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Letter to the editor
Two Cases of Genetically Proven SCARB2-Related Progressive Myoclonic Epilepsy Without Renal Failure: A Report From India -
Pavankumar Katragadda1*
, Vikram V Holla1*, Gautham Arunachal2, Nitish Kamble1, Ravi Yadav1, Pramod Kumar Pal1
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Epub ahead of print
DOI: https://doi.org/10.14802/jmd.24222
Published online: December 27, 2024
1Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India
2Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bengaluru, India
- Corresponding author: Pramod Kumar Pal, MD, DNB, DM Department of Neurology, National Institute of Mental Health and Neurosciences, Hosur Road, Bengaluru 560029, Karnataka, India / Tel: +91-80-26995147 / Fax: +91-80-26564830 / E-mail: palpramod@hotmail.com
- *These authors contributed equally to this work.
• Received: October 27, 2024 • Revised: December 17, 2024 • Accepted: December 17, 2024
Copyright © 2025 The Korean Movement Disorder Society
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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Dear Editor,
SCARB2-related action-myoclonus renal failure (SCARB2-AMRF) is an autosomal-recessive disorder that encompasses a spectrum of two major manifestations: progressive myoclonic epilepsy type-4 (EPM4) and renal impairment. All reported patients have neurological involvement, while renal involvement is not universal and can predate or occur after the neurological involvement [1,2]. In this report, we describe two unrelated patients who presented with EPM4 without renal impairment.
A 32-year-old female, without significant perinatal, family or past history, presented with chronic progressive imbalance while walking and postural and action predominant upper limb (UL) tremulousness for 10 years. Over the past 5 years, she developed sudden brief generalized multifocal jerks involving all four limbs, the face, and trunk. In addition, she had generalized tonic–clonic seizures (GTCSs), often preceded by a cluster of myoclonus and occurring 3–4 times a year. At presentation, she was wheelchair dependent. There were no other significant neurological or systemic symptoms.
On examination (Supplementary Video 1 in the online-only Data Supplement), she had normal cognition, hyperkinetic dysarthria, generalized multifocal myoclonic jerks involving the face, all four limbs and trunk, and UL incoordination with superimposed action-induced myoclonus. The ataxia and severe truncal and lower limb (LL) myoclonus interfered with her gait, necessitating support to ambulate. In addition, she had generalized hyperreflexia. The rest of the examination was normal.
On investigation, complete blood count and biochemical blood parameters, routine urine examination, 24-hour urinary protein and cerebrospinal fluid cytology, and biochemical analysis were normal. Magnetic resonance imaging (MRI) of the brain revealed mild cerebral atrophy. Renal ultrasonography was normal. Electroencephalography revealed background theta slowing with independent bilateral frontal and temporal spike-wave discharges (Figure 1). Nerve conduction studies (NCSs) and visual, auditory, and somatosensory evoked potentials (SSEPs) were normal. Exome sequencing revealed a known pathogenic homozygous splice site variant (SCARB2[NM_005506.4]:c.704+1G>A) in intron 5 of the SCARB2 gene, confirming the diagnosis of EPM4. She received levetiracetam (2 g/day), clonazepam (0.5 mg/day), and perampanel (4 mg/day). She had mild improvement in the frequency and severity of the myoclonus at the 6-month follow-up.
A 23-year-old female born to a third-degree consanguineous parent with an otherwise normal developmental and family history presented with a 2-year history of progressive imbalance while walking and LL tremulousness. She also had left-side predominant jerky tremulousness of bilateral ULs while holding or reaching for objects. A month before her presentation at our hospital, three episodes of GTCSs of unknown onset occurred. She was on treatment for hypothyroidism and irregular menstrual cycles.
On examination (Supplementary Video 2 in the online-only Data Supplement), hyperpigmentation was noted in the periorbital region, lips, neck, knuckles, and flexural creases of the limbs. She had normal cognition, bilateral ill-sustained gaze-evoked nystagmus, postural UL tremors, and occasional superimposed multifocal myoclonus in all four limbs, along with mild gait ataxia and impaired tandem gait. The rest of the examination was normal.
On evaluation, except for elevated thyroid-stimulating hormone (TSH) (7.5 mU/L) and anti-thyroid peroxidase (anti-TPO) antibody titers (1,300 IU/mL), her complete blood count, other biochemical blood investigations, routine urine examination, 24-hour urinary protein, cerebrospinal fluid cytology, and biochemistry, brain MRI, renal ultrasonography, electroencephalography, NCS, and evoked potentials were normal. In view of the myoclonus-ataxia and elevated anti-TPO antibodies, the possibility of atypical Hashimoto’s encephalopathy was considered despite the absence of cognitive and sensorium abnormalities. The patient received intravenous methyl prednisolone (1 g/day for 5 days), along with levetiracetam (1 g/day), clonazepam (0.5 mg/day), and dose optimization of levothyroxine. Initially, she experienced mild improvement in her imbalance and tremors. However, at the 6-month follow-up, she reported worsening of tremors and walking difficulty. Repeat TSH and anti-TPO antibodies were normal. Exome sequencing revealed a known pathogenic homozygous stop-gain variant (SCARB2 [NM_005506.4]:c.361C>T;p.Arg121Ter) in exon 3 of the SCARB2 gene, confirming the diagnosis of EPM4. The dose of levetiracetam was further optimized to 2 g/day. Currently, she is independent in her activities of daily living.
In both cases, the presentation was early third-decade-onset chronic progressive myoclonus epilepsy with ataxia syndrome with no significant biochemical abnormalities or MRI changes, an abnormal electroencephalogram (EEG) in only the first case, and normal evoked potentials in both cases. The patients were approached in line with myoclonus-ataxia with epilepsy [3]. In the first case, in view of a decade-long illness with normal biochemical parameters and only mild cerebral atrophy, inherited causes were considered. Progressive myoclonus epilepsy syndromes such as Lafora body disease, sialidosis, neuronal ceroid lipofuscinosis, Gaucher’s disease, and mitochondrial disorders were considered in the differential diagnosis. In the second case, as there was a shorter history, acquired causes such as Hashimoto’s encephalopathy, celiac disease, and metabolic causes were also considered. As anti-TPO antibodies were elevated, a trial of steroids was given but with no long-term benefit. Eventually, exome sequencing confirmed the diagnosis of SCARB2-related progressive myoclonus ataxia. Owing to the broad differentials and multiple genetic etiologies that can lead to myoclonus ataxia, whole-exome sequencing was performed instead of a targeted gene panel [3].
SCARB2-AMRF symptoms usually start in the 2nd or 3rd decade of life in the form of positive and/or negative myoclonus, postural tremor, and epilepsy. Myoclonus can be exacerbated by action, tactile stimuli, anxiety, stress, and fatigue [2]. GTCSs typically occur a few years after the myoclonus, can be triggered by light and eye closure, and can progress to status epilepticus. Ataxia and dysarthria occur later in the disease course. Patients can also develop peripheral neuropathy, sensorineural hearing loss, and cognitive dysfunction.
Renal manifestations can be highly variable even within a single family. Asymptomatic proteinuria can occur initially, progressing to nephrotic syndrome and eventually to end-stage kidney disease with tubular abnormalities and focal segmental glomerulosclerosis on histopathology. Dibbens et al. [4] first reported the absence of renal manifestations in four SCARB2-AMRF patients with a prolonged neurological course. The absence of renal impairment has subsequently been noted in approximately half of the reported cases [1,2,4]. Neurologic manifestations can appear before, simultaneously, or after the renal manifestations. In both of our patients, there was no renal involvement. However, neither of the patients underwent functional renal neuroimaging to identify early changes. Long-term monitoring is necessary to identify the renal involvement, if any, in the early stage.
Cerebral, cerebellar, and brainstem atrophy can be observed by neuroimaging. However, it can be normal early in the illness, as observed in patient 2 [2]. The EEG can be normal and with disease progression, may show diffuse background slowing at 6.5– 7.5 Hz, low-voltage spike/polyspike-wave discharges, and photo paroxysmal response with fixation-off sensitivity. Myoclonic jerks are often preceded by contralateral and somatotopically organized cortical discharges [5,6]. The EEG was abnormal in patient 1 but normal in patient 2. Despite the cortical origin of the myoclonus, giant SSEPs are rare compared with other progressive myoclonic epilepsy syndromes, as observed in both of our patients. This could be due to coexistent neuropathy during the later course of the illness [6,7].
Most of the variants identified thus far in SCARB2-AMRF are truncating variants and are located in the luminal domain of the Lysosomal integral membrane protein-2 [2]. The c.704+1G>A variant observed in patient 1 was previously reported by Dibbens et al. [4] in a patient of Italian origin with only neurological manifestations. The c.361C>T;p.Arg121Ter variant observed in patient 2 was previously reported by Fu et al. [8] in a Japanese patient who had additional cognitive impairment.
There is no disease-modifying treatment for SCARB2-AMRF. Relentless progression leads to neurological deterioration and/or end-stage kidney disease, resulting in death within 10–15 years. Neurological management includes symptomatic treatment for the myoclonus and seizures and supportive care. Mild improvement has been noted in a few patients who were administered miglustat [9]. However, significant side effects such as nausea, vomiting, and diarrhea may limit its use [10]. Renin-angiotensin–aldosterone system inhibitors can be considered for the treatment of proteinuria. Immunosuppressive therapy is usually ineffective, and dialysis and renal transplantation may eventually be necessary. Renal transplantation can prolong survival but does not improve the neurologic features [5].
Supplementary Materials
The online-only Data Supplement is available with this article at https://doi.org/10.14802/jmd.24222.
Video 1.
Video of patient 1 demonstrating multifocal myoclonus involving the face, tongue, all four limbs, and trunk, which was present at rest and exacerbated by posture and action. The patient had impaired finger-to-nose test results due to the ataxia and myoclonic jerks.
Video 2.
Video of patient 2 demonstrating distal predominant multifocal myoclonus involving all four limbs, and trunk, which was present at rest and exacerbated by posture and action. The patient had impaired finger-to-nose test results due to the ataxia and myoclonic jerks. There was mild ataxic gait with impaired tandem walking.
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Ethics Statement
The written informed consent was obtained for video recording and publication in print and in online.
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Conflicts of Interest
The authors have no financial conflicts of interest.
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Funding Statement
None
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Acknowledgments
None
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Author Contributions
Conceptualization: Pavankumar Katragadda, Vikram V Holla, Pramod Kumar Pal. Data curation: Pavankumar Katragadda, Vikram V Holla, Pramod Kumar Pal. Formal analysis: Pavankumar Katragadda, Vikram V Holla. Investigation: all authors. Methodology: all authors. Resources: Pavankumar Katragadda, Vikram V Holla. Supervision: Pramod Kumar Pal. Validation: Gautham Arunachal, Ravi Yadav, Pramod Kumar Pal. Visualization: Vikram V Holla, Pramod Kumar Pal. Writing—original draft: Pavankumar Katragadda. Writing—review & editing: Vikram V Holla, Nitish Kamble, Gautham Arunachal, Ravi Yadav, Pramod Kumar Pal.
Notes
Figure 1.
Electroencephalograph of patient 1 showing spike-wave discharges preceding the myoclonic jerk recording on the surface EMG trace (A) and focal epileptiform discharges in the right frontal and temporal leads (B). EMG, electromyography.
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XML DownloadTwo Cases of Genetically Proven SCARB2-Related Progressive Myoclonic Epilepsy Without Renal Failure: A Report From India
Figure 1. Electroencephalograph of patient 1 showing spike-wave discharges preceding the myoclonic jerk recording on the surface EMG trace (A) and focal epileptiform discharges in the right frontal and temporal leads (B). EMG, electromyography.
Figure 1.
Two Cases of Genetically Proven SCARB2-Related Progressive Myoclonic Epilepsy Without Renal Failure: A Report From India
