back to cited text no. 12
    


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