Long-term efficacy of low-dose perampanel for progressive myoclonus epilepsy in a patient with Gaucher disease type 3.

PURPOSE: We report the case of a patient with progressive myoclonus epilepsy due to Gaucher disease type 3 whose seizures and ability to perform activities of daily living were significantly improved after starting low-dose perampanel therapy. CASE: Our patient's generalized tonic-clonic seizures and myoclonus did not improve despite the administration of multiple antiseizure medications and enzyme replacement therapy. The myoclonus reduced following pharmacological chaperone therapy, but this effect was temporary, and the generalized tonic-clonic seizures continued to occur. However, the generalized tonic-clonic seizures disappeared following treatment with 2 mg/day of perampanel. In addition, the decrease in myoclonus dramatically improved motor function such as talking, eating, and walking and stabilized the patient's mental status. These effects have been sustained for more than 4 years. CONCLUSION: Perampanel is expected to be effective in the treatment of progressive myoclonus epilepsy associated with Gaucher disease type 3 and should be considered the drug of choice for this condition.

Emerging treatments for progressive myoclonus epilepsies.

Introduction: 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.Areas covered: 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.Expert opinion: 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.

The best evidence for progressive myoclonic epilepsy: A pathway to precision therapy.

Progressive Myoclonus Epilepsies (PMEs) are a group of uncommon clinically and genetically heterogeneous disorders characterised by myoclonus, generalized epilepsy, and neurological deterioration, including dementia and ataxia. PMEs may have infancy, childhood, juvenile or adult onset, but usually present in late childhood or adolescence, at variance from epileptic encephalopathies, which start with polymorphic seizures in early infancy. Neurophysiologic recordings are suited to describe faithfully the time course of the shock-like muscle contractions which characterize myoclonus. A combination of positive and negative myoclonus is typical of PMEs. The gene defects for most PMEs (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. PMEs are uncommon disorders, difficult to diagnose in the absence of extensive experience. Thus, aetiology is undetermined in many patients, despite the advance in molecular medicine. Treatment of PMEs remains essentially symptomaticof seizures and myoclonus, together with palliative, supportive, and rehabilitative measures. The response to therapy may initially be relatively favourable, afterwards however, seizures may become more frequent, and progressive neurologic decline occurs. The prognosis of a PME depends on the specific disease. The history of PMEs revealed that the international collaboration and sharing experience is the right way to proceed. This emerging picture and biological insights will allow us to find ways to provide the patients with meaningful treatment.

[Progressive myoclonic epilepsy secondary to Lafora's body disease]. / Epilepsia mioclónica progresiva secundaria a enfermedad por cuerpos de Lafora.

Lafora's disease is infrequent. However, it is one of the most common causes of progressive myoclonus epilepsy. We present the case of a 19-year-old woman, without comorbidities and normal development that started at 8 years with seizures and that from 15 years, had progressive cognitive deterioration. She was admitted to our institution with a diagnosis of super refractory status epilepticus. The diagnosis of Lafora's disease was made through pathological anatomy, later a genetic test was performed that reported a pathogenic variant of the EPM2A gene, confirming the diagnosis. We present a cause of progressive myoclonic epilepsy, with an ominous prognosis and a treatment oriented to palliative measures, so it is important to analyze the differential diagnoses with other entities, in order to establish a prognosis, offer better quality of life, adequate medical care and provide genetic counseling to family members.

Epilepsia mioclónica progresiva secundaria a enfermedad por cuerpos de Lafora / Progressive myoclonic epilepsy secondary to Lafora's body disease

La enfermedad de Lafora es infrecuente; sin embargo, es una de las causas más comunes de epilepsia mioclónica progresiva. Presentamos el caso de una mujer de 19 años sin comorbilidades y pautas madurativas normales, que inició a los 8 años con convulsiones y que a partir de los 15 años agregó deterioro cognitivo progresivo. Fue internada en nuestra institución con diagnóstico de estatus epiléptico super refractario. Se diagnosticó enfermedad de Lafora, confirmada por la anatomía patológica, y posteriormente se realizó un test genético que informó una variante patogénica del gen EPM2A, que confirmó el diagnóstico. Presentamos una causa de epilepsia mioclónica progresiva, con un pronóstico ominoso y un tratamiento orientado a medidas paliativas, por lo que es importante analizar los diagnósticos diferenciales con otras entidades, a fin de establecer un pronóstico, ofrecer mejor calidad de vida, asistencia médica adecuada y brindar asesoría genética a los familiares.

Lafora's disease is infrequent. However, it is one of the most common causes of progressive myoclonus epilepsy. We present the case of a 19-year-old woman, without comorbidities and normal development that started at 8 years with seizures and that from 15 years, had progressive cognitive deterioration. She was admitted to our institution with a diagnosis of super refractory status epilepticus. The diagnosis of Lafora's disease was made through pathological anatomy, later a genetic test was performed that reported a pathogenic variant of the EPM2A gene, confirming the diagnosis. We present a cause of progressive myoclonic epilepsy, with an ominous prognosis and a treatment oriented to palliative measures, so it is important to analyze the differential diagnoses with other entities, in order to establish a prognosis, offer better quality of life, adequate medical care and provide genetic counseling to family members.

Spinocerebellar ataxias.

There are over 40 autosomal dominant spinocerebellar ataxias (SCAs) now identified. In this chapter we delineate the phenotypes of SCAs 1-44 and dentatorubral-pallidoluysian atrophy (DRPLA) and highlight the clinical and genetic features of the well characterised SCAs in detail in the main section of the chapter, along with their frequency and age at onset. We have included a section on the key phenotypic features of rare spinocerebellar ataxias and discuss rare and unusual presentations and genetic mechanisms of the ataxias and show differences between adult and paediatric presentations. We look at unusual mechanisms where knowledge is evolving in some dominant ataxias. For ease of reference we have tabulated historical aspects of the ataxias, major neurological diagnostic features, ataxias with predominant paediatric and infantile onset and list recognisable nerve conduction features. We comment on the anti-sense ataxia gene mechanisms and we discuss potential developments including exome sequencing and potential therapeutic options. A gene table listing all of the identified SCAs and DRPLA is also included with key references and gene locations and symbols with OMIM reference numbers for further reading.

Uniparental disomy as a cause of spinal muscular atrophy and progressive myoclonic epilepsy: phenotypic homogeneity due to the homozygous c.125C>T mutation in ASAH1.

Spinal muscular atrophy and progressive myoclonic epilepsy (SMAPME, OMIM#159950) is a rare autosomal recessive disorder characterized by the combination of progressive myoclonic epilepsy and muscular weakness due to lower motor neuron disease. Mutations in ASAH1, previously associated only to Farber disease, have been recently described in seven patients with SMAPME. A homozygous c.125C>T mutation was initially found in six patients with a clinical homogeneous phenotype. A heterozygous compound mutation found in an additional patient has broadened the clinical and genetic spectrum of clinical SMAPME. We report a new case of a 13-year-old girl with SMAPME with the homozygous ASAH1 c.125C>T mutation, unique in that it is due to paternal uniparental disomy. She experienced muscle weakness from the age of three due to lower motor neuron involvement that lead to severe handicap and onset in late childhood of a progressive myoclonic epilepsy. This clinical picture fully overlaps with that of previously reported patients with this mutation and supports our view that the clinical phenotype associated with the homozygous c.125C>T mutation constitutes a clinically homogenous and recognizable disease.

Progressive myoclonus epilepsy in Down syndrome patients with dementia.

This study aimed to elucidate the natural history of senile myoclonic epilepsy, a type of myoclonic epilepsy associated with Alzheimer's disease in adult Down syndrome patients. Twelve Down syndrome patients over the age of 40 years with myoclonic epilepsy and Alzheimer's disease underwent clinical, neuropsychological, neurophysiological, and neuroradiological study. The kariotypes, APOE polymorphisms, all exons in the PSEN1 and PSEN2 genes, and exons 16 and 17 in the APP gene were determined for all patients. CSF Aß42, p-tau181, and t-tauAg were determined for two patients. Three main stages appeared during the course of the syndrome. The first stage was characterized by dementia onset (mean age: 51 ± 6.6 years), diffuse EEG abnormalities during sleep, and cerebral atrophy determined using neuroimaging. During the second stage, myoclonic epilepsy manifested (mean age: 51.4 ± 7.2 years) with myoclonic jerks time-locked to diffuse epileptiform abnormalities upon awakening, which was controlled with antiepileptic drugs. During the third stage (mean age: 54.8 ± 7.6 years), myoclonic seizures were replaced with nonepileptic myoclonus, and cerebellar signs, severe dementia, and photosensitivity developed. All patients showed complete trisomy 21. Mutations were ruled out on the APP, PSEN1, and PSEN2 genes, and APOE analysis revealed ε3/ε3 homozygosity. CSF biomarkers showed a decrease in Aß42 and an increase in p-tau181. The natural history of senile myoclonic epilepsy is consistent with progressive myoclonus epilepsy. Chromosome 21 is implicated in its pathophysiology; however, other genetic and/or environmental risk factors cannot be excluded. The absence of the APOE type 4 allele could predict its progression.

[Successful treatment of epilepsy and circadian rhythm disturbance with levetiracetam in a patient with dentatorubral-pallidoluysian atrophy (DRPLA)].

We report a 21-year-old male patient with dentatorubral-pallidoluysian atrophy (DRPLA) showing progressive myoclonus epilepsy (PME), who responded to levetiracetam (LEV) at an initial dose of 1,000 mg/day. The patient developed epilepsy at the age of 10 years, and also showed intellectual regression. Various antiepileptic drugs showed no effects on generalized tonic seizures, tonic-clonic seizures, and myoclonus. Addition of LEV (1,000 mg/day) led to the reduction of myoclonus and tonic-clonic seizures, and improved the EEG and sleep-wake rhythm. He had a better appetite and gain weight. It is suggested that LEV may improve quality of life in patients with DRPLA, in addition to reducing the frequency of epileptic seizures.

Hashimoto encephalopathy presenting as progressive myoclonus epilepsy syndrome.

We report an 11 year old girl with multi-focal spontaneous myoclonus, generalized seizures and behavioural changes. She was found to have sub-clinical hypothyroidism and elevated anti-thyroid peroxidase antibodies. A diagnosis of Hashimoto encephalopathy (or Steroid Responsive Encephalopathy with Autoimmune Thyroiditis) was made in view of consistent clinical and laboratory features. The patient showed and maintained significant improvement with valproate, clonazepam and long term prednisolone. Other findings included mild cerebral cortical grey matter atrophy on brain magnetic resonance imaging and intermittent slowing with generalized poly-spike-and-wave discharges on electroencephalography. Other causes of progressive myoclonus epilepsy (PME) syndrome including subacute sclerosing panencephalitis, Lafora body disease, Juvenile Neuronal Ceroid Lipofuscinosis, Late onset gangliosidosis, Sialidosis, mitochondrial disorders and coeliac disease were ruled out by appropriate investigations. No other auto-immune abnormality was detected. This case emphasizes that Hashimoto encephalopathy should be considered in the etiologies of PME syndrome in adolescents since it is a treatable entity.

Atrophin contributes to the negative regulation of epidermal growth factor receptor signaling in Drosophila.

Dentato-rubral and pallido-luysian atrophy (DRPLA) is a dominant, progressive neurodegenerative disease caused by the expansion of polyglutamine repeats within the human Atrophin-1 protein. Drosophila Atrophin and its human orthologue are thought to function as transcriptional co-repressors. Here, we report that Drosophila Atrophin participates in the negative regulation of Epidermal Growth Factor Receptor (EGFR) signaling both in the wing and the eye imaginal discs. In the wing pouch, Atrophin loss of function clones induces cell autonomous expression of the EGFR target gene Delta, and the formation of extra vein tissue, while overexpression of Atrophin inhibits EGFR-dependent vein formation. In the eye, Atrophin cooperates with other negative regulators of the EGFR signaling to prevent the differentiation of surplus photoreceptor cells and to repress Delta expression. Overexpression of Atrophin in the eye reduces the EGFR-dependent recruitment of cone cells. In both the eye and wing, epistasis tests show that Atrophin acts downstream or in parallel to the MAP kinase rolled to modulate EGFR signaling outputs. We show that Atrophin genetically cooperates with the nuclear repressor Yan to inhibit the EGFR signaling activity. Finally, we have found that expression of pathogenic or normal forms of human Atrophin-1 in the wing promotes wing vein differentiation and acts as dominant negative proteins inhibiting endogenous fly Atrophin activity.

Progressive myoclonic epilepsies: a review of genetic and therapeutic aspects.

The progressive myoclonic epilepsies (PMEs) are a group of symptomatic generalised epilepsies caused by rare disorders, most of which have a genetic component, a debilitating course, and a poor outcome. Challenges with PME arise from difficulty with diagnosis, especially in the early stages of the illness, and further problems of management and drug treatment. Recent advances in molecular genetics have helped achieve better understanding of the different disorders that cause PME. We review the PMEs with emphasis on updated genetics, diagnosis, and therapeutic options.

[Improvement of action myoclonus in a patient with dentatorubral-pallidoluysian atrophy by piracetam].

We report a 13-year-old girl with dentatorubal-pallidoluysian atrophy (DRPLA), presenting clinically as progressive myoclonic epilepsy. The action myoclonus, which severely impaired her daily life, was markedly improved by administration of piracetam, a drug reportedly useful for myoclonus of cortical origin. In our case, piracetam effectively suppressed severe subcortical myoclonus of DRPLA, suggesting that the drug may be useful in the treatment of both cortical, and subcortical myoclonus.

Prevalence of dentatorubral-pallidoluysian atrophy in a large series of white patients with cerebellar ataxia.

BACKGROUND: Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare neurodegenerative disorder mainly diagnosed in Japan. Its prevalence is low in other countries. Three phenotypes are described: choreoathetoid movements, cerebellar ataxia, and progressive myoclonic epilepsy. OBJECTIVE: To evaluate the frequency of DRPLA in European patients with sporadic or autosomal dominant cerebellar ataxia. METHODS: We analyzed a series of 809 index patients with either autosomal dominant cerebellar ataxia (416 families) or progressive cerebellar ataxia without a family history of the disease (393 cases) for the DRPLA mutation. RESULTS: We identified a CAG repeat expansion in the DRPLA gene in one family and in one patient without a family history. The familial case illustrates the phenomenon of anticipation and the previously established correlation between the phenotype and size of the expansion. A censored-history family or expansion of large normal CAG repeats during paternal transmission could be implicated in the patient without a family history. CONCLUSIONS: This study enables us to estimate the frequency of the disease as 0.25% in both families with autosomal dominant cerebellar ataxia and sporadic cases of ataxia in our series, confirming the very low frequency of DRPLA in Europe. In both familial and sporadic cases, molecular testing for DRPLA could be restricted to patients with ataxia with one of the following features: chorea, dementia, or myoclonic epilepsy.

Cystatin-B is expressed by neural stem cells and by differentiated neurons and astrocytes.

Mutation in the gene encoding cystatin-B (CSTB) has been shown to cause progressive myoclonus epilepsy. Mice with a gene deletion of CSTB exhibit increased apoptosis of specific neurons but the physiological role of CSTB in brain cells is not fully understood. In the present study, we have examined the expression of CSTB in neural stem cells (NSC) and in differentiating mature brain cells. The results show that CSTB is present in embryonic and adult NSC and in the neuroepithelium. CSTB was expressed by both neurons and glial cells differentiated from NSC and in hippocampal cultures. CSTB localized mainly to the nucleus in NSC and in neurons, whilst in astrocytes CSTB was also in the cytoplasm. Double labeling showed that CSTB was present in the lysosomes in glial cells. The results demonstrate a nuclear expression of CSTB in NSC and in neurons, suggesting novel function for this molecule.

Transcriptional derepression as a cause of genetic diseases.

Transcription of DNA into mRNA is a highly regulated process directed by a complex molecular machine comprising more than 100 proteins. Regulation of transcription occurs by both positive (transcriptional activation) and negative (transcriptional repression) mechanisms. Recently, inappropriate transcriptional derepression has been found as the underlying basis of several human genetic diseases. The putative target genes, whose inappropriate expression is thought to cause disease, have remained elusive but are being searched for intensively.

New insights into the molecular basis of progressive myoclonus epilepsy: a multiprotein complex with cystatin B.

Cystatin B is an anti-proteolytic polypeptide implicated in progressive myoclonus epilepsy (EPM1), a degenerative disease of the central nervous system. The knock-out mouse model of the disease shows apoptosis of the cerebellar granule cells. We have identified five recombinant proteins interacting with cystatin B and none of them is a protease. We show that three of these proteins (RACK-1, beta-spectrin and NF-L) co-immunoprecipitate with cystatin B in rat cerebellum. Confocal immunofluorescence analysis shows that the same proteins are present in the granule cells of developing cerebellum, as well as in Purkinje cells of adult rat cerebellum. We propose that a cystatin B multiprotein complex has a specific cerebellar function and that the loss of this function might contribute to the disease in EPM1 patients.