Myoclonic Epilepsy of Unverricht and Lundborg in a Filipino Woman

Kruzette Khloe L. Solijon; Sheina B. Magtuba; Noel Belonguel; Gerard Saranza

doi:10.14802/jmd.24172

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Letter to the editor Myoclonic Epilepsy of Unverricht and Lundborg in a Filipino Woman: Kruzette Khloe L. Solijon¹, Sheina B. Magtuba², Noel Belonguel², Gerard Saranza^1,3,4,5; Journal of Movement Disorders 2025;18(1):96-98.
DOI: https://doi.org/10.14802/jmd.24172
Published online: October 7, 2024

¹Section of Adult Neurology, Department of Internal Medicine, Chong Hua Hospital, Cebu, Philippines

²Department of Internal Medicine, Perpetual Succor Hospital, Cebu, Philippines

³Movement Disorders Service, Chong Hua Hospital and Vicente Sotto Memorial Medical Center, Cebu, Philippines

⁴Departments of Anatomy and Internal Medicine, Cebu Institute of Medicine, Cebu, Philippines

⁵Department of Neurosciences, University of the Philippines-Philippine General Hospital, Manila, Philippines

Corresponding author: Gerard Saranza, MD Movement Disorders Service, Chong Hua Hospital and Vicente Sotto Memorial Medical Center, Room 617, Medical Arts Bldg., Mantawi Drive, Mandaue, Cebu, 6014 Philippines / Tel: +63-9176364206 / E-mail: gerardsaranza@gmail.com

• Received: August 2, 2024 • Revised: October 2, 2024 • Accepted: October 7, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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REFERENCES

Dear Editor,

Myoclonic epilepsy of Unverricht and Lundborg, also known as Unverricht-Lundborg disease (ULD), is a rare autosomal recessive progressive myoclonus epilepsy (PME) disorder, characterized by early-onset neurodegeneration that can severely retard functional capacity [1,2]. Mutation in the Cystatin B (CSTB) gene in chromosome 21q22.3 is known to cause the disease, with an abnormal dodecamer repeat expansion (CCC-CGCCCC-GCG) in the promoter region accounting for approximately 90% of cases [1,3]. In ULD, the onset of stimulus-sensitive myoclonus and tonic-clonic seizures occurs between ages 6 to 15, which may progressively worsen in the following 5 to 10 years [1,3]. Unlike other forms of PME, the disease stabilizes in early adulthood, and there is minimal to no cognitive decline.2 The prevalence of ULD is highest in Finland, with a known familial occurrence and an annual incidence rate of 0.022 per 100,000 persons [4,5]. Although sporadic cases are reported in some Asian countries, including Japan and Korea, the worldwide incidence remains relatively low [6,7]. Herein, we present a case of a 40-year-old Filipino woman with clinical features suggestive of PME and genetic test results supporting the diagnosis of ULD in a compound heterozygous state.

A 40-year-old woman presented with jerky movements of the extremities and face. She started having myoclonic jerks at the age of 8, initially localized to the upper limbs. Within a few months, jerky movements of the lower limbs were also observed. Symptoms were heightened by stress, sudden movements, and even performing activities involving self-care. At 9 years old, episodes of generalized tonic-clonic seizures (GTCS) were noted, occurring at least one to two times per month. She dropped out of school due to the continued progression of myoclonic jerks, dysarthria, and gait disturbance. Her symptoms worsened until she lost her ability to walk and became wheelchair-bound at the age of 12. No comprehensive workup or treatment was done due to the family’s limited resources.

The patient was born to non-consanguineous Filipino parents with an unremarkable family history. Earlier developmental milestones were at par with age. There were no reports of family members having similar signs and symptoms. The patient was then referred to a neurologist and subsequently to a movement disorders specialist. She was seen alert and coherent. Her speech was appropriate but slurred. On inspection, she had generalized atrophy of muscles, which was more evident in the lower limbs. No limb ataxia was noted during the examination, but her gait was wide-based. Myoclonic jerks were present and triggered by movements and tactile stimulation (Supplementary Video 1 in the online-only Data Supplement). The rest of the neurological examination was unremarkable.

Electroencephalogram (EEG) revealed generalized background slowing with diffuse delta activity. No epileptiform discharges or paroxysmal response was elicited during photic stimulation. Cranial contrast-enhanced magnetic resonance imaging (MRI) was unremarkable. Fundoscopy was unremarkable, and no cherry red spot was noted. PME was considered based on her clinical features. Genetic testing (Epilepsy panel; Centogene^®, Rostock, Germany) revealed a heterozygous pathogenic expansion (≥30 dodecamer repeats) as well as a variant of uncertain significance (VUS), c.87del p.(Glu31Lysfs*50), which causes a frameshift mutation. She was started on levetiracetam (1,000 mg/day) and clonazepam (0.5 mg/day) for symptomatic control. On follow-up consult, increased frequency of myoclonic jerks and gait imbalance were reported; thus, medication adjustments were made. At present, she has been maintained on piracetam (2,400 mg/day), levetiracetam (3,000 mg/day), and clonazepam (2 mg/day), with good symptom control (Supplementary Video 2 in the online-only Data Supplement).

The patient’s course of illness follows the typical presentation of ULD. She had an unremarkable medical history before manifesting with myoclonic jerks and GTCS at the age of 8. The progression of her myoclonus, the associated dysarthria, and ataxia severely affected her functional capacity. ULD can be suspected in a previously healthy child with the following features: worsening myoclonic jerks or GTCS, usually with associated ataxia, slow background activity on EEG, and a normal brain MRI. Confirmatory diagnosis, however, requires genetic testing. The implicated gene is CSTB in chromosome 21, with the CCCCGC-CCC-GCG dodecamer repeat expansion of ≥30 being the most common mutation. Being an autosomal recessive condition, the genetic diagnosis of ULD requires either a homozygous dodecamer repeat expansion or a compound heterozygous mutation, with a dodecamer repeat expansion and a CSTB sequence variant [1]. In this case, the pathogenic dodecamer repeat and the VUS, which causes a frameshift mutation, support the genetic diagnosis of ULD in a compound heterozygous state. The VUS, which results in a frameshift mutation at codon 31, has not been reported in previous literature. Admittedly, segregation analysis was recommended; however, this was not pursued due to financial constraints.

The symptoms of ULD typically stabilize and improve in early adulthood. However, there have been reports indicating that individuals with compound heterozygosity for a dodecamer repeat expansion and a sequence variant in the CSTB gene may experience earlier onset, more severe myoclonus, and potentially drug-resistant seizures [8]. In addition, there are also gender-related differences in the clinical presentation of ULD. Female patients tend to have better clinical outcomes than male patients, which we also observed in our patient. The favorable clinical outcomes observed in females compared to males with ULD may be associated with the interaction of sex hormones [9]. The role of estrogen in the CSTB gene can potentially influence the expression of CSTB, which is essential in proper cell proliferation and interneuron migration. This association may explain why females with ULD present with milder phenotypes.

In ULD, the possible mechanism underlying myoclonus and epilepsy may involve the loss of gamma-aminobutyric acid (GABA) neuronal elements at the synaptic terminus [10]. Myoclonus in ULD is known to be resistant to antiseizure medications [1]. Nonetheless, our patient had a remarkable improvement in the amplitude and frequency of her myoclonic jerks. We attribute the improvement to the combination of medications given and the female sex of the patient, which tends to have a more benign course. Typically, valproic acid is the preferred medication for addressing myoclonus; levetiracetam can be used as an alternative, and clonazepam can be used as an additional treatment [3]. Piracetam can also be used to treat myoclonus due to its GABAergic action [11]. Clonazepam works by enhancing GABAergic neurotransmission through benzodiazepine receptors, while levetiracetam functions by binding to synaptic vesicle protein 2A and facilitating neurotransmitter release [12]. Valproic acid was also tried but without any notable improvement. Since there is currently no cure for ULD, the primary goal should be focused on symptom control and rehabilitation.

Although PME is rarely described in the Asian region, we believe investigating the genetic cause of patients clinically suspected to have PME is paramount. Understanding this condition’s clinical features with a good genotype and phenotype correlation can help enhance our knowledge of its etiology, symptomatology, prognosis, and treatment outcomes. Through collaborative efforts and research, we can support individuals affected by this debilitating genetic condition.

Supplementary Materials

The online-only Data Supplement is available with this article at https://doi.org/10.14802/jmd.24172.

Video 1.

A 40-year-old Filipino woman presented with frequent spontaneous and action-induced myoclonus. Her gait was unstable and ataxic.

Video 2.

She has been maintained on levetiracetam (3,000 mg/day), clonazepam (2 mg/day), and piracetam (2,400 mg/day). On follow-up, she had good control of her symptoms.

Notes

Ethics Statement

The authors confirm that the approval of an institutional review board was not required for this work. Informed consent was separately obtained for the videotapes taken as part of the routine clinical evaluation. The patient and her family also provided informed consent for publication.

Conflicts of Interest

The authors have no conflicts of interest to declare.

Funding Statement

None

Author Contributions

Conceptualization: Kruzette Khloe L. Solijon. Data curation: Kruzette Khloe L. Solijon, Sheina B. Magtuba. Supervision : Noel Belonguel, Gerard Saranza. Validation : Gerard Saranza. Visualization: Noel Belonguel, Gerard Saranza. Writing—original draft: Kruzette Khloe L. Solijon, Sheina B. Magtuba. Writing—review & editing: Kruzette Khloe L. Solijon, Sheina B. Magtuba, Gerard Saranza.

Acknowledgments

The authors would like to express utmost gratitude to the patient and to her family for their consent to report the case.

REFERENCES

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