2019年癫痫领域十大突破盘点

1. Lancet—治疗肥胖的药物盐酸氟苯丙胺可显著改善Dravet综合征的癫痫症状

英文摘要：

BACKGROUND:

Dravetsyndrome is a rare, treatment-resistant developmental epileptic encephalopathycharacterised by multiple types of frequent, disabling seizures. Fenfluraminehas been reported to have antiseizure activity in observational studies ofphotosensitive epilepsy and Dravet syndrome. The aim of the present study wasto assess the efficacy and safety of fenfluramine in patients with Dravetsyndrome.

METHODS:

Inthis randomised, double-blind, placebo-controlled clinical trial, we enrolledchildren and young adults with Dravet syndrome. After a 6-week observationperiod to establish baseline monthly convulsive seizure frequency (MCSF;convulsive seizures were defined as hemiclonic, tonic, clonic, tonic-atonic,generalised tonic-clonic, and focal with clearly observable motor signs),patients were randomly assigned through an interactive web response system in a1:1:1 ratio to placebo, fenfluramine 0·2 mg/kg per day, or fenfluramine 0·7mg/kg per day, added to existing antiepileptic agents for 14 weeks. The primaryoutcome was the change in mean monthly frequency of convulsive seizures duringthe treatment period compared with baseline in the 0·7 mg/kg per day groupversus placebo; 0·2 mg/kg per day versus placebo was assessed as a key secondaryoutcome. Analysis was by modified intention to treat. Safety analyses includedall participants who received at least one dose of study medication. This trialis registered with ClinicalTrials.gov with two identical protocols NCT02682927and NCT02826863.

FINDINGS:

BetweenJan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients(mean age 9·0 years, 64 [54%] male) were randomly assigned to receive eitherfenfluramine 0·2 mg/kg per day (39), fenfluramine 0·7 mg/kg per day (40) orplacebo (40). During treatment, the median reduction in seizure frequency was74·9% in the fenfluramine 0·7 mg/kg group (from median 20·7 seizures per 28days to 4·7 seizures per 28 days), 42·3% in the fenfluramine 0·2 mg/kg group(from median 17·5 seizures per 28 days to 12·6 per 28 days), and 19·2% in theplacebo group (from median 27·3 per 28 days to 22·0 per 28 days). The study metits primary efficacy endpoint, with fenfluramine 0·7 mg/kg per day showing a62·3% greater reduction in mean MCSF compared with placebo (95% CI 47·7-72·8,p<0·0001); fenfluramine 0·2 mg/kg per day showed a 32·4% reduction in meanMCSF compared with placebo (95% CI 6·2-52·3, p=0·0209). The most common adverseevents (occurring in at least 10% of patients and more frequently in thefenfluramine groups) were decreased appetite, diarrhoea, fatigue, lethargy,somnolence, and decreased weight. Echocardiographic examinations revealed valvefunction within the normal physiological range in all patients during the trialand no signs of pulmonary arterial hypertension.

INTERPRETATION:

InDravet syndrome, fenfluramine provided significantly greater reduction inconvulsive seizure frequency compared with placebo and was generally welltolerated, with no observed valvular heart disease or pulmonary arterialhypertension. Fenfluramine could be an important new treatment option forpatients with Dravet syndrome.

参考文献：

Lagae et al (2020). Fenfluramine hydrochloride for thetreatment of seizures in Dravet syndrome: a randomised, double-blind,placebo-controlled trial. Lancet. 2020 Dec 21;394(10216):2243-2254.

2. Science—大钾通道（BK通道）障碍是天使人综合症中癫痫的发生机制

英文摘要:

Disruptionsin the ubiquitin protein ligase E3A (UBE3A) gene cause Angelman syndrome(AS). Whereas AS model mice have associated synaptic dysfunction and alteredplasticity with abnormal behavior, whether similar or other mechanismscontribute to network hyperactivity and epilepsysusceptibility in AS patients remains unclear. Using human neurons and brainorganoids, we demonstrate that UBE3A suppresses neuronal hyperexcitability viaubiquitin-mediated degradation of calcium- and voltage-dependent big potassium(BK) channels. We provide evidence that augmented BK channel activity manifestsas increased intrinsic excitability in individual neurons and subsequentnetwork synchronization. BK antagonists normalized neuronal excitability inboth human and mouse neurons and ameliorated seizure susceptibility in an ASmouse model. Our findings suggest that BK channelopathy underlies epilepsy in AS and support the use of human cells tomodel human developmental diseases.

参考文献：

Sun et al (2019). Potassium channel dysfunction in humanneuronal models of Angelman syndrome. Science. 2019 Dec 20;366(6472):1486-1492.

3. Lancet—癫痫二线治疗突破：左乙拉西坦治疗儿童癫痫持续状态并不优于苯妥英

详细见：Lancet：左乙拉西坦二线治疗小儿惊厥性癫痫效果不优于苯妥英

Lancet：左乙拉西推荐作为小儿惊厥性癫痫的二线治疗首选 

英文摘要1:

BACKGROUND:

Phenytoinis the current standard of care for second-line treatment of paediatricconvulsive status epilepticus after failure of first-line benzodiazepines, butis only effective in 60% of cases and is associated with considerable adverseeffects. A newer anticonvulsant, levetiracetam, can be given more quickly, ispotentially more efficacious, and has a more tolerable adverse effect profile.We aimed to determine whether phenytoin or levetiracetam is the superiorsecond-line treatment for paediatric convulsive status epilepticus.

METHODS:

ConSEPTwas an open-label, multicentre, randomised controlled trial conducted in 13 emergencydepartments in Australia and New Zealand. Children aged between 3 months and 16years, with convulsive status epilepticus that failed first-line benzodiazepinetreatment, were randomly assigned (1:1) using a computer-generated permutedblock (block sizes 2 and 4) randomisation sequence, stratified by site and age(≤5years, >5 years), to receive 20 mg/kg phenytoin (intravenous or intraosseousinfusion over 20 min) or 40 mg/kg levetiracetam (intravenous or intraosseousinfusion over 5 min). The primary outcome was clinical cessation of seizureactivity 5 min after the completion of infusion of the study drug. Analysis wasby intention to treat. This trial is registered with the Australian and NewZealand Clinical Trials Registry, number ACTRN12615000129583.

FINDINGS:

BetweenMarch 19, 2015, and Nov 29, 2017, 639 children presented to participatingemergency departments with convulsive status epilepticus; 127 were missed, and278 did not meet eligibility criteria. The parents of one child declined togive consent, leaving 233 children (114 assigned to phenytoin and 119 assignedto levetiracetam) in the intention-to-treat population. Clinical cessation ofseizure activity 5 min after completion of infusion of study drug occurred in68 (60%) patients in the phenytoin group and 60 (50%) patients in thelevetiracetam group (risk difference -9·2% [95% CI -21·9 to 3·5]; p=0·16). Oneparticipant in the phenytoin group died at 27 days because of haemorrhagicencephalitis; this death was not thought to be due to the study drug. Therewere no other serious adverse events.

INTERPRETATION:

Levetiracetamis not superior to phenytoin for second-line management of paediatricconvulsive status epilepticus.

英文摘要2：

BACKGROUND:

Phenytoinis the recommended second-line intravenous anticonvulsant for treatment ofpaediatric convulsive status epilepticus in the UK; however, some evidencesuggests that levetiracetam could be an effective and safer alternative. Thistrial compared the efficacy and safety of phenytoin and levetiracetam forsecond-line management of paediatric convulsive status epilepticus.

METHODS:

Thisopen-label, randomised clinical trial was undertaken at 30 UK emergencydepartments at secondary and tertiary care centres. Participants aged 6 monthsto under 18 years, with convulsive status epilepticus requiring second-linetreatment, were randomly assigned (1:1) using a computer-generatedrandomisation schedule to receive levetiracetam (40 mg/kg over 5 min) orphenytoin (20 mg/kg over at least 20 min), stratified by centre. The primaryoutcome was time from randomisation to cessation of convulsive statusepilepticus, analysed in the modified intention-to-treat population (excludingthose who did not require second-line treatment after randomisation and thosewho did not provide consent). This trial is registered with ISRCTN, numberISRCTN22567894.

FINDINGS:

BetweenJuly 17, 2015, and April 7, 2018, 1432 patients were assessed for eligibility.After exclusion of ineligible patients, 404 patients were randomly assigned.After exclusion of those who did not require second-line treatment and thosewho did not consent, 286 randomised participants were treated and had availabledata: 152 allocated to levetiracetam, and 134 to phenytoin. Convulsive statusepilepticus was terminated in 106 (70%) children in the levetiracetam group andin 86 (64%) in the phenytoin group. Median time from randomisation to cessationof convulsive status epilepticus was 35 min (IQR 20 to not assessable) in thelevetiracetam group and 45 min (24 to not assessable) in the phenytoin group(hazard ratio 1·20, 95% CI 0·91-1·60; p=0·20). One participant who receivedlevetiracetam followed by phenytoin died as a result of catastrophic cerebraloedema unrelated to either treatment. One participant who received phenytoinhad serious adverse reactions related to study treatment (hypotensionconsidered to be immediately life-threatening [a serious adverse reaction] andincreased focal seizures and decreased consciousness considered to be medicallysignificant [a suspected unexpected serious adverse reaction]).

INTERPRETATION:

Althoughlevetiracetam was not significantly superior to phenytoin, the results,together with previously reported safety profiles and comparative ease ofadministration of levetiracetam, suggest it could be an appropriate alternativeto phenytoin as the first-choice, second-line anticonvulsant in the treatmentof paediatric convulsive status epilepticus.

参考文献：

1.Dalzielet al (2019). Levetiracetam versus phenytoin for second-line treatment ofconvulsive status epilepticus in children (ConSEPT): an open-label,multicentre, randomised controlled trial. Lancet. 2019 May25;393(10186):2135-2145.

2.Lyttleet al (2019). Levetiracetam versus phenytoin for second-line treatment ofpaediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label,randomised trial. Lancet. 2019 May 25;393(10186):2125-2134.

4. Lancet Neurol—钠离子通道阻断剂Cenobamate可治疗不受控制的局灶性癫痫

详细见：Lancet Neurol：Cenobamate治疗不受控制的局灶性癫痫 

英文摘要:

BACKGROUND:

Morethan a third of patients with epilepsy are treatment resistant, and thus new,more effective therapies to achieve seizure freedom are needed. Cenobamate(YKP3089), an investigational antiepileptic drug, has shown broad-spectrumanticonvulsant activity in preclinical studies and seizure models. We aimed toevaluate the safety, efficacy, and tolerability of adjunctive cenobamate inpatients with uncontrolled focal (partial)-onset epilepsy.

METHODS:

Wedid a multicentre, double-blind, randomised, placebo-controlled, dose-responsestudy at 107 epilepsy and neurology centres in 16 countries. Adult patients(aged 18-70 years) with focal seizures despite treatment with 1-3 antiepilepticdrugs were randomly assigned (1:1:1:1) via an interactive web response system,by block sizes of 4 within each country, to adjuvant once daily oral cenobamateat dose groups of 100 mg, 200 mg, or 400 mg, or placebo following an 8-weekbaseline assessment. Patients, investigators, and study personnel were maskedto treatment assignment. The study included a 6-week titration phase and12-week maintenance phase. The primary efficacy outcomes were percentage changein 28-day focal seizure frequency (focal aware motor, focal impaired awareness,or focal to bilateral tonic-clonic seizures) from baseline analysed in themodified intention-to-treat population (≥1 dose and any post-baseline seizure data) and responderrates (≥50%reduction) analysed in the maintenance phase population (≥1 dose in the maintenance phase andany maintenance phase seizure data). The primary efficacy outcomes wereanalysed using a hierarchal step-down procedure comparing 200 mg versusplacebo, 400 mg versus placebo, then 100 mg versus placebo. Safety and tolerabilitywere compared descriptively across treatment groups for all randomisedpatients. This study is registered with ClinicalTrials.gov, number NCT01866111.

FINDINGS:

BetweenJuly 31, 2013, and June 22, 2015, 437 patients were randomly assigned to eitherplacebo (n=108) or cenobamate 100 mg (n=108), 200 mg (n=110), or 400 mg(n=111). Of these patients, 434 (106 [98%] in placebo group, 108 [100%] in 100mg group, 109 [99%] in 200 mg group, and 111 [100%] in 400 mg group) wereincluded in the modified intention-to-treat population, and 397 (102 [94%] inplacebo group, 102 [94%] in 100 mg group, 98 [89%] in 200 mg group, and 95[86%] in 400 mg group) were included in the modified intention-to-treatmaintenance phase population. Median percentage changes in seizure frequencywere -24·0% (IQR -45·0 to -7·0%) for the placebo group compared with -35·5%(-62·5 to -15·0%; p=0·0071) for the 100 mg dose group, -55·0% (-73·0 to -23·0%;p<0·0001) for the 200 mg dose group, and -55·0% (-85·0 to -28·0%; p<0·0001)for the 400 mg dose group. Responder rates during the maintenance phase were25% (26 of 102 patients) for the placebo group compared with 40% (41 of 102;odds ratio 1·97, 95% CI 1·08-3·56; p=0·0365) for the 100 mg dose group, 56% (55of 98; 3·74, 2·06-6·80; p<0·0001) for the 200 mg dose group, and 64% (61 of95; 5·24, 2·84-9·67; p<0·0001) for the 400 mg dose group. Treatment-emergentadverse events occurred in 76 (70%) of 108 patients in the placebo group, 70(65%) of 108 in the 100 mg group, 84 (76%) of 110 in the 200 mg group, and 100(90%) of 111 in the 400 mg group. Treatment-emergent adverse events led todiscontinuation in five (5%) patients in the placebo group, 11 (10%) in the 100mg dose group, 15 (14%) in the 200 mg dose group, and 22 (20%) in the 400 mgdose group. One serious case of drug reaction with eosinophilia and systemicsymptoms occurred in the 200 mg cenobamate group. No deaths were reported.

INTERPRETATION:

Adjunctivecenobamate reduced focal (partial)-onset seizure frequency, in a dose-relatedfashion. Treatment-emergent adverse events were most frequent in the highestdose group. Cenobamate appears to be an effective treatment option in patientswith uncontrolled focal seizures.

参考文献：

Krausset al (2020). Safety and efficacy of adjunctive cenobamate (YKP3089) inpatients with uncontrolled focal seizures: a multicentre, double-blind,randomised, placebo-controlled, dose-response trial. Lancet Neurol. 2020Jan;19(1):38-48.

5. Lancet Neurol—全球疾病负担研究组发布1990-2016年间全球癫痫负担

英文摘要:

BACKGROUND:

Seizuresand their consequences contribute to the burden of epilepsy because they cancause health loss (premature mortality and residual disability). Data on theburden of epilepsy are needed for health-care planning and resource allocation.The aim of this study was to quantify health loss due to epilepsy by age, sex,year, and location using data from the Global Burden of Diseases, Injuries, andRisk Factors Study.

METHODS:

Weassessed the burden of epilepsy in 195 countries and territories from 1990 to2016. Burden was measured as deaths, prevalence, and disability-adjustedlife-years (DALYs; a summary measure of health loss defined by the sum of yearsof life lost [YLLs] for premature mortality and years lived with disability),by age, sex, year, location, and Socio-demographic Index (SDI; a compoundmeasure of income per capita, education, and fertility). Vital registrationsand verbal autopsies provided information about deaths, and data on theprevalence and severity of epilepsy largely came from population representativesurveys. All estimates were calculated with 95% uncertainty intervals (UIs).

FINDINGS:

In2016, there were 45·9 million (95% UI 39·9-54·6) patients with all-activeepilepsy (both idiopathic and secondary epilepsy globally; age-standardisedprevalence 621·5 per 100 000 population; 540·1-737·0). Of these patients, 24·0million (20·4-27·7) had active idiopathic epilepsy (prevalence 326·7 per100 000 population; 278·4-378·1). Prevalence of active epilepsy increased withage, with peaks at 5-9 years (374·8 [280·1-490·0]) and at older than 80 yearsof age (545·1 [444·2-652·0]). Age-standardised prevalence of active idiopathicepilepsy was 329·3 per 100 000 population (280·3-381·2) in men and 318·9 per100 000 population (271·1-369·4) in women, and was similar among SDI quintiles.Global age-standardised mortality rates of idiopathic epilepsy were 1·74 per100 000 population (1·64-1·87; 1·40 per 100 000 population [1·23-1·54] forwomen and 2·09 per 100 000 population [1·96-2·25] for men). Age-standardisedDALYs were 182·6 per 100 000 population (149·0-223·5; 163·6 per 100 000population [130·6-204·3] for women and 201·2 per 100 000 population[166·9-241·4] for men). The higher DALY rates in men were due to higher YLLrates compared with women. Between 1990 and 2016, there was a non-significant6·0% (-4·0 to 16·7) change in the age-standardised prevalence of idiopathicepilepsy, but a significant decrease in age-standardised mortality rates (24·5%[10·8 to 31·8]) and age-standardised DALY rates (19·4% [9·0 to 27·6]). A thirdof the difference in age-standardised DALY rates between low and high SDIquintile countries was due to the greater severity of epilepsy in low-incomesettings, and two-thirds were due to a higher YLL rate in low SDI countries.

INTERPRETATION:

Despitethe decrease in the disease burden from 1990 to 2016, epilepsy is still animportant cause of disability and mortality. Standardised collection of data onepilepsy in population representative surveys will strengthen the estimates,particularly in countries for which we currently have no or sparse data and ifadditional data is collected on severity, causes, and treatment. Sizeable gainsin reducing the burden of epilepsy might be expected from improved access toexisting treatments in low-income countries and from the development of neweffective drugs worldwide.

参考文献：

GBD2016 Epilepsy Collaborators. Global, regional, and national burden of epilepsy,1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. LancetNeurol. 2019 Apr;18(4):357-375.

6. N Engl J Med—左乙拉西坦、磷苯妥英和丙戊酸可显著降低苯二氮卓类药物难治性惊厥持续状态的癫痫发生率

详细见：NEJM：左乙拉西坦、磷苯妥英和2-丙基戊酸钠治疗难治性持续癫痫

英文摘要:

BACKGROUND:

Thechoice of drugs for patients with status epilepticus that is refractory totreatment with benzodiazepines has not been thoroughly studied.

METHODS:

In arandomized, blinded, adaptive trial, we compared the efficacy and safety ofthree intravenous anticonvulsive agents - levetiracetam, fosphenytoin, andvalproate - in children and adults with convulsive status epilepticus that wasunresponsive to treatment with benzodiazepines. The primary outcome was absenceof clinically evident seizures and improvement in the level of consciousness by60 minutes after the start of drug infusion, without additional anticonvulsantmedication. The posterior probabilities that each drug was the most or leasteffective were calculated. Safety outcomes included life-threateninghypotension or cardiac arrhythmia, endotracheal intubation, seizure recurrence,and death.

RESULTS:

Atotal of 384 patients were enrolled and randomly assigned to receivelevetiracetam (145 patients), fosphenytoin (118), or valproate (121). Reenrollmentof patients with a second episode of status epilepticus accounted for 16additional instances of randomization. In accordance with a prespecifiedstopping rule for futility of finding one drug to be superior or inferior, aplanned interim analysis led to the trial being stopped. Of the enrolledpatients, 10% were determined to have had psychogenic seizures. The primaryoutcome of cessation of status epilepticus and improvement in the level ofconsciousness at 60 minutes occurred in 68 patients assigned to levetiracetam(47%; 95% credible interval, 39 to 55), 53 patients assigned to fosphenytoin(45%; 95% credible interval, 36 to 54), and 56 patients assigned to valproate(46%; 95% credible interval, 38 to 55). The posterior probability that eachdrug was the most effective was 0.41, 0.24, and 0.35, respectively. Numericallymore episodes of hypotension and intubation occurred in the fosphenytoin groupand more deaths occurred in the levetiracetam group than in the other groups,but these differences were not significant.

CONCLUSIONS:

Inthe context of benzodiazepine-refractory convulsive status epilepticus, theanticonvulsant drugs levetiracetam, fosphenytoin, and valproate each led toseizure cessation and improved alertness by 60 minutes in approximately halfthe patients, and the three drugs were associated with similar incidences ofadverse events. (Funded by the National Institute of Neurological Disorders andStroke; ESETT ClinicalTrials.gov number, NCT01960075.).

参考文献：

Kapuret al (2019). Randomized Trial of Three Anticonvulsant Medications for StatusEpilepticus. N Engl J Med. 2019 Nov 28;381(22):2103-2113.

7. Neuron—研究发现线粒体是海马放电频率的调定点并影响癫痫易感性

英文摘要:

Maintainingaverage activity within a set-point range constitutes a fundamental property ofcentral neural circuits. However, whether and how activity set points areregulated remains unknown. Integrating genome-scale metabolic modeling andexperimental study of neuronal homeostasis, we identified mitochondrialdihydroorotate dehydrogenase (DHODH) as a regulator of activity set points inhippocampal networks. The DHODH inhibitor teriflunomide stably suppressed meanfiring rates via synaptic and intrinsic excitability mechanisms by modulatingmitochondrial Ca²⁺ buffering and spare respiratory capacity.Bi-directional activity perturbations under DHODH blockade triggered firingrate compensation, while stabilizing firing to the lower level, indicating achange in the firing rate set point. In vivo, teriflunomide decreasedCA3-CA1 synaptic transmission and CA1 mean firing rate and attenuatedsusceptibility to seizures, even in theintractable Dravet syndrome epilepsy model. Our results uncover mitochondria asa key regulator of activity set points, demonstrate the differential regulationof set points and compensatory mechanisms, and propose a new strategy to treatepilepsy.

参考文献：

Styret al (2019). Mitochondrial Regulation of the Hippocampal Firing Rate Set Pointand Seizure Susceptibility. Neuron. 2019 Jun 5;102(5):1009-1024.e8.

8. Nat Commun—研究发现MARCH6和STARD7内含子重复扩增是成年家族性肌阵挛型癫痫的致病机制

英文摘要:

FamilialAdult Myoclonic Epilepsy (FAME) is a geneticallyheterogeneous disorder characterized by cortical tremor and seizures. IntronicTTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME inAsia. Using genome sequencing and repeat-primed PCR, we identify another siteof this repeat expansion, in MARCH6 (FAME3) in four European families. Analysisof single DNA molecules with nanopore sequencing and molecular combing showthat expansions range from 3.3 to 14 kb on average. However, we observeconsiderable variability in expansion length and structure, supporting theexistence of multiple expansion configurations in blood cells and fibroblastsof the same individual. Moreover, the largest expansions are associated withmicro-rearrangements occurring near the expansion in 20% of cells. This studyprovides further evidence that FAME is caused by intronic TTTTA/TTTCAexpansions in distinct genes and reveals that expansions exhibit anunexpectedly high somatic instability that can ultimately result in genomicrearrangements.

FamilialAdult Myoclonic Epilepsy (FAME) is characterisedby cortical myoclonic tremor usually from the second decade of life and overtmyoclonic or generalised tonic-clonic seizures. Four independent loci have beenimplicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genomesequencing and repeat primed PCR, we provide evidence that chr2-linked FAME(FAME2) is caused by an expansion of an ATTTC pentamer within the first intronof STARD7. The ATTTC expansions segregate in 158/158 individuals typicallyaffected by FAME from 22 pedigrees including 16 previously reported familiesrecruited worldwide. RNA sequencing from patient derived fibroblasts shows noaccumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expressionis not affected. These data, in combination with other genes bearing similarmutations that have been implicated in FAME, suggest ATTTC expansions may causethis disorder, irrespective of the genomic locus involved.

参考文献：

1. Florian et al (2019). Unstable TTTTA/TTTCA expansions inMARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3. NatCommun. 2019 Oct 29;10(1):4919.

2. Corbett et al (2019). Intronic ATTTC repeat expansions inSTARD7 in familial adult myoclonic epilepsy linked to chromosome 2. Nat Commun.2019 Oct 29;10(1):4920.

9. Nat Commun—氨酰合成酶编码基因VARS基因突变和进行性发育性癫痫脑病显著相关

英文摘要:

Aminoacyl-tRNAsynthetases (ARSs) function to transfer amino acids to cognate tRNA molecules,which are required for protein translation. To date, biallelic mutations in 31ARS genes are known to cause recessive, early-onset severe multi-organdiseases. VARS encodes the only known valine cytoplasmic-localizedaminoacyl-tRNA synthetase. Here, we report seven patients from five unrelatedfamilies with five different biallelic missense variants in VARS. Subjectspresent with a range of global developmental delay, epileptic encephalopathyand primary or progressive microcephaly. Longitudinal assessment demonstratesprogressive cortical atrophy and white matter volume loss. Variants map to theVARS tRNA binding domain and adjacent to the anticodon domain, and disrupthighly conserved residues. Patient primary cells show intact VARS protein butreduced enzymatic activity, suggesting partial loss of function. Theimplication of VARS in pediatric neurodegeneration broadens the spectrum ofhuman diseases due to mutations in tRNA synthetase genes.

AminoacyltRNA synthetases (ARSs) link specific amino acids with their cognate transferRNAs in a critical early step of protein translation. Mutations in ARSs haveemerged as a cause of recessive, often complex neurological disease traits.Here we report an allelic series consisting of seven novel and two previouslyreported biallelic variants in valyl-tRNA synthetase (VARS) in ten patientswith a developmental encephalopathy with microcephaly, often associated withearly-onset epilepsy. In silico, in vitro, andyeast complementation assays demonstrate that the underlying pathomechanism ofthese mutations is most likely a loss of protein function. Zebrafish modelingaccurately recapitulated some of the key neurological disease traits. Theseresults provide both genetic and biological insights into neurodevelopmentaldisease and pave the way for further in-depth research on ARS related recessivedisorders and precision therapies.

参考文献：

1.Friedman et al (2019). Biallelic mutations in valyl-tRNA synthetase gene VARSare associated with a progressive neurodevelopmental epileptic encephalopathy. NatCommun. 2019 Feb 12;10(1):707.

2.Siekierska et al (2019). Biallelic VARS variants cause developmentalencephalopathy with microcephaly that is recapitulated in vars knockoutzebrafish. Nat Commun. 2019 Feb 12;10(1):708.

10. J Clin Invest—血浆tRNA片段升高是人类癫痫的重要预测标志物

英文摘要:

TransferRNAs (tRNAs) are a major class of noncoding RNA. Stress-induced cleavage oftRNA is highly conserved and results in tRNA fragments. Here we find specifictRNA fragments in plasma are associated with epilepsy. Small RNA sequencing ofplasma samples collected during video-EEG monitoring of focal epilepsy patientsidentified significant differences in three tRNA fragments (5', 5'AlaTGC, and5'GluCTC) from controls. Levels of these tRNA fragments were higher in pre-seizure than post-seizuresamples, suggesting they may serve as biomarkers of seizurerisk in epilepsy patients. In vitro studies confirmed that production andextracellular release of tRNA fragments was lower after epileptiform-likeactivity in hippocampal neurons. We designed PCR-based assays to quantify tRNAfragments in a cohort of pre- and post-seizureplasma samples from focal epilepsy patients and healthy controls (n =32/group). Receiver operating characteristic analysis indicated that tRNAfragments potently distinguished pre- from post-seizurepatients (area under the curve of 0.8-0.95). Elevated tRNA fragments levelswere not detected in patients with psychogenic non-epileptic seizures, and did not result from medication tapering.This study identifies a novel class of epilepsy biomarker and reveals thepotential existence of prodromal molecular patterns in blood that could be usedto predict seizure risk.

参考文献：

Hogget al (2019). Elevation in plasma tRNA fragments precede seizures in humanepilepsy. J Clin Invest. 2019 Apr 30;129(7):2946-2951.