Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) is an autosomal recessively inherited neurodegenerative disease, manifesting with myoclonus, seizures and ataxia, caused by mutations in the cystatin B (CSTB) gene. With the aim of understanding the molecular basis of pathogenetic events in EPM1 we characterized gene expression changes in the cerebella of pre-symptomatic postnatal day 7 (P7) and symptomatic P30 cystatin B -deficient (Cstb(-/-) ) mice, a model for the disease, and in cultured Cstb(-/-) cerebellar granule cells using a pathway-based approach. Differentially expressed genes in P7 cerebella were connected to synaptic function and plasticity, and in cultured cerebellar granule cells, to cell cycle, cytoskeleton, and intracellular transport. In particular, the gene expression data pinpointed alterations in GABAergic pathway. Electrophysiological recordings from Cstb(-/-) cerebellar Purkinje cells revealed a shift of the balance towards decreased inhibition, yet the amount of inhibitory interneurons was not declined in young animals. Instead, we found diminished number of GABAergic terminals and reduced ligand binding to GABAA receptors in Cstb(-/-) cerebellum. These results suggest that alterations in GABAergic signaling could result in reduced inhibition in Cstb(-/-) cerebellum leading to the hyperexcitable phenotype of Cstb(-/-) mice. At P30, the microarray data revealed a marked upregulation of immune and defense response genes, compatible with the previously reported early glial activation that precedes neuronal degeneration. This further implies the role of early-onset neuroinflammation in the pathogenesis of EPM1.
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PMID:Gene expression alterations in the cerebellum and granule neurons of Cstb(-/-) mouse are associated with early synaptic changes and inflammation. 2458 87

Unverricht-Lundborg type progressive myoclonus epilepsy (EPM1, OMIM 254800) is an autosomal recessive disorder characterized by onset at the age of 6 to 16 years, incapacitating stimulus-sensitive myoclonus and tonic-clonic epileptic seizures. It is caused by mutations in the gene encoding cystatin B. Previously, widespread white matter changes and atrophy has been detected both in adult EPM1 patients and in 6-month-old cystatin B-deficient mice, a mouse model for the EPM1 disease. In order to elucidate the spatiotemporal dynamics of the brain atrophy and white matter changes in EPM1, we conducted longitudinal in vivo magnetic resonance imaging and ex vivo diffusion tensor imaging accompanied with tract-based spatial statistics analysis to compare volumetric changes and fractional anisotropy in the brains of 1 to 6 months of age cystatin B-deficient and control mice. The results reveal progressive but non-uniform volume loss of the cystatin B-deficient mouse brains, indicating that different neuronal populations possess distinct sensitivity to the damage caused by cystatin B deficiency. The diffusion tensor imaging data reveal early and progressive white matter alterations in cystatin B-deficient mice affecting all major tracts. The results also indicate that the white matter damage in the cystatin B-deficient brain is most likely secondary to glial activation and neurodegenerative events rather than a primary result of CSTB deficiency. The data also show that diffusion tensor imaging combined with TBSS analysis provides a feasible approach not only to follow white matter damage in neurodegenerative mouse models but also to detect fractional anisotropy changes related to normal white matter maturation and reorganisation.
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PMID:Progressive volume loss and white matter degeneration in cstb-deficient mice: a diffusion tensor and longitudinal volumetry MRI study. 2460 71

New antiepileptic drug (AED) options for generalised seizure types have been adopted for use as treatment for Unverricht-Lundborg disease. Whether this has led to improved seizure control or functional outcome in ULD patients remains obscure. We retrospectively identified all patients seen at Helsinki University Hospital due to Unverricht-Lundborg disease during 2003-2008 in order to determine which AED treatments had been retained for long-term use. The majority of the patients had severe functional disabilities. In the year preceding the last hospital visit, all patients (n=20) were receiving polytherapy and 14 patients had been free of tonic-clonic seizures. During follow-up, improvement in myoclonia had been recorded for the majority of patients with either add-on piracetam, topiramate, or levetiracetam, but valproate was still in use by all patients. Treatment with lamotrigine had been started and retained less often relative to other AEDs. Add-on AED treatment was often associated with significant adverse effects. Unverricht-Lundborg disease patients may benefit from add-on treatment with levetiracetam or topiramate for seizure control. Treatment of eventual comorbidities with other than AEDs is also discussed.
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PMID:Seizure control in Unverricht-Lundborg disease: a single-centre study. 2477 17

Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) is an autosomal-recessively inherited neurodegenerative disorder characterized by severely incapacitating myoclonus, seizures, and ataxia, and caused by loss-of-function mutations in the cystatin B gene (CSTB). A central neuropathological finding in the Cstb(-/-) mouse, an animal model for EPM1, is early microglial activation, which precedes astroglial activation, neuronal loss, and onset of myoclonus, thus implying a critical role for microglia in EPM1 pathogenesis. Here, we characterized phenotypic and functional properties of microglia from Cstb(-/-) mice utilizing brain tissue, microglia directly isolated from the brain, and primary microglial cultures. Our results show significantly higher Cstb mRNA expression in microglia than in neurons and astrocytes. In Cstb(-/-) mouse brain, expression of the inflammatory marker p-p38 MAPK and the proportion of both pro-inflammatory M1 and anti-inflammatory M2 microglia is higher than in control mice. Moreover, M1/M2 polarization of microglia in presymptomatic Cstb(-/-) mice is, compared to control mice, skewed towards M2 type at postnatal day 14 (P14), but towards M1 type at P30, a time point associated with onset of myoclonus. At this age, the high expression of both pro-inflammatory inducible nitric oxide synthase (iNOS) and anti-inflammatory arginase 1 (ARG1) in Cstb(-/-) mouse cortex is accompanied by the presence of peripheral immune cells. Consistently, activated Cstb(-/-) microglia show elevated chemokine release and chemotaxis. However, their MHCII surface expression is suppressed. Taken together, our results link CSTB deficiency to neuroinflammation with early activation and dysfunction of microglia and will open new avenues for therapeutic interventions for EPM1.
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PMID:Abnormal microglial activation in the Cstb(-/-) mouse, a model for progressive myoclonus epilepsy, EPM1. 2532 91

The progressive myoclonus epilepsies (PMEs) comprise a group of rare and heterogeneous disorders defined by the combination of action myoclonus, epileptic seizures, and progressive neurologic deterioration. Neurologic deterioration may include progressive cognitive decline, ataxia, neuropathy, and myopathy. The gene defects for the most common forms of PME (Unverricht-Lundborg disease, Lafora disease, several forms of neuronal ceroid lipofuscinoses, myoclonus epilepsy with ragged-red fibers [MERRF], and type 1 and 2 sialidoses) have been identified. The prognosis of a PME depends on the specific disease. Lafora disease, the neuronal ceroid lipofuscinoses, and the neuronopathic form of Gaucher disease have an invariably fatal course. In contrast, Unverricht-Lundborg disease has a much slower progression, and with adequate care many patients have a normal life span. The specific diseases that cause PME are diagnosed by recognition of their age of onset, the associated clinical symptoms, the clinical course, the pattern of inheritance, and by special investigations such as enzyme measurement, skin/muscle biopsy, or gene testing.
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PMID:Progressive Myoclonus Epilepsies. 2606 Sep 9

ASAH1 gene encodes for acid ceramidase that is involved in the degradation of ceramide into sphingosine and free fatty acids within lysosomes. ASAH1 variants cause both the severe and early-onset Farber disease and rare cases of spinal muscular atrophy (SMA) with progressive myoclonic epilepsy (SMA-PME), phenotypically characterized by childhood onset of proximal muscle weakness and atrophy due to spinal motor neuron degeneration followed by occurrence of severe and intractable myoclonic seizures and death in the teenage years. We studied two subjects, a 30-year-old pregnant woman and her 17-year-old sister, affected with a very slowly progressive non-5q SMA since childhood. No history of seizures or myoclonus has been reported and EEG was unremarkable. The molecular study of ASAH1 gene showed the presence of the homozygote nucleotide variation c.124A>G (r.124a>g) that causes the amino acid substitution p.Thr42Ala. Biochemical evaluation of cultured fibroblasts showed both reduction in ceramidase activity and accumulation of ceramide compared with the normal control. This study describes for the first time the association between ASAH1 variants and an adult SMA phenotype with no myoclonic epilepsy nor death in early age, thus expanding the phenotypic spectrum of ASAH1-related SMA. ASAH1 molecular analysis should be considered in the diagnostic testing of non-5q adult SMA patients.
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PMID:ASAH1 variant causing a mild SMA phenotype with no myoclonic epilepsy: a clinical, biochemical and molecular study. 3029 39

Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1, OMIM254800) is an autosomal recessive neurodegenerative disorder characterized by stimulus-sensitive and action-activated myoclonus, tonic-clonic epileptic seizures, and ataxia. Loss-of-function mutations in the gene encoding the cysteine protease inhibitor cystatin B (CSTB) underlie EPM1. The deficiency of CSTB in mice (Cstb-/- mice) generates a phenotype resembling the symptoms of EPM1 patients and is accompanied by microglial activation at two weeks of age and an upregulation of immune system-associated genes in the cerebellum at one month of age. To shed light on molecular pathways and processes linked to CSTB deficiency in microglia we characterized the transcriptome of cultured Cstb-/- mouse microglia using microarray hybridization and RNA sequencing (RNA-seq). The gene expression profiles obtained with these two techniques were in good accordance and not polarized to either pro- or anti-inflammatory status. In Cstb-/- microglia, altogether 184 genes were differentially expressed. Of these, 33 genes were identified by both methods. Several interferon-regulated genes were weaker expressed in Cstb-/- microglia compared to control. This was confirmed by quantitative real-time PCR of the transcripts Irf7 and Stat1. Subsequently, we explored the biological context of CSTB deficiency in microglia more deeply by functional enrichment and canonical pathway analysis. This uncovered a potential role for CSTB in chemotaxis, antigen-presentation, and in immune- and defense response-associated processes by altering JAK-STAT pathway signaling. These data support and expand the previously suggested involvement of inflammatory processes to the disease pathogenesis of EPM1 and connect CSTB deficiency in microglia to altered expression of interferon-regulated genes.
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PMID:Gene-Expression Profiling Suggests Impaired Signaling via the Interferon Pathway in Cstb-/- Microglia. 2735 30

We first review the clinical presentation and current therapeutic approaches available for treating Unverricht-Lundborg disease (ULD), a progressive myoclonus epilepsy. Next, we describe the identification of disease causing mutations in the gene encoding cystatin B (CSTB). A Cstb-deficient mouse model, which recapitulates the key features of ULD including myoclonic seizures, ataxia, and neuronal loss, was generated to shed light on the mechanisms contributing to disease pathophysiology. Studies with this model have elucidated the diverse biological roles for Cstb from functioning as a protease inhibitor, to regulating glial activation, oxidative stress, serotonergic neurotransmission, and hyperexcitability. These findings set the stage for future studies that may open avenues to improved therapeutic approaches.
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PMID:Unverricht-Lundborg disease. 2758 36

GOSR2-associated PME is associated with a homozygous mutation in GOSR2 (c.430G>T, p.Gly144Trp), a Golgi vesicle transport gene. The functional effect of this mutation is a loss of function that results in failure of the GOSR2 protein to localize to the cis-Golgi. The main clinical features of the GOSR2-associated PME are early-onset ataxia, areflexia, action myoclonus and seizures, scoliosis, elevated creatine kinase levels, relative preservation of cognitive function until the late stages of the disease, and relentless disease course. Severe photosensitive myoclonus is a common feature. GOSR2-associated PME is a rare disease with very few cases reported so far and it can be expected that the identification of further patients will contribute to expanding the phenotype and genotype of this condition.
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PMID:GOSR2: a progressive myoclonus epilepsy gene. 2761 68

Generalized motor seizures, usually tonic-clonic, tonic-vibratory, myoclonic or clonic, and stimulus-sensitive/action myoclonus are typical features of progressive myoclonus epilepsies (PMEs). Despite the introduction of many anticonvulsants, the treatment of these symptoms, particularly myoclonus, remains challenging, due to the incomplete and often transitory effects of most drugs. Moreover, treatment is only symptomatic, since therapy targeting the underlying aetiology for these genetic conditions is in its infancy. Traditional antiepileptic drugs for the treatment of PMEs are valproate, clonazepam, and phenobarbital (or primidone). These drugs may improve the overall performance of PME patients by decreasing their generalized seizures and, to a lesser extent, their myoclonic jerks. Newer drugs which have been shown to be effective include piracetam, levetiracetam, topiramate, zonisamide, and possibly perampanel for Lafora disease. The potential of other drugs (such as L-triptophan and N-acetylcysteine) and procedures (such as vagal and deep brain stimulation) has also been discussed. The available data on the efficacy of drugs are mainly based on small series or anecdotal reports. Two prospective, randomized, double blind studies investigating the novel SV2A ligand, brivaracetam, in genetically confirmed Unverricht-Lundborg patients have been performed with disappointing results. When treating PMEs, particular care should be paid to avoid drugs known to aggravate myoclonus or myoclonic seizures, such as phenytoin, carbamazepine, oxcarbazepine, lamotrigine, vigabatrin, tiagabine, gabapentin, and pregabalin. The emergency treatment of motor status, which often complicates the course of PMEs, consists of intravenous administration of benzodiazepines, valproate, or levetiracetam.
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PMID:Myoclonus and seizures in progressive myoclonus epilepsies: pharmacology and therapeutic trials. 2762 98


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