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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 -
Brain : a Journal of Neurology Sep 2020Cortical tremor is a fine rhythmic oscillation involving distal upper limbs, linked to increased sensorimotor cortex excitability, as seen in cortical myoclonus.... (Review)
Review
Cortical tremor is a fine rhythmic oscillation involving distal upper limbs, linked to increased sensorimotor cortex excitability, as seen in cortical myoclonus. Cortical tremor is the hallmark feature of autosomal dominant familial cortical myoclonic tremor and epilepsy (FCMTE), a syndrome not yet officially recognized and characterized by clinical and genetic heterogeneity. Non-coding repeat expansions in different genes have been recently recognized to play an essential role in its pathogenesis. Cortical tremor is considered a rhythmic variant of cortical myoclonus and is part of the 'spectrum of cortical myoclonus', i.e. a wide range of clinical motor phenomena, from reflex myoclonus to myoclonic epilepsy, caused by abnormal sensorimotor cortical discharges. The aim of this update is to provide a detailed analysis of the mechanisms defining cortical tremor, as seen in FCMTE. After reviewing the clinical and genetic features of FCMTE, we discuss the possible mechanisms generating the distinct elements of the cortical myoclonus spectrum, and how cortical tremor fits into it. We propose that the spectrum is due to the evolution from a spatially limited focus of excitability to recruitment of more complex mechanisms capable of sustaining repetitive activity, overcoming inhibitory mechanisms that restrict excitatory bursts, and engaging wide areas of cortex. Finally, we provide evidence for a possible common denominator of the elements of the spectrum, i.e. the cerebellum, and discuss its role in FCMTE, according to recent genetic findings.
Topics: Cerebellum; Epilepsies, Myoclonic; Epilepsy; Evoked Potentials, Somatosensory; Humans; Myoclonus; Tremor
PubMed: 32417917
DOI: 10.1093/brain/awaa129 -
Epileptic Disorders : International... Apr 2019To determine the integrity of colour perception, related to photic sensitivity, in patients with juvenile myoclonic epilepsy. Twenty-four patients with photoparoxysmal...
To determine the integrity of colour perception, related to photic sensitivity, in patients with juvenile myoclonic epilepsy. Twenty-four patients with photoparoxysmal response, 27 patients without photoparoxysmal response, and 32 healthy individuals were investigated using the Farnsworth Munsell-100 Hue test to calculate error scores for total colour, blue/yellow, and red/green. No significant differences were observed regarding blue/yellow, red/green or total error score between juvenile myoclonic epilepsy patients with or without photoparoxysmal response. However, the data for all three scores were significantly higher in both patient groups compared to the healthy control group. In both patient groups, the blue/yellow error score was significantly higher than the red/green error score. We were unable to identify a relationship between photoparoxysmal response and colour vision in patients with juvenile myoclonic epilepsy. We believe that the underlying reason why juvenile myoclonic epilepsy patients had significantly higher blue/yellow, red/green, and total error score compared to the healthy control group may be due to GABA dysfunction, which is considered to play a role in the pathophysiology of this disease as well as the physiology of colour vision.
Topics: Adult; Color Perception; Color Vision; Epilepsies, Myoclonic; Female; Humans; Male; Myoclonic Epilepsy, Juvenile; Photosensitivity Disorders; Young Adult
PubMed: 30945640
DOI: 10.1684/epd.2019.1043 -
Seminars in Pediatric Neurology May 2016Pediatric epileptic encephalopathies represent a clinically challenging and often devastating group of disorders that affect children at different stages of infancy and... (Review)
Review
Pediatric epileptic encephalopathies represent a clinically challenging and often devastating group of disorders that affect children at different stages of infancy and childhood. With the advances in genetic testing and neuroimaging, the etiologies of these epileptic syndromes are now better defined. The various encephalopathies that are reviewed in this article include the following: early infantile epileptic encephalopathy or Ohtahara syndrome, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, West syndrome, severe myoclonic epilepsy in infancy (Dravet syndrome), Landau-Kleffner syndrome, Lennox-Gastaut syndrome, and epileptic encephalopathy with continuous spike-and-wave during sleep. Their clinical features, prognosis as well as underlying genetic etiologies are presented and updated.
Topics: Epilepsies, Myoclonic; Humans; Infant; Landau-Kleffner Syndrome; Lennox Gastaut Syndrome; Spasms, Infantile
PubMed: 27544470
DOI: 10.1016/j.spen.2016.06.002 -
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 -
Epilepsy & Behavior : E&B Nov 2016Premature mortality is a major issue in Dravet syndrome (DS). To improve understanding of DS premature mortality, we conducted a comprehensive literature search with a... (Review)
Review
INTRODUCTION
Premature mortality is a major issue in Dravet syndrome (DS). To improve understanding of DS premature mortality, we conducted a comprehensive literature search with a particular emphasis on SUDEP.
METHODS
We searched PubMed, Embase, Web of Science, Cochrane, CENTRAL, CINAHL, PsycINFO, Academic Search Premier, and ScienceDirect on the following terms: "Dravet syndrome", "severe myoclonic epilepsy", "SMEI", "mortality", "survivors", "prognosis", and "death". DS cases or cohorts studies reporting mortality were included.
RESULTS
The search yielded 676 articles and 86 meeting abstracts. After removing duplicates and screening titles and abstracts, full text of 73 articles was reviewed. Only 28 articles and six meeting abstracts met inclusion criteria. Five articles and four meeting abstracts were excluded, as the case(s) were also described elsewhere. After checking the references, five additional studies were included. The 30 items reported 177 unique cases. Sudden unexpected death in epilepsy was the likely cause in nearly half of the cases (n=87, 49%), followed by status epilepticus (n=56, 32%). Drowning or accidental death was reported in 14 cases (8%), infections in 9 (5%), other causes in six (3%), and unknown in five (3%). Age at death was reported for 142 of the 177 cases (80%), with a mean age of 8.7±9.8years (SD); 73% died before the age of 10years.
DISCUSSION
Dravet syndrome is characterized by high epilepsy-related premature mortality and a marked young age at death. Sudden unexpected death in epilepsy is the leading reported cause of death in DS, accounting for nearly half of all deaths. The cause of this excess mortality remains elusive but may be explained by epilepsy severity, as well as genetic susceptibility to SUDEP.
Topics: Child; Death, Sudden; Epilepsies, Myoclonic; Humans
PubMed: 27732919
DOI: 10.1016/j.yebeh.2016.09.007 -
Epileptic Disorders : International... Sep 2016Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a conformational proteinopathy characterised by neuronal inclusion bodies composed of the serine... (Review)
Review
Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a conformational proteinopathy characterised by neuronal inclusion bodies composed of the serine protease inhibitor (SERPIN), neuroserpin. Presenting clinically as a familial dementia-epilepsy syndrome, the molecular mechanism of the pathogenic abnormalities in neuroserpin has been characterised at atomic resolution. There is a remarkable genotype-phenotype correlation between the degree of molecular destabilisation of the several variants of the neuroserpin protein, their propensity to self-associate and the age of onset of the dementia-epilepsy complex. As with other serpinopathies there appears to be a mix of cell-autonomous toxicity, due to neuronal accumulation of neuroserpin, and non-cell autonomous toxicity, caused by loss of protease inhibition, in this case the dysregulated protease is likely to be tissue plasminogen activator (tPA). FENIB should be considered in cases of progressive myoclonic epilepsy and dementia particularly where there is family history of neuropsychiatric disease.
Topics: Epilepsies, Myoclonic; Heredodegenerative Disorders, Nervous System; Humans
PubMed: 27618835
DOI: 10.1684/epd.2016.0847 -
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 -
Continuum (Minneapolis, Minn.) Feb 2016Infantile, childhood, and adolescent epilepsies comprise a diverse group of entities. Careful characterization of epilepsy into a specific electroclinical syndrome or... (Review)
Review
PURPOSE OF REVIEW
Infantile, childhood, and adolescent epilepsies comprise a diverse group of entities. Careful characterization of epilepsy into a specific electroclinical syndrome or etiology assists greatly in understanding both the natural history of the seizure disorder (pharmacoresistant versus pharmacoresponsive and self-limited versus lifelong) and the best therapeutic options for the child.
RECENT FINDINGS
Tremendous growth has been seen in the understanding of both genetic factors predisposing to epilepsy and neuroimaging techniques. Additionally, a number of studies have focused on the efficacy of certain therapies in specific syndromes or etiologies.
SUMMARY
This article reviews both common epilepsy syndromes (including benign focal epilepsy of childhood, absence epilepsy, and juvenile myoclonic epilepsy) and the rarer syndromes with associated management implications (eg, Dravet syndrome, progressive myoclonic epilepsy, and mitochondrial disorders) and addresses genetic and metabolic investigations.
Topics: Adolescent; Child; Child, Preschool; Electroencephalography; Epilepsies, Myoclonic; Epilepsy, Absence; Female; Humans; Infant; Male
PubMed: 26844731
DOI: 10.1212/CON.0000000000000269 -
Epileptic Disorders : International... Feb 2023The purpose of this study was to investigate the timing of generalized electroencephalographic abnormalities in patients with juvenile myoclonic epilepsy who were...
The purpose of this study was to investigate the timing of generalized electroencephalographic abnormalities in patients with juvenile myoclonic epilepsy who were followed up long term before the onset of juvenile myoclonic epilepsy. We enrolled juvenile myoclonic epilepsy patients whose course of epilepsy had been observed for >5 years before the onset of juvenile myoclonic epilepsy, those who had undergone electroencephalogram recording more than twice before the onset of juvenile myoclonic epilepsy, and those who had terminated antiseizure medications for at least 2 years before the onset of juvenile myoclonic epilepsy. Patients who had transitioned from childhood absence epilepsy to juvenile myoclonic epilepsy were excluded. We retrospectively reviewed the medical records and neurophysiological data of the patients. Four patients met the inclusion criteria. One patient was diagnosed with febrile seizures during childhood, and the remaining three had transitioned to juvenile myoclonic epilepsy from other epileptic disorders, such as self-limited epilepsy with autonomic seizures, genetic epilepsy with febrile seizure plus, or nonspecific genetic generalized epilepsy. All patients exhibited generalized spike-wave discharges or photoparoxysmal responses for >2 years before the onset of juvenile myoclonic epilepsy. The four patients had transitioned to juvenile myoclonic epilepsy from other epileptological preconditions. Patients with juvenile myoclonic epilepsy may show generalized electroencephalographic abnormality many years prior to the onset of symptoms. Generalized spike-waves on the electroencephalogram during the course of any type of epilepsy or febrile seizure may be a risk factor for developing juvenile myoclonic epilepsy.
Topics: Humans; Myoclonic Epilepsy, Juvenile; Epilepsies, Myoclonic; Retrospective Studies; Seizures, Febrile; Electroencephalography; Epilepsy, Generalized
PubMed: 36946369
DOI: 10.1002/epd2.20052