Spinocerebellar ataxias are a diverse group of autosomal dominant cerebellar ataxias. SCA2 is a complex ataxia with various extracerebellar symptoms, including parkinsonism, dystonia, hyporeflexia, and cognitive impairment. ATXN2 is a modulator of neurologic disease: Expansions of at least 37 CAG (glutamine) repeats are pathogenic for SCA2, while expansions in the intermediate range (30-32) convey risk for the development of neurodegenerative disorders including Parkinson disease and amyotrophic lateral sclerosis. Homozygous variants are exceedingly rare. This study describes a novel ATXN2 presentation identified in an Acadian family from New Brunswick, Canada: a CAG repeat expansion within the fully penetrant range of SCA2, asymptomatic in the heterozygous state and resulting in a neurodegenerative disorder in homozygous patients. Three individuals, 2 siblings and their cousin, were investigated for a neurodegenerative disorder with overlapping phenotypes. The affected individuals and their 5 immediate family members underwent whole-genome sequencing analyzed by ExpansionHunter, repeat-primed PCR and Sanger sequencing. Sequencing revealed a homozygous 39/39 CAG repeat expansion with 4 CAA interruptions in ATXN2 across all 3 affected individuals. After experiencing childhood intellectual or learning difficulties, the patients developed a pyramidal syndrome with spastic gait and a major neurocognitive disorder characterized by prominent frontal signs during their late twenties. Within a decade, all patients completely lost their autonomy. Shared phenotypic features included ataxia, spasticity, aphasia, dysphagia, myoclonus, atypical parkinsonism, incontinence, diffuse cortical atrophy with frontal predominance, and cerebellar atrophy. The same 39 CAG repeat allele with 4 CAA interruptions was identified in heterozygous state in 4 asymptomatic parents (age 65+) and 1 sibling in their thirties. Three carriers consented to further investigation with a neurologic examination, neuropsychological assessment, and cerebral MRI. Clinical and radiologic signs of disease were absent, despite the carriers' ages and their heterozygous expansion in the fully penetrant range of SCA2. This study describes a novel ATXN2 expansion within the classic pathogenic range for SCA2 that manifests as an early-onset neurodegenerative disorder in the homozygous state, while being asymptomatic into late adulthood in the heterozygous state.

Cortical tremor (CT), a rhythmic variant of cortical myoclonus (CM), is the hallmark of benign adult familial myoclonus epilepsy (BAFME), though the underlying mechanism of rhythmicity remains unproven. This study aimed to reveal the cortical rhythmic activity of CT using induced activity analysis for somatosensory evoked potentials (SEP). We investigated 46 SEP datasets from 23 patients (11 with BAFME, 12 with other CM) and 35 SEPs from 18 healthy controls. SEPs were recorded by 1.1-Hz stimuli at a sampling rate of 10,000 Hz. A short-time Fourier transform was applied to each SEP epoch, and the power spectrums were averaged. We set an analysis window of 0-150 ms and a frequency range of 0-1,000 Hz for time-frequency representation and compared the induced power changes between groups. Stimulus-induced power changes over a wide-band (0-1000 Hz) were conspicuously prominent in BAFME patients compared to both CM and controls. These activities presented repetitive and alternating increases and decreases in power and its total number of induced activities were the highest in age 40s and declined with aging. We demonstrated rhythmic cortical activity in BAFME patients, which may reflect the underlying pathophysiology of CT. Detecting the induced activity of a single somatosensory stimulus may offer novel insights into the pathophysiology of BAFME.

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.

Benign adult familial myoclonus epilepsy (BAFME) is an autosomal dominantly inherited disease characterized by infrequent seizures and tremorous myoclonus. The disease is also called familial adult myoclonic epilepsy (FAME) or familial cortical myoclonic tremor with epilepsy (FCMTE). Although the causes of BAFME had been unknown for a long, we identified TTTCA and TTTTA repeat expansions in intron 4 of SAMD12 as a cause of BAFME type 1. We also found TTTCA and TTTTA repeat expansions in TNRC6A and RAPGEF2 also cause the disease (BAFME types 6 and 7, respectively), thus proposing a concept of repeat motif-phenotype correlation. After that, TTTCA and TTTTA repeat expansions in STARD7, MARCHF6, YEATS2, and RAI1 have been identified as causes of BAFME types 2, 3, 4, and 8. The findings further supported the concept. The involvement of RNA-mediated toxicity, particularly of UUUCA repeats, is assumed to be the pathomechanism of this disease. The next step will be understanding the molecular pathomechanism of BAFME and identifying molecular targets of more efficient therapeutic approaches.

Familial adult myoclonic epilepsy (FAME), an autosomal dominant disorder, is characterized by cortical myoclonus and occasional generalized tonic-clonic seizures. To date, intronic pentanucleotide repeat expansions in at least seven genes, including SAMD12, TNRC6A, YEATS2, MARCHF6, STARD7, RAPGEF2, and RAI1, have been reported as causative. Detecting these repeat expansions using conventional sequencing techniques (Sanger or short-read next-generation sequencing) is not feasible as they cannot reliably span or characterize long repetitive elements. Although genetic testing has been performed in some research laboratories, comprehensive long read-based panel is unavailable for clinical application. To address this gap, we developed a targeted long-read sequencing panel and applied it in a clinical diagnostic context for the first time. We designed a custom long-read sequencing panel targeting all seven known FAME-associated repeat loci using Oxford Nanopore Cas9-enrichment technology and applied it to a 47-year-old woman with familial cortical myoclonic tremor, clinically suspected to have FAME. The panel functioned as intended, providing robust on-target coverage across all loci, facilitating confident interrogation of each repeat region. At the SAMD12 locus, strand-aware histograms and read-level inspection demonstrated a clear pathogenic expansion, encompassing mixed TTTTA/TTTCA motifs with detectable TTTGA interruptions, consistent with FAME1. Using the crude allele prediction option of tandem-genotypes, the expanded allele contained approximately 689 additional repeats relative to the reference genome. The other six loci showed no pathogenic expansions. This targeted long-read panel enabled the first clinical molecular diagnosis of FAME using a comprehensive assay, yielding allele-resolved characterization of the pathogenic repeat and its motif composition. With further validation, this approach may serve as a clinically practical tool for reliable detection of FAME1 and for broader screening of other FAME subtypes, potentially reducing reliance on prolonged clinical observation or specialized electrophysiological testing.