Frequency of Juvenile Myoclonic Epilepsy Clinical Phenotypes in Siberia

Juvenile myoclonic epilepsy (JME) is characterised by myoclonia during awakening, generalised tonic-clonic seizures, typical absences and usually presents for the first time at the age of 12 to 18 years old. This article describes the results of a clinical study into JME phenotypes in patients living in the Siberian Federal District. We have shown that the incidence of JME among males was lower than among females (1:1.9) and JME debut age for males was higher than in those women. Classical phenotype of JME (Type I) was dominant and more common in males compared to females—70.4% vs. 58.5%, respectively. The JME phenotype with worse prognosis in terms of achieving stable clinical remission (Type II) occurred 3.5 times more frequently among female patients compared to male (13.2% vs. 3.7% respectively). The findings resulting from this study give a deeper insight into the diagnosis and prognosis of this form of idiopathic generalised epilepsy in predisposed families.

Case Report of Management Problem of Juvenile Myoclonic Epilepsy

Juvenile myoclonic epilepsy (JME) is one of the most common types of idiopathic generalised epilepsy. It starts in teenage years, yet it is frequently misdiagnosed or diagnosed very late, thereby resulting in inadequate therapy plan and worsening of symptoms. Timely diagnosis of JME is crucial for the correct management of symptoms and prevention of disease development. In this case report we describe a case of a 33-year-old woman who did not receive appropriate care due to a late diagnosis of her JME condition.

Antimyoclonic Effect of Levetiracetam and Clonazepam Combined Treatment on Myoclonic Epilepsy with Ragged-Red Fiber Syndrome with m.8344A〉G Mutation

Background： Treatment of myoclonic seizures in myoclonic epilepsy with ragged-red fibers （MERRFs） has been empirical and ineffective. Guideline on this disease is not available. Additional trials must be conducted to find more suitable treatments for it. In this study, the antimyoclonic effects ofmonotherapies, including levetiracetam （LEV）, clonazepam （CZP）, valproic acid （VPA）, and topiramate （TPM） compared to combination therapy group with LEV and CZP on MERRF, were evaluated to find a more advantageous approach on the treatment of myoclonic seizures. Methods： Treatments of myoclonic seizures with VPA, LEV, CZP, and TPM were reported as monotherapies in 17 MERRF patients from Qilu Hospital between 2003 and 2016, who were diagnosed through clinical data and genetic testing. After 1-4 months oflbllow-up （mean： 82.9 ± 28.1 days）, 12 patients that exhibited poor responses to monotherapy were given a combined treatment consisting of LEV and CZP subsequently. The lbllow-up period was 4-144 months （mean： 66.3 ± 45.3 months）, the effective rates of monotherapy group （17 patients） and combination therapy group （12 patients） were analyzed by Chi-square test. Results： The m.8344 A〉G mutation was detected in all patients. There were lbur patients with partial response （4/17, two in the CZP group and two in the LEV group）, ten patients with stable disease （10/17, six in the CZP group, three in the LEV group, and one in the TPM group）, and three patients with progressive disease （3/18, two in the VPA group and one in the TPM group）. Twelve of the patients with LEV combined with CZP showed a positive effect and good tolerance （12/12）, eight of them demonstrated improved cognition and coordination. There was a significant difference between the monotherapy group and combination therapy gToup in the efficacy ofantimyoclonic seizures （χ^2 = 13.7, P 〈 0.001 ）. Conclusions： LEV in combination with CZP is an efficient and sale treatment for myoclonic seizures in patients with this disease exhibiting the m.8344A〉G mutation.

A Novel Mutation of Mitochondrial T14709C Causes Myoclonic Epilepsy with Ragged Red Fibers Syndrome in a Chinese Patient

Background： Myoclonic epilepsy with ragged red fibers （MERRF） syndrome is characterized by myoclonus, generalized epilepsy, cerebellar ataxia, and ragged red fibers （RRFs） in the muscle. T-to-C transition at nucleotide position 14709 in the mitochondrial tRNA glutamic acid （tRNA^Gla） gene has previously been associated with maternally inherited diabetes and deathess. However, the association between MERRF and mitochondrial T14709C mutation （m.TI4709C） has never been reported before. Methods： Clinical information of a 17-year-old patient was collected; muscle biopsy and next-generation sequencing （NGS） of whole mitochondrial and neuromuscular disease panel were then conducted. Finally, sanger sequencing was carried out to confirm the mutations. Results： The patient presented a typical MERRF phenotype with muscle weakness, epileptic seizure, clonic episodes, cerebellar ataxia, and spinal scoliosis. Muscle biopsy showed RRFs which indicated abnormal mitochondrial functions. NGS of whole mitochondrial gene revealed m.TI4709C mutation, confirmed by Sanger sequencing. Conclusion： We present a sporadic patient with typical MERRF presentation carrying the mutation ofm.T14709C, which expanded the spectrum of re.T14709C.

Clinical phenotype features and genetic etiologies of 38 children with progressive myoclonic epilepsy

Background:Progressive myoclonic epilepsy(PME)is a group of neurodegenerative diseases with genetic heterogeneity and phenotypic similarities,and many cases remain unknown of the genetic causes.This study is aim to summarize the clinical features and study the genetic causes of PME patients.Methods:Sanger sequencing of the target gene,Next Generation Sequencing(NGS)panels of epilepsy,trio-based Whole Exome Sequencing(WES)and detection of cytosine-adenine-guanine(CAG)repeat number were used to investigate the genetic causes of PME patients.Results:Thirty-eight children with PME whose seizure onset age ranged from 3 months to 12 years were collected from February 2012 to November 2019 in three hospitals in Beijing,China.The seizure types included myoclonic seizures(n=38),focal seizures(n=19),generalized tonic-clonie seizure(GTCS)(n=13),absence seizures(n=4),atonic seizures(n=3),epileptic spasms(n=2)and tonic seizures(n=1).Twenty-seven cases were sporadic and 11 had family members affected.Established PME-related genes were identified in 30 out of 38(78.9%)patients who had either recessively inherited or de novo heterozygous mutations.Among these 30 cases,there were 12 cases(31.6%)of neuronal ceroid lipofuscinoses(the causing gene contains TPP1,PPT1,CLN5,CLN6 and MFSD8),two cases of sialidosis(the causing gene is NEU1),two cases of neuronopathic Gaucher disease(the causing gene is GBA),one case of spinal muscular atrophy-progressive myoclonic epilepsy(the causing gene is ASAH1),four cases of KCNC1 mutation-related PME,four cases of KCTD7 mutation-related PME,two cases of TBC1D24 mutation-related PME,one case of GOSR2 related PME,and two of dentatorubral-pallidoluysian atrophy(the causing gene is ATN1).In total,13 PME genes were identified in our cohort.The etiology was not clear in eight patients.Conclusion:PME is a group of clinically and genetically heterogeneous diseases.Genetic diagnosis was clear in 78.9%of PME patients.Various of genetic testing methods could increase the rate of genetic diagnosis.Neuronal ceroid lipofuscinoses(NCL)is the most common etiology of PME in children.Nearly one third PME children were diagnosed with NCL.GOSR2 related PME was in our cohort in Asia for the first time.

A ＂Triple Trouble＂ Case of Facioscapulohumeral Muscular Dystrophy Accompanied by Peripheral Neuropathy and Myoclonic Epilepsy

Background： Facioscapulohumeral muscular dystrophy （FSHD） is characterized by asymmetric muscular deficit of facial, shoulder-girdle muscles, and descending to lower limb muscles, but it exists in several extramuscular manifestations or overlapping syndromes. Herein, we report a ＂complex disease plus＂ patient with FSHD1, accompanied by peripheral neuropathy and myoclonic epilepsy. Methods： Standard clinical assessments, particular auxiliary examination, histological analysis, and molecular analysis were performed through the new Comprehensive Clinical Evaluation Form, pulsed-field gel electrophoresis-based Southern blot, Multiplex Ligation-dependent Probe Amplification （MLPA）, whole exome sequencing （WES）, and targeted methylation sequencing. Results： The patient presented with mild facial weakness, humeral poly-hill sign, scapular winging, peroneal weakness, drop foot, pes cavus, and myoclonic epilepsy. Furthermore, electrophysiology revealed severely demyelinated and axonal injury. The muscle and nerve biopsy revealed broadly fiber Type II grouping atrophy and myelinated nerve fibers that significantly decreased with thin myelinated fibers and onion bulbs changes. Generalized sharp and sharp-slow wave complexes on electroencephalography support the diagnosis toward myoclonic epilepsy. In addition, molecular testing demonstrated a co-segregated 20-kb 4q35-EcoRI fragment and permissive allele A, which corresponded with D4Z4 hypomethylation status in the family. Both the patient＇s mother and brother only presented the typical FSHD but lacked overlapping syndromes. However, no mutations for hereditary peripheral neuropathy and myoclonic epilepsy were discovered by MLPA and WES. Conclusions： The present study described a ＂tripe trouble＂ with FSHD, peripheral neuropathy, and myoclonic epilepsy, adding the spectrum of overlapping syndromes and contributing to the credible diagnosis of atypical phenotype. It would provide a direct clue on medical care and genetic counseling.

Altered brain activity in juvenile myoclonic epilepsy with a monotherapy:a resting-state fMRI study

Background:Juvenile myoclonic epilepsy(JME)is the most common syndrome of idiopathic generalized epilepsy.Although resting-state functional magnetic resonance imaging(rs-fMRI)studies have found thalamocortical circuit dysfunction in patients with JME,the pathophysiological mechanism of JME remains unclear.In this study,we used three complementary parameters of rs-fMRI to investigate aberrant brain activity in JME patients in comparison to that of healthy controls.Methods:Rs-fMRI and clinical data were acquired from 49 patients with JME undergoing monotherapy and 44 ageand sex-matched healthy controls.After fMRI data preprocessing,the fractional amplitude of low-frequency fluctuation(fALFF),regional homogeneity(ReHo),and degree centrality(DC)were calculated and compared between the two groups.Correlation analysis was conducted to explore the relationship between local brain abnormalities and clinical features in JME patients.Results:Compared with the controls,the JME patients exhibited significantly decreased fALFF,ReHo and DC in the cerebellum,inferior parietal lobe,and visual cortex(including the fusiform and the lingual and middle occipital gyri),and increased DC in the right orbitofrontal cortex.In the JME patients,there were no regions with reduced ReHo compared to the controls.No significant correlation was observed between regional abnormalities of fALFF,ReHo or DC,and clinical features.Conclusions:We demonstrated a wide range of abnormal functional activity in the brains of patients with JME,including the prefrontal cortex,visual cortex,default mode network,and cerebellum.The results suggest dysfunctions of the cerebello-cerebral circuits,which provide a clue on the potential pathogenesis of JME.