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Progressive Myoclonus Epilepsy: A Scoping Review of Diagnostic, Phenotypic and Therapeutic Advances.Genes Jan 2024The progressive myoclonus epilepsies (PME) are a diverse group of disorders that feature both myoclonus and seizures that worsen gradually over a variable timeframe.... (Review)
Review
The progressive myoclonus epilepsies (PME) are a diverse group of disorders that feature both myoclonus and seizures that worsen gradually over a variable timeframe. While each of the disorders is individually rare, they collectively make up a non-trivial portion of the complex epilepsy and myoclonus cases that are seen in tertiary care centers. The last decade has seen substantial progress in our understanding of the pathophysiology, diagnosis, prognosis, and, in select disorders, therapies of these diseases. In this scoping review, we examine English language publications from the past decade that address diagnostic, phenotypic, and therapeutic advances in all PMEs. We then highlight the major lessons that have been learned and point out avenues for future investigation that seem promising.
Topics: Humans; Myoclonus; Myoclonic Epilepsies, Progressive
PubMed: 38397161
DOI: 10.3390/genes15020171 -
Orphanet Journal of Rare Diseases Jul 2018Acid ceramidase (ACDase) deficiency is a spectrum of disorders that includes a rare lysosomal storage disorder called Farber disease (FD) and a rare epileptic disorder... (Review)
Review
Acid ceramidase (ACDase) deficiency is a spectrum of disorders that includes a rare lysosomal storage disorder called Farber disease (FD) and a rare epileptic disorder called spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). Both disorders are caused by mutations in the ASAH1 gene that encodes the lysosomal hydrolase that breaks down the bioactive lipid ceramide. To date, there have been fewer than 200 reported cases of FD and SMA-PME in the literature. Typical textbook manifestations of classical FD include the formation of subcutaneous nodules, accumulation of joint contractures, and development of a hoarse voice. In reality, however, the clinical presentation is much broader. Patients may develop severe pathologies leading to death in infancy or may develop attenuated forms of the disorder wherein they are often misdiagnosed or not diagnosed until adulthood. A clinical variability also exists for SMA-PME, in which patients develop progressive muscle weakness and seizures. Currently, there is no known cure for FD or for SMA-PME. The main treatment is symptom management. In rare cases, treatment may include surgery or hematopoietic stem cell transplantation. Research using disease models has provided insights into the pathology as well as the role of ACDase in the development of these conditions. Recent studies have highlighted possible biomarkers for an effective diagnosis of ACDase deficiency. Ongoing work is being conducted to evaluate the use of recombinant human ACDase (rhACDase) for the treatment of FD. Finally, gene therapy strategies for the treatment of ACDase deficiency are actively being pursued. This review highlights the broad clinical definition and outlines key studies that have improved our understanding of inherited ACDase deficiency-related conditions.
Topics: Animals; Farber Lipogranulomatosis; Humans; Muscular Atrophy, Spinal; Myoclonic Epilepsies, Progressive; Sphingolipids
PubMed: 30029679
DOI: 10.1186/s13023-018-0845-z -
Cells Jun 2023Familial adult myoclonus Epilepsy (FAME) is a non-coding repeat expansion disorder that has been reported under different acronyms and initially linked to four main... (Review)
Review
Familial adult myoclonus Epilepsy (FAME) is a non-coding repeat expansion disorder that has been reported under different acronyms and initially linked to four main loci: FAME1 (8q23.3-q24.1), FAME 2 (2p11.1-q12.1), FAME3 (5p15.31-p15.1), and FAME4 (3q26.32-3q28). To date, it is known that the genetic mechanism underlying FAME consists of the expansion of similar non-coding pentanucleotide repeats, TTTCA and TTTTA, in different genes. FAME is characterized by cortical tremor and myoclonus usually manifesting within the second decade of life, and infrequent seizures by the third or fourth decade. Cortical tremor is the core feature of FAME and is considered part of a spectrum of cortical myoclonus. Neurophysiological investigations as jerk-locked back averaging (JLBA) and corticomuscular coherence analysis, giant somatosensory evoked potentials (SEPs), and the presence of long-latency reflex I (or C reflex) at rest support cortical tremor as the result of the sensorimotor cortex hyperexcitability. Furthermore, the application of transcranial magnetic stimulation (TMS) protocols in FAME patients has recently shown that inhibitory circuits are also altered within the primary somatosensory cortex and the concomitant involvement of subcortical networks. Moreover, neuroimaging studies and postmortem autoptic studies indicate cerebellar alterations and abnormal functional connectivity between the cerebellum and cerebrum in FAME. Accordingly, the pathophysiological mechanism underlying FAME has been hypothesized to reside in decreased sensorimotor cortical inhibition through dysfunction of the cerebellar-thalamic-cortical loop, secondary to primary cerebellar pathology. In this context, the non-coding pentameric expansions have been proposed to cause cerebellar damage through an RNA-mediated toxicity mechanism. The elucidation of the underlying pathological mechanisms of FAME paves the way to novel therapeutic possibilities, such as RNA-targeting treatments, possibly applicable to other neurodegenerative non-coding disorders.
Topics: Humans; Adult; Myoclonus; Tremor; Epilepsies, Myoclonic; Reflex; Neurodegenerative Diseases
PubMed: 37371086
DOI: 10.3390/cells12121617 -
Seizure Apr 2021Dravet Syndrome (DS) is a rare and severe infantile-onset epileptic encephalopathy. DS research focuses mainly on children. We did a systematic review, completed on... (Review)
Review
Dravet Syndrome (DS) is a rare and severe infantile-onset epileptic encephalopathy. DS research focuses mainly on children. We did a systematic review, completed on January 18, 2021, examining the number of clinical DS studies. We show that there are 208 studies on children exclusively, 28 studies on adults exclusively, and 116 studies involving adults and children combined. This 7:1 ratio of children to adult studies exclusively shows the dearth of research that addresses long-term natural history of DS into adulthood. Through this systematic review, we examine the most up-to-date information in DS adults as it pertains to seizures, electroencephalogram, imaging, treatment, motor abnormalities, cognitive and social behavior outcomes, cardiac abnormalities, sleep disturbances, diagnosis in adults, and mortality. Overall, the frequency of seizures increases in the first decade of life and then myoclonic, atypical absences and focal seizures with impaired awareness tend to decrease in frequency or even disappear in adulthood. Adults tend to have a notable reduction in status epilepticus, especially after 30 years of age. Parkinsonian features were seen in patients as young as 19 years old and are more severe in older patients, suggesting a progression of the parkinsonian symptoms. In adulthood, patients continue to present with behavior problems, associated with a lower health-related quality of life. The leading reported cause of death in DS adults is Sudden Unexpected Death in Epilepsy (SUDEP). Further studies in older adults are needed to understand the long-term outcomes of patients with DS.
Topics: Adult; Epilepsies, Myoclonic; Humans; Infant; Mutation; NAV1.1 Voltage-Gated Sodium Channel; Quality of Life; Spasms, Infantile; Young Adult
PubMed: 33677403
DOI: 10.1016/j.seizure.2021.02.025 -
Expert Review of Neurotherapeutics Apr 2020: Progressive myoclonus epilepsies (PMEs) are a group of neurodegenerative diseases, invariably leading to severe disability or fatal outcome in a few years or decades.... (Review)
Review
: Progressive myoclonus epilepsies (PMEs) are a group of neurodegenerative diseases, invariably leading to severe disability or fatal outcome in a few years or decades. Nowadays, PMEs treatment remains challenging with a significant burden of disability for patients. Pharmacotherapy is primarily used to treat seizures, which impact patients' quality of life. However, new approaches have emerged in the last few years, which try to curb the neurological deterioration of PMEs through a better knowledge of the pathogenetic process. This is a review on the newest therapeutic options for the treatment of PMEs.: Experimental and clinical results on novel therapeutic approaches for the different forms of PME are reviewed and discussed. Special attention is primarily focused on the efficacy and tolerability outcomes, trying to infer the role novel approaches may have in the future.: The large heterogeneity of disease-causing mechanisms prevents researchers from identifying a single approach to treat PMEs. Understanding of pathophysiologic processes is leading the way to targeted therapies, which, through enzyme replacement or underlying gene defect correction have already proved to potentially strike on neurodegeneration.
Topics: Humans; Myoclonic Epilepsies, Progressive
PubMed: 32153206
DOI: 10.1080/14737175.2020.1741350 -
Seizure Dec 2021To better characterize the clinical phenotype of Poirier-Bienvenu neurodevelopmental syndrome (OMIM ID: 618,732) due to pathogenic variants of the CSNK2B gene. (Review)
Review
AIM
To better characterize the clinical phenotype of Poirier-Bienvenu neurodevelopmental syndrome (OMIM ID: 618,732) due to pathogenic variants of the CSNK2B gene.
METHOD
We reviewed the electro-clinical and developmental data of all 14 patients with de novo mutations of the CSNK2B gene reported in the literature and describe a further individual with a novel CSNK2B pathogenic variant.
RESULTS
Clustered generalized tonic-clonic or myoclonic seizures with onset before the age of 18 months and delayed neurodevelopment were present in more than 75% of patients. Epilepsy was pharmaco-resistant in 40%. All the individuals (27%) with normal neurological development had pharmaco-sensitive epilepsy. The severity of cognitive and motor impairments was higher in the group with pharmaco-resistant epilepsy, and a statistically significant correlation between seizure control and the severity of cognitive impairment was documented (χ2(3) = 9.44; p = .024) INTERPRETATION: Early seizure onset, clustered seizures and delayed development in both males and females were early clinical markers in most patients with CSNK2B mutations. The entity of neurodevelopmental abnormalities was related to epilepsy severity. Prospective studies are required to better assess the relationship between epilepsy and developmental outcomes in this condition.
Topics: Epilepsies, Myoclonic; Epilepsy; Epilepsy, Generalized; Female; Humans; Infant; Male; Phenotype; Seizures
PubMed: 34740143
DOI: 10.1016/j.seizure.2021.10.019 -
Seizure Jul 2023The endophenotype of Idiopathic Generalized Epilepsies (IGE) comprises distinct neuropsychological deficits compared to normal controls. It is unknown if the severity of...
PURPOSE
The endophenotype of Idiopathic Generalized Epilepsies (IGE) comprises distinct neuropsychological deficits compared to normal controls. It is unknown if the severity of features of the endophenotype correlates with resistance to anti-seizure medication. Therefore, we here studied the association of neuropsychological profiles with treatment response.
METHODS
We evaluated 106 Danish patients aged ≥18 and diagnosed with IGE using a neuropsychological test battery comprising tests for executive dysfunction, visual attention, episodic memory, and verbal comprehension. Tests were complemented by the Purdue Pegboard test. Patients with suspected ongoing psychogenic non-epileptic seizures were excluded.
RESULTS
At testing, 72 patients were seizure free, and 34 patients had recent seizures despite anti-seizure medication. As compared to age corrected Danish normative values, IGE patients showed significant impairments in semantic fluency and performed significantly worse in the Purdue Pegboard test. The vocabulary subtest of the WAIS-IV suggested lower verbal comprehension in IGE patients. We found no signs of memory impairment. Comparisons between results of the test battery, drug resistance, and the different IGE subsyndromes revealed consistent null-associations in various predefined and exploratory univariate and multivariate analyses.
CONCLUSION
We here found and confirmed the distinct neuropsychological profile comprising impaired executive functions, reduced psychomotor speed, and normal memory previously described in juvenile myoclonic epilepsy. This profile was, however, not restricted to juvenile myoclonic epilepsy but equally affected all IGE patients. The neuropsychological deficits were not significantly associated with drug treatment outcome.
Topics: Humans; Myoclonic Epilepsy, Juvenile; Executive Function; Neuropsychological Tests; Epilepsy, Generalized; Immunoglobulin E
PubMed: 37178660
DOI: 10.1016/j.seizure.2023.04.021 -
Communications Biology May 2023Mutations in ASAH1 have been linked to two allegedly distinct disorders: Farber disease (FD) and spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME)....
Mutations in ASAH1 have been linked to two allegedly distinct disorders: Farber disease (FD) and spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). We have previously reported FD-like phenotypes in mice harboring a single amino acid substitution in acid ceramidase (ACDase), P361R, known to be pathogenic in humans (P361R-Farber). Here we describe a mouse model with an SMA-PME-like phenotype (P361R-SMA). P361R-SMA mice live 2-3-times longer than P361R-Farber mice and have different phenotypes including progressive ataxia and bladder dysfunction, which suggests neurological dysfunction. We found profound demyelination, loss of axons, and altered sphingolipid levels in P361R-SMA spinal cords; severe pathology was restricted to the white matter. Our model can serve as a tool to study the pathological effects of ACDase deficiency on the central nervous system and to evaluate potential therapies for SMA-PME.
Topics: Humans; Mice; Animals; Farber Lipogranulomatosis; Muscular Atrophy, Spinal; Sphingolipids; Myoclonic Epilepsies, Progressive; Phenotype
PubMed: 37231125
DOI: 10.1038/s42003-023-04932-w -
Epilepsia Jun 2023Familial adult myoclonus epilepsy (FAME) is a genetic epilepsy syndrome that for many years has resisted understanding of its underlying molecular cause. This review... (Review)
Review
Familial adult myoclonus epilepsy (FAME) is a genetic epilepsy syndrome that for many years has resisted understanding of its underlying molecular cause. This review covers the history of FAME genetic studies worldwide, starting with linkage and culminating in the discovery of noncoding TTTTA and inserted TTTCA pentanucleotide repeat expansions within six different genes to date (SAMD12, STARD7, MARCHF6, YEATS2, TNRC6A, and RAPGEF2). FAME occurs worldwide; however, repeat expansions in particular genes have regional geographical distributions. FAME repeat expansions are dynamic in nature, changing in length and structure within germline and somatic tissues. This variation poses challenges for molecular diagnosis such that molecular methods used to identify FAME repeat expansions typically require a trade-off between cost and efficiency. A rigorous evaluation of the sensitivity and specificity of each molecular approach remains to be performed. The origin of FAME repeat expansions and the genetic and environmental factors that modulate repeat variability are not well defined. Longer repeats and particular arrangements of the TTTTA and TTTCA motifs within an expansion are correlated with earlier onset and increased severity of disease. Other factors such as maternal or paternal inheritance, parental age, and repeat length alone have been suggested to influence repeat variation; however, further research is required to confirm this. The history of FAME genetics to the present is a chronicle of perseverance and predominantly collaborative efforts that yielded a successful outcome. The discovery of FAME repeats will spark progress toward a deeper understanding of the molecular pathogenesis of FAME, discovery of new loci, and development of cell and animal models.
Topics: Humans; Epilepsies, Myoclonic; Pedigree; Research
PubMed: 37021642
DOI: 10.1111/epi.17610 -
Medicine Sep 2022Myoclonic epilepsy in infancy (MEI) is a rare syndrome characterized by generalized myoclonic seizures (MS) that occur within the first 3 years of life. In the present...
Myoclonic epilepsy in infancy (MEI) is a rare syndrome characterized by generalized myoclonic seizures (MS) that occur within the first 3 years of life. In the present study, the form of onset, and clinical and electroencephalogram (EEG) features were analyzed. A retrospective chart review was conducted for 16 MEI patients between March 2009 and July 2022 in Peking Union Medical College. The clinical and video EEG (VEEG) characteristics, treatment strategy, and follow-up information were analyzed. Four cases presented with afebrile generalized tonic-clonic seizures (GTCS) at the onset of MEI (GTCS at onset or atypical MEI), while 12 cases presented with MS at onset (MS at onset or typical MEI). The 24-hour VEEG revealed a generalized discharge of polyspike (or spike)-and-wave complexes that lasted for 1-3 seconds in the ictal phase. All patients were treated with valproic acid monotherapy, and none of the patients experienced seizure recurrence. Furthermore, all patients had normal psychomotor development at the end of the follow up period. Typical MEI (MS at onset) and atypical MEI (GTCS at onset) were described in the present study. These 2 groups differed in form of onset, but there were no significant differences in clinical or EEG features.
Topics: Electroencephalography; Epilepsies, Myoclonic; Humans; Retrospective Studies; Seizures; Valproic Acid
PubMed: 36197249
DOI: 10.1097/MD.0000000000030512