Progressive myoclonic epilepsy type 1 (EPM1) is a neurodegenerative disease caused by biallelic variants in the cystatin B (CSTB) gene. Despite a progressive course, phenotype severity varies among patients, even within families. We studied the potential role of APOE ε4 in modifying phenotypic diversity in EPM1, given its established association with neurodegeneration, particularly in Alzheimer's disease. APOE genotypes were determined for 65 genetically verified EPM1 patients homozygous for the CSTB expansion mutation. The Unified Myoclonus Rating Scale (UMRS), Quality of Life in Epilepsy Inventory-31 questionnaire (QOLIE-31), intellectual ability (WAIS-R), clinical data, and quantitative neuroimaging data were compared between APOE ε4 carriers and noncarriers to assess potential correlations with EPM1 severity. Volumetric analysis was performed on MRI data, while diffusion tensor imaging (DTI) was analyzed using Tract-Based Spatial Statistics (TBSS) and atlas-based white matter (WM) tract region of interest (ROI) analysis. The cohort included 20 ε4 carriers (16 ε3/ε4 and 4 ε4/ε4) and 45 ε4 noncarriers (36 ε3/ε3, 8 ε2/ε3, and 1 ε2/ε2). No significant differences were found in UMRS or disease duration. Carriers had better QOLIE-31 scores in emotional well-being (p = .047), energy/fatigue (p = .048), and medical effects (p = .024). In volumetric analysis, carriers exhibited greater preservation of bilateral hippocampal and amygdalar volumes but demonstrated more pronounced cortical thinning in the left lingual gyrus, right lateral occipital gyrus, and right posterior cingulate (p < .05). Carriers exhibited more widespread WM degeneration in DTI, characterized by reduced fractional anisotropy (FA) and increased mean diffusivity (MD). Despite greater white matter degeneration and reduced cortical thickness, APOE ε4 carriers exhibited preserved deep brain volumes and better self-reported well-being. This study highlights the complex interplay between genetic factors and neurodegenerative processes. Our future research aims to provide more natural history data of EPM1 and correlate long-term phenotypic data with additional geno-phenotypic analyses.

Progressive myoclonic epilepsy type 1 (EPM1) is an autosomal recessive disorder, also known as Unverricht-Lundborg disease (ULD). EPM1 patients suffer from photo-sensitive seizures, stimulus-sensitive myoclonus, nocturnal myoclonic seizures, ataxia and dysarthria. In addition, cerebral ataxia and impaired GABAergic inhibition are typically present. EPM1 is caused by mutations in the Cystatin B gene (CSTB). The CSTB protein functions as an intracellular thiol protease inhibitor and inhibits Cathepsin function. It also plays a crucial role in brain development and regulates various functions in neurons beyond maintaining cellular proteostasis. These include controlling cell proliferation and differentiation, synaptic functions and protection against oxidative stress, likely through regulation of mitochondrial function. Depending on the differentiation stage and status of neurons, the protein localizes either to the cytoplasm, nucleus, lysosomes or mitochondria. Further, CSTB can also be secreted to the extracellular matrix for interneuron rearrangement and migration. In this review, we will review the various functions of CSTB in the brain and discuss the putative pathophysiological mechanism underlying EPM1.

Progressive myoclonic epilepsy type 1 (EPM1) is an autosomal recessive disorder caused by mutations in the cystatin B gene (CSTB). Affected individual's manifest stimulus-sensitive and action myoclonus and tonic-clonic epileptic seizures. In this study, we have generated iPSCs from an EPM1 patient's skin fibroblasts with Sendai virus mediated transgene delivery. The iPSCs retained the patient specific promoter region expansion mutation, expressed pluripotency markers, differentiated into all three germ layers, and presented a normal karyotype. The line can in future be used to develop an in-vitro model for EPM1 and may help in understanding disease mechanisms at cellular and molecular level.

Progressive myoclonic epilepsy, type 1A (EPM1, Unverricht-Lundborg disease), is a rare neurodegenerative autosomal recessive disorder characterized by stimulus-sensitive and action myoclonus and tonic-clonic epileptic seizures. Patients develop neurological symptoms, including ataxia, intention tremor, and dysarthria, over time, with relatively limited and nonspecific MRI atrophy findings. The effects of the disease on brain metabolism are largely unknown. Eighteen EPM1 patients (9 M, 9F) underwent clinical evaluation and neuropsychological testing, which included the assessment of intellectual ability, verbal memory, and psychomotor and executive functions. Magnetic resonance spectroscopy (MRS) and imaging (MRI) were performed on a 1.5 T MRI system. 2D MRS chemical shift imaging (CSI) maps (TE = 270) were obtained from the following regions of the brain: basal ganglia, thalamus, insula, splenium, and occipital white and gray matter, and N-acetyl-aspartate (NAA)-, choline (Cho)-, and lactate (Lac)-to-creatine (Cr) ratios were analyzed. Ten healthy age-and sex-matched subjects (5M, 5F) were used as controls for MRS. We found significant brain metabolic changes involving lactate, NAA, and choline, which are widespread in the basal ganglia, thalamic nuclei, insula, and occipital areas of EPM1 patients. Changes, especially in the right insula, basal ganglia, and thalamus, were associated with intellectual abilities and impairment of the psychomotor and executive functions of EPM1 patients. Multiple brain metabolic alterations suggest the presence of neurodegeneration associated with EPM1 progression. The changes in metabolite ratios are associated with the neurocognitive dysfunction caused by the disease. However, the role of MRS findings in understanding pathophysiology of EPM1 warrants further studies.

Progressive myoclonic epilepsy type 1 (EPM1) is caused by biallelic alterations in the CSTB gene, most commonly dodecamer repeat expansions. Although transcranial magnetic stimulation (TMS)-induced long-interval intracortical inhibition (LICI) was previously reported to be normal in EPM1, short-interval intracortical inhibition (SICI) was reduced. We explored the association between these measures and the clinical and genetic features in a separate group of patients with EPM1. TMS combined with electromyography was performed under neuronavigation. LICI was induced with an inter-stimulus interval (ISI) of 100 ms, and SICI with ISIs of 2 and 3 ms, and their means (mSICIs) were expressed as the ratio of conditioned to unconditioned stimuli. LICI and mSICI were compared between patients and controls. Nonparametric correlation was used to study the association between inhibition and parameters of clinical severity, including the Unified Myoclonus Rating Scale (UMRS); among patients with EPM1 due to biallelic expansion repeats, also the association with the number of repeats was assessed. The study protocol was completed in 19 patients (15 with biallelic expansion repeats and 4 compound heterozygotes), and 7 healthy, age- and sex-matched control participants. Compared to controls, patients demonstrated significantly less SICI (median mSICI ratio 1.18 vs 0.38; p < .001). Neither LICI nor SICI was associated with parameters of clinical severity. In participants with biallelic repeat expansions, the number of repeats in the more affected allele (greater repeat number [GRN]) correlated with LICI (rho = 0.872; p < .001) and SICI (rho = 0.689; p = .006). Our results strengthen the finding of deranged γ-aminobutyric acid (GABA)ergic inhibition in EPM1. LICI and SICI may have use as markers of GABAergic impairment in future trials of disease-modifying treatment in this condition. Whether a higher number of expansion repeats leads to greater GABAergic impairment warrants further study.