Repetitive wide-band cortical power in benign adult familial myoclonus epilepsy.

BackgroundFamilial 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.MethodsWe 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.ResultsThe 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.ConclusionsThis 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.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12920-025-02247-9.

Neuronal ceroid lipofuscinoses (NCL) are a group of hereditary monogenic neurodegenerative disorders, classified as lysosomal storage diseases. They are characterized by a polymorphic presentation of progressive neurological syndromes, severe pharmacoresistant epilepsy often accompanied by cortical myoclonus, rapidly advancing cognitive impairments, regression of acquired skills, and vision loss due to optic nerve atrophy. Currently, there are no available treatments that can reverse the progression of these diseases, which typically lead to premature death between the ages of 20 and 30 years. The treatment of NCL is primarily focused on symptomatic management, including the use of anticonvulsants, antiepileptic drugs, and antispasmodics. The aim of this review is to present the findings of experimental and clinical studies on therapeutic agents (ТА) for the treatment of patients with neuronal ceroid lipofuscinoses. Materials and Method. A thorough and comprehensive search for data on NCL was conducted on the PubMed platform using scientific articles and systematic reviews with meta-reviews. Results. The results of experimental and clinical studies on ТА have been described, including cerliponase alfa, milasen, gene therapy vectors, gemfibrozil, flupirtine, ataluren, trehalose, miglustat, tamoxifen, cysteamine bitartrate, a combination of cysteamine bitartrate with N-acetylcysteine, and acidified drinking water with hydrochloric acid. Conclusions. All studies of drugs for the treatment of NCL demonstrate only slow and subjective improvements in neurobehavioral and neurological characteristics, along with an objective trend toward normalization of biochemical and histological parameters. In the case of such a fatal neurodegenerative disorder as NCL, any improvement is highly valued.

BackgroundThe hallmark feature of tremor is rhythmicity, which can be quantified using power spectral density (PSD) analysis. However, tremor exhibits considerable variability, ranging from highly regular to more irregular patterns. Similarly, rhythmicity in myoclonus varies, but it typically manifests as arrhythmic jerks.ObjectivesTo develop PSD‐based measures of movement regularity for the classification of tremor and myoclonus.MethodsElectromyography data from 153 patients were analyzed retrospectively, including orthostatic tremor (OT) (n = 36), essential tremor (ET) (n = 40), hand dystonic tremor (DT) (n = 42), and limb cortical myoclonus (n = 35). Five PSD analysis‐derived variables were assessed: peak prominence, peak‐to‐broadband power ratio, peak frequency, peak width, and harmonics. Discriminant analysis evaluated classification accuracy across groups.ResultsPeak prominence was highest in OT and higher in ET than DT or myoclonus. Peak‐to‐broadband power ratio showed similar trends. Peak frequency differed across groups, with myoclonus highest and OT exceeding ET and DT. Peak width was larger in myoclonus and, to a less extent, in DT compared with ET. Harmonics were greater in OT and ET compared with DT and myoclonus. Discriminant analysis correctly classified 86.3% of cases, with overlap between ET and DT. Receiver operating characteristic (ROC) curve analysis for peak prominence and width demonstrated high classification accuracy between ET and DT.ConclusionsOur findings represent a promising step toward establishing objective, PSD‐based measures for the classification of tremor and myoclonus. These tools could enhance diagnostic accuracy and deepen insights into these disorders. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Next move in movement disorders (NEMO): the best clinical tasks for the visibility of essential tremor, dystonia, cortical myoclonus and myoclonus-dystonia.

Stimulus-sensitive myoclonus is a rare condition that can occur following prolonged cardiothoracic surgery. It is similar to Lance-Adams syndrome, which is characterised by post-cardiac arrest myoclonus, and both conditions are related to nervous system hypoxia. In our case, myoclonus developed after a patient underwent an elective replacement of the ascending aorta and total aortic arch due to an aortic aneurysm. The myoclonus primarily affected the right side of the body and was triggered by touch, sound, and light. After a thorough evaluation and comprehensive investigations, we concluded that this case represented post-hypoxic brain injury stimulus-sensitive myoclonus, resembling Lance-Adams syndrome with both cortical and subcortical myoclonus. Eight antiseizure medications were trialled, and significant relief was only achieved with Perampanel.

Explainable machine learning for movement disorders - Classification of tremor and myoclonus.

BackgroundFamilial adult myoclonus epilepsy (FAME) is a rare autosomal dominant disorder caused by the same intronic TTTTA/TTTCA repeat expansion in seven distinct genes. TTTTA‐only expansions are benign, whereas those containing TTTCA insertions are pathogenic.ObjectiveWe investigated the genetic basis of dominant cortical myoclonus without seizures in two unrelated families.MethodsRepeat‐primed polymerase chain reaction (PCR), long‐range PCR, and nanopore sequencing were used to detect and characterize expansions at known FAME loci.ResultsWe identified a novel repeat expansion in MARCHF6, comprising 388 to 454 elongated TTTTA repeats and 5 to 11 TTTCA repeats at the 3′‐terminus, segregating with cortical myoclonus in 8 affected individuals. This configuration shows meiotic stability but low‐level somatic variability in blood. We observed an inverse correlation between the number of TTTCA repeats and the age at myoclonus onset.ConclusionsThese findings indicate that as little as five TTTCA repeats combined with expanded TTTTA repeats can cause cortical myoclonus without epilepsy, highlighting the potential mechanisms underlying FAME pathophysiology. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BackgroundMyoclonus is a brief shock‐like, involuntary movement, which can be distinguished in physiologic, essential, epileptic, and symptomatic, according to its etiology. Physiologic myoclonus typically occurs in healthy people without disability or progression.ObjectivesWe suggest a new nosological entity in the physiologic group: “benign idiopathic myoclonus.”MethodsWe present a cohort of patients with isolated adolescent‐onset, distal limb myoclonus at rest and during action, in absence of a known cause and disabling progression, who underwent both clinical and neurophysiological examination in our tertiary Movement Disorders Expertise Center Groningen.ResultsFifteen patients (4 men [26.7%]; age at onset, 18.1 ± 3.6 years; disease‐duration, 5.3 ± 3.7 years) were assessed. Neurophysiological examinations, including electromyography (EMG) (n = 14), somatosensory evoked potentials (SEPs, n = 4); electroencephalography (EEG)–EMG with back‐averaging (BA, n = 11) and cortico‐muscular coherence (CMC, n = 10), confirmed the clinical diagnosis of myoclonus in all patients. Mean EMG burst duration was 62.6 ± 13.7 ms and a cortical origin of myoclonus was demonstrated in six cases (40%). No genetic causes were found. Follow‐up at 0.5 to 8 years depicted clinically stable conditions in eight patients (61.5%), complete remission in four (30.8%), whereas one patient (7.7%) reported slight progression.ConclusionsWe suggest a new phenotype of physiologic myoclonus, which might be called “benign idiopathic myoclonus.” It is characterized by distal myoclonus with onset during adolescence and benign course, without requiring treatment. Clinically and neurophysiologically these jerky movements were compatible with cortical myoclonus in some patients. We were unable to establish any genetic causes in explored cases. This phenotype might represent a particular subgroup of physiologic myoclonus, to be substantiated in multicenter cohorts.

Cortical Myoclonus in an Adolescent Boy With a De Novo Pathogenic Variant in NUS1 Gene.

Diaphragmatic myoclonus, also called diaphragmatic flutter, has characteristic abdominal movements resembling those of a belly dancer; hence, it is also called belly dancer syndrome (BDS). BDS is characterized by high-frequency involuntary diaphragmatic contractions. BDS can occur due to a lesion anywhere in the pathway for diaphragmatic control, from the motor cortex to the neural supply to the diaphragm. Here we report a 21-year-old girl who presented with acute-onset abdominal movements of 5 days duration. Clinical examination showed abdominal jerky movements with preserved awareness. Electroencephalograms (EEG) showed polyspike wave discharges consistent with cortical myoclonus. These abdominal myoclonic jerks disappeared dramatically on treatment with lacosamide, a third-generation antiepileptic drug. There are few case reports of BDS in the literature with a cortical myoclonus origin instead of the widely described segmental myoclonus form. The case also highlights the efficacy of lacosamide in treating diaphragmatic myoclonus jerk in young adults.

Neuronal ceroid lipofuscinoses (NCLs) are genetically heterogeneous neurodegenerative disorders, characterized by progressive cognitive and motor decline, epilepsy, visual impairment, and shortened life-expectancy. CLN6-related NCLs include both late-infantile and adult myoclonic form. We report a 21-year-old patient, with mild developmental delay, who developed occipital seizures at 14 years, and subsequently cognitive decline, cortical myoclonus, and photosensitivity at low and higher frequencies. Overall, the picture suited progressive myoclonus epilepsy. Electroretinogram was normal. A skin biopsy revealed a mixed storage of curvilinear and fingerprint profiles. A brain MRI showed severe cortical atrophy. Performing genetic analyses, two biallelic variants were identified in the CLN6 gene, each inherited from one of the healthy parents, one c.722T>C, p.(Met241Thr) already described in the late-infantile form and the other one c.486+28T>C, intronic and novel, causing aberrant splicing. In the patient, the expression of the allele containing c.722T>C variant was increased, in comparison with the carrier parent. The peculiar genetic pattern observed in the patient could explain a milder clinical picture when compared with late-infantile form, since CLN6expression was partially preserved. However, the presence of a delay, and the early cognitive decline suggested a continuum phenotype connecting late-infantile and adult CLN6-related forms. PLAIN LANGUAGE SUMMARY: We report a patient with CLN6 disease who developed symptoms at an intermediate age: 9 years for mild intellectual disability and 14 years for occipital seizures and progressive myoclonus epilepsy, without visual impairment. The patient is compound heterozygous for a CLN6 missense variant c.722T>C, p.(Met241Thr) already described in the late-infantile form and for a novel intronic variant c.486+28T>C, causing aberrant splicing. In the patient, the expression of the allele containing c.722T>C variant was increased, compared with the carrier parent. The splice site variant had a milder effect. The peculiar genetic pattern may explain the continuum phenotype between late-infantile and adult forms.

Myoclonus and other jerky movement disorders are hyperkinetic disorders, the diagnosis of which heavily relies on clinical neurophysiological testing. However, formal diagnostic criteria are lacking, and recently the utility and reliability of these tests have been questioned. The aim of this review was to assess the utilization of clinical neurophysiology testing to identify possible gaps and boundaries that might guide the development of new methods for a more precise diagnosis and in-depth understanding of myoclonus. We reviewed electrophysiological features of cortical myoclonus, subcortical myoclonus (ie, myoclonus associated with dystonia, brainstem myoclonus), excessive startle reflex, spinal myoclonus (ie, spinal segmental and propriospinal myoclonus), peripheral myoclonus and mimics of myoclonus of peripheral origin (hemifacial spasm, minipolymyoclonus, myokymia), functional jerky movements, chorea, and tics. Electrophysiological features that support the recognition of myoclonus subtypes, such as muscle burst duration, muscle pattern of activation, measures of cortical excitability, or movement-related cortical potentials, have been identified. These significantly contribute to the diagnosis of jerky movement disorders, but their reliability is uncertain. Despite the significant advancements, several unresolved questions persist. Factors contributing to this include the absence of systematic neurophysiological assessment and standardized methods, alongside the limited number of patients investigated using these techniques. Although clinical neurophysiology remains the "gold standard" for defining and diagnosing myoclonus, our review highlighted the need to enhance the quality and reliability of neurophysiological testing in jerky movement disorders. Further studies including larger cohorts of patients recruited from different centers, employing standardized and optimized electrophysiological techniques, are warranted.

Lance-Adams syndrome (LAS), or chronic posthypoxic myoclonus, is a long-term disabling neurologic disorder occurring in survivors of anoxia. The cortical or subcortical origin of this myoclonus is unclear. We aimed to identify the neuroanatomical origin of myoclonus in LAS. We conducted a cross-sectional study and investigated patients diagnosed with LAS from the Department of Neurology of Pitié-Salpêtrière Hospital, using multimodal neurologic explorations: EEG with quantitative analyses, polygraphic EMG recording of myoclonus, coupled EEG-EMG analyses with jerk-locked back averaging, and 18fluorodeoxyglucose PET/CT imaging. All 18 patients had action multifocal or generalized myoclonus. Eleven patients also presented seizures, mainly generalized tonic-clonic seizures. For 8 patients, myoclonus decreased after seizures for a variable duration, from 1 day to 2 weeks. Epileptiform discharges were identified over the central median region (n = 14), with a maximal amplitude on the Cz (65 ± 20 µV, n = 12) and Fz (107 µV, n = 1) electrodes, and a significantly increased frequency during non-rapid eye movement sleep stages 1 (12 ± 8.5 events/minute, p = 0.004, n = 9) and 2 (11 ± 8.8 events/minute, p = 0.016, n = 7) compared with wake (5.5 ± 5.4 events/minute). The duration of the cortical and muscular events was significantly and positively correlated (ρ = 0.58, p < 0.001, n = 9). Action myoclonic jerks with a duration of <50 ms were confirmed in all patients, with a fast-descending corticospinal way organization with a mean biceps brachii-first interossei dorsalis delay of 9.8 ± 1 ms (n = 8). A central cortical transient preceding the muscular jerks was identified (n = 14), with a mean latency of -31.9 ± 2.9 ms for the tibialis anterior muscle (n = 7). A regional metabolism decrease was observed in the precentral cortex, supplementary motor area, paracentral lobule (n = 6), and postcentral cortex and precuneus (n = 5). This metabolism decrease was bilateral in the precentral cortex for 83% of the patients and in the postcentral cortex for 100%. Hypometabolism in the precentral, supplementary motor, and postcentral areas was confirmed with a voxelwise analysis (p < 10-3, n = 6). Our findings, based on a large cohort of patients with LAS, strongly suggest a cortical myoclonus, originating within the motor cortex and related to epileptiform mechanisms.

Abstract Mitochondrial disorders often present with ataxia, myoclonus, and epilepsy. Valproic acid may be selected for treating myoclonus if it is the presenting feature. While it is efficacious in suppressing cortical myoclonus, valproic acid is a known mitochondrial toxin and, therefore, not recommended. We report a family carrying the mitochondrial A8344G mutation. The proband, after being treated with valproic acid for myoclonic epilepsy, presented with gradually progressive cerebellar ataxia. He had a re-emergence of myoclonus upon withdrawal of valproic acid about 15 years later. The mitochondrial A8344G mutation, given its diverse clinical manifestations and intrafamilial phenotypic heterogeneity, evaded early recognition. Individuals carrying this mutation need life-long anti-epileptic therapy for myoclonus. Thus, it is important to recognize the mitochondrial disorder and select appropriate drugs.

The natural history of progressive myoclonus ataxia

Redefined giant somatosensory evoked potentials: Evoked epileptic complexes of excitatory and inhibitory components

Background: Cortical myoclonus originates at cerebral cortex, predominantly occurring on voluntary movements. Few case reports described usage of Acetazolamide (ACZ) for myoclonus. Methods: Chart review of 2 patients was performed. Literature review was conducted on myoclonus and ACZ using Pubmed. Results: 22-year-old female was diagnosed with Progressive Myoclonic Epilepsy (PME) secondary to a KCNC1 mutation. Her symptoms started at 10 years old with bilateral tonic clonic seizures (BTCS), later developing progressive ataxia and myoclonus, involving face and limbs, which worsened with stimulus and menses. Medications included Perampanel, Clonazepam and Levetiracetam, however myoclonus was still limiting. At the age of 19, ACZ 250 mg BID was started for 2 weeks around her menses. Follow up revealed significant improvement of myoclonus, resulting in better ambulation, balance and speech, sustained 2.5 years after. 67-year-old male presented BTCS at the age of 53 along with cortical myoclonus, dementia and ataxia, leading to diagnosis of PME with a mutation on IRF2BPL. Improvement of myoclonus occurred with ACZ 250 mg BID biweekly, although balance and cognition still deteriorated. Conclusions: Previous literature outlines 4 cases of action myoclonus that responded to ACZ. We believe that ACZ should be considered to treat myoclonus, especially in cases with cortical involvement and hormonal fluctuations.

22q11.2 microdeletion is the most common microdeletion syndrome in humans with a prevalence of 13 per 100000 live births, and it is a multisystem condition with variable phenotypic presentations. We present a case of an adult patient with Dandy-Walker syndrome who presented to our epilepsy clinic with 2 years of new-onset seizures and cognitive decline and 1 year of psychotic symptoms. Patient had a non-revealing autoimmune and malignancy work-up. Continuous scalp vEEG study showed bursts of 1-2Hz generalized fronto-centrally predominant spike or polyspike and slow wave discharges. Several myoclonic jerks were time-locked with the generalized discharges indicative of cortical myoclonus. MRI brain revealed periventricular nodular heterotopia in addition to findings suggestive of Dandy-Walker syndrome. Array-based comparative genomic hybridization demonstrated a 22q11.2 microdeletion seen in 22q11.2 deletion syndrome. Our case illustrates the challenges of diagnosing genetic disorders in adults especially when the initial diagnosis is dependent on a number of factors, including the patient's age, the severity of the phenotypic features, and the awareness of the physician.

To investigate and characterize epileptic seizures and electrophysiological features of familial cortical myoclonic tremor with epilepsy (FCMTE) type 1 patients in a large Chinese cohort. We systematically evaluated 125 FCMTEtype 1 patients carrying the pentanucleotide (TTTCA) repeat expansion in the SAMD12 gene in China. Among the 28 probands, epileptic seizures (96.4%, 27/28) were the most common reason for an initial clinic visit. Ninety-seven (77.6%, 97/125) patients had experienced seizures. The seizures onset age was 36.5 ± 9.0 years, which was 6.9 years later than cortical tremors. The seizures were largely rare (<1/year, 58.8%) and occasional (1-6/year, 37.1%). Prolonged prodromes were reported in 57.7% (56/97). Thirty-one patients (24.8%, 31/125) reported photosensitivity history, and 79.5% (31/39) had a photoparoxysmal response. Interictal epileptiform discharges (IEDs) were recorded in 69.1% (56/81) of patients. Thirty-three patients showed generalized IEDs and 72.7% (24/33) were occipitally dominant, while 23 patients presented with focal IEDs with 65.2% (15/23) taking place over the occipital lobe. Overnight EEG of FCMTE patients displayed paradoxical sleep-wake fluctuation, with a higher average IED index of 0.82 ± 0.88/min during wakefulness and a lower IED index of 0.04 ± 0.06/min during non-rapid eye movement sleep stages I-II. FCMTE type 1 has a benign course of epilepsy and distinct clinical and electrophysiological features. In addition to a positive family history and cortical myoclonus tremor, the seizure prodromes, specific seizure triggers, photosensitivity, distribution of IEDs, and unique fluctuations during sleep-wake cycle are cues for proper genetic testing and an early diagnosis of FCMTE.