Posted on Authorea 1 Apr 2020 — CC BY 4.0 — https://doi.org/10.22541/au.158575904.44855209 — This a preprint and has not been peer reviewed. Data may be preliminary. otf Hotait Mostafa Phenotypes Two Than More : FARS2 feryosteietcecpaoah n psi aalgahv enlne oFR2gn mutations. FARS2 consisting to phenotypes, linked distinct been two my- have time, , paraplegia delay, that spastic developmental Since and with encephalopathy 2012). girl epileptic two-year-old al., onset a et early pathogenic in (Shamseldin first of 2012 acidosis The in lactic mitochondria. synthetase reported and in a phenylalanyl-tRNA was oclonus, tRNA FARS2, mitochondrial gene cognate linked FARS2 the its synthetases. of been to encodes variant have (Phe) aminoacyl-tRNA (6p25.1), phenylalanine diseases 6 mitochondrial transfers mitochondrial which encoding (mtPheRS), various in on Recently, result located V). nuclear can gene mitochondrially- and mt-aaRSs in nuclear containing variants IV the complexes of pathogenic III, are OXPHOS any I, to aaRSs the in mitochondrially- (complexes cytoplasmic Defects affecting cognate subunits and their , 2013). encoded mitochondrial to Tyynismaa, intramitochondrial the acids & defective of (Konovalova amino a Most genes 20 biosynthesis nuclear of 2013). by mitochondrial each Tyynismaa, encoded in of & role (Konovalova attachment key tRNAs the a play encoded catalyzing that synthetases for tRNA amino-acyl responsible of mitochondrial trans- and group nuclear The and well-described 2017) by transcription Although a Scaglia, in encoded & are 2012) implicated are Craigen, (mt-aaRSs) 60 (Rahman, the (El-Hattab, proteins and to subunits, by mitochondrial . others. complexes up among the characterized focal ETC lation in of of of commonly majority reported 99% onset the is (mtDNA), been including the DNA have epilepsy genes, after own Seizures mitochondrial soon their contain continua and function. mitochondria partialis diseases their Mitochondrial epilepsia or mitochondrial of complexes complexes. with occurrence those (ETC) patients in chain phos- in defect oxidative transport % the any electron through to the generation refer energy exploiting diseases cellular (OXPHOS) in system organelles phorylation important extremely are Mitochondria synthetase tRNA Mitochondrial epilepsy; Introduction onset Juvenile epilepticus; status Refractory gene FARS2; FARS2 of manifestation phenotypic third a Keywords confirms report This months. contralateral few the a from bioener- originating for the seizures free for mitochondrial . motor mechanism showed aware compensatory biopsy being focal a muscle experiencing of after suggestive on started hemisphere IV, patient includ- activities and interventions, the biochemical Postoperatively, II therapeutic and complexes deficiency. all of Pathological getic focal after activities refractory isolated status seizures. super enhanced her her a with aborted control with proliferation surgery presented to development life-saving failed normal emergency mutation anesthesia, with an hemizygous ing woman Only a This old by 17-year- epilepticus. paraplegia. caused A status epilepsy, spastic refractory motor and microdeletion). onset encephalopathy 2 juvenile epileptic FARS2-linked, onset and of early (p.V197M phenotype an distinctive described have a mutation: reports gene describes FARS2 Previous report to (mtPheRS). linked synthetase phenylalanyl-tRNA phenotypes mitochondrial distinct the two encodes gene, nuclear a FARS2, Abstract 2020 28, April 1 Beydoun Ahmad and mrcnUiest fBiu eia Center Medical Beirut of University American 1 asmNasreddine Wassim , 1 1 ia El-Khoury Riyad , 1 1 aaDirani Maya , 1 mrNawfal Omar , 1 , Posted on Authorea 1 Apr 2020 — CC BY 4.0 — https://doi.org/10.22541/au.158575904.44855209 — This a preprint and has not been peer reviewed. Data may be preliminary. E eeldanvlhmzgu uaini AS ee ihadlto feo noeo h parent the of one in 2 exon of deletion a with months gene, FARS2 3 in hemisphere, for mutation right contralateral free hemizygous the the seizures. novel seizure hemiclonic from from a remained right revealed seizures originating and She WES clonic deviation discharges extremity aware gaze GSWDs. epileptiform right focal upper of by focal experience distal characterized fragments rare to semiologically left to started revealed and addition then time palsy in post-operatively that facial region at head central EEG motor centroparietal left Her face transient right a the weakness. over experienced transections patient subpial Postoperatively, with disappeared along insula nearly nearly eventually resection right revealed 1D). that prefrontal frontal the 1C) electrocorticography (Fig and right in area Intraoperative (Fig. insular area with region right flow. head suspicious edematous a centrofrontal decided blood the was following right was increased the and brain from of area it the discharges evidence opercular Intra-operatively, continuous epilepticus, right and status analysis. the hyperemia refractory morphometric on lobe the brain focusing and patient on dose patient the identified 1B). high the on (Fig. to of operate EEG respond the deterioration to the of to clinical on control burst-suppression failed the no a with seizures Considering reaching propofol status The despite patient on the the persisted compromise of status, that hemodynamic initiated. mental persistence seizures developed the was patient’s patient the electrographic in the anesthetic the of the extent in and Because with change in lesser infusion 2B). the treatment wider midazolam to diffusion with (Fig. and were and conjunction restricted lobe intubated that in thalamus showed frontal findings, was right seizures MRI left EEG insula, frequent and the brain right and very lobes repeat epilepticus lobe, parietal show A frontal both to right temporal, continued hemisphere. the right EEG left of patient Her the areas the involved cortical-subcortical time, extremity. and that upper At distribution developed and left in twitches seizures. facial her her negative left subtle of methylprednisolone abort intermittent glucose, with to were paresis experience treatment and to failed enzymes continued Pulse hepatic encephalitis obtunded, protein drawn. progressively autoimmune and was became of acid possible (WES) lactic levels a sequencing (CBC), exome for normal count whole administered for counts, blood blood Complete cell and panel. normal white meningitis no negative and revealed culture (CSF) physical the and fluid her valproate Over continuousCerebrospinal lamotrigine, and area. levetiracetam, with stable with fronto-central monitored treatment right were despite was the signs persisted from patient lacosamide. seizures vital with originating the The Her hours, seizures associated 24 continuous deviation subsequent unrevealing. jerking. near gaze revealed otherwise clonic left that motor extremity were by aware video/EEG upper examinations characterized focal in left neurological seizures (ED) and with and department twitches emergency duration the facial days no to two left presented revealed or patient of atrophy analysis the global epilepticus brain admission, any volumetric status her show of a not day Moreover, did the and insula 2A). On structures right (Fig matter hemispheres. the map grey two in junction left the lesion between and the suspicious right asymmetry on a the score between revealed 1A). z difference MRI (Fig volume high trait video/EEG brain EEG a hours the inherited 3 on of an a represent based analysis to and discharges morphometric spike-wave thought normal predominance, generalized post-acquisition was amplitude of one A and that sided fragments every right and lamotrigine MRI a background seizure of protocol with posterior breakthrough combination epilepsy (GSWDs) seizures normal a an a clonic a revealed included with aware On which workup controlled focal goes recording, face. Her well brief history the relatively rare months. Her of two were experience side to seizures epilepticus. to left status opercular started the aware she her neurodevelopment of motor when levetiracetam, normal twitching presentation focal a by to with with characterized presented prior parents semiologically year who unrelated one epilepsy to to for born back factors girl, risk right-handed no 17-year-old and a is patient distinctive The third a of presence the Report and Case epilepsy mutation. onset gene focal FARS2 refractory of onset manifestation juvenile phenotypic with patient a report We 2 Posted on Authorea 1 Apr 2020 — CC BY 4.0 — https://doi.org/10.22541/au.158575904.44855209 — This a preprint and has not been peer reviewed. Data may be preliminary. ni e et tteaeo 5yas(akre l,21) h eodcs sta fayugmnwith man young a of that is case second The 2016). al., et (Walker persisted years that 15 myoclonus of refractory multifocal age developed constant progressed the she near then at when with symptoms et Her years (Walker associated death years callosotomy. 13 deterioration her corpus the 8 cognitive of until a during of severe age underwent noted age global the she delays the a which until speech at to for controlled and seizure epilepticus motor poorly tonic-clonic status with generalized remained motor girl first seizures focal & a her Her (Chen of developed epilepsy. is 2016). who onset Her case life al., juvenile first of linked, The area. years FARS2- status few a 2016). opercular super-refractory first al., describing developing right focal et reports before (Walker the year recent experiencing 2019) two one with to by Zhang, of only started children localized at are period She onset initially of a There et for seizure zone adolescent. 30% epilepticus. controlled (Almannai a normal symptomatogenic well Although with relatively 2) developmentally the mutation remained (Table otherwise with seizures gene life. an self-limited FARS2 seizures, of in of and clonic years, years phenotype mild aware 16 distinctive 5 typically of a first age are represents the patient manifests the those mainly Our within seizures, phenotype 2019). onset onset experience al., late an phenotype The with 2018) late al., paraplegia the et spastic associated (Almannai are a descent. encephalopathy Arab with epileptic from early-onset patients the 2017; in of of have al., reported (c.431A Most age children variant et the affected 2019). pathogenic before the al., Cho the die et addition, typically with 2018; (Almannai In and rapidly dysfunction 2) al., . (Table liver that 2015) et years of life onset two evidence Naidu, (Almannai of early acidosis, & months lactic epilepticus The Batista, delay, 6 developmental McClellan, status first Vernon, profound 2019). of 2016; the al., al., in episodes et onset et onset frequent (Almannai Raviglione early an with 2) an with (Table intractable 2012), seizures of phenotypes FARS2 by al., become consisting of two characterized et phenotypes majority those is vast (Shamseldin clinical encephalopathy the of with distinct 2012 epileptic one recognized Two in were 3/119,738 fitting paraplegia reported of (35/37) spastic reported. missense onset prevalence first mutations were late This was reported a cases mutation and a 2019). additional encephalopathy gene epileptic with Zhang, 37 FARS2 & Polyphen-2 of Since (Chen using total mutation causing a 2019). compound disease Zhang, a as & of analyzed (Chen part clonic which been as of mutation, aware Val197Met has once combination encompassing focal mutation only mutation a 2-3 hemizygous reported novel on of a previously maintained present cluster was we while a report, area this experiencing In frontocentral Discussion is left and clonazepam. the and operation from all phenobarbital her originating lacosamide, for since weeks, levetiracetam, ranges months 6 reference 14 every normal now seizures their terms is within in patient were expressed normal. The activities, complex, was indicated Normalized activity individual Combined dehydrogenase as each synthase. lactate preserved 1). for citrate Cytosolic was (Table level mass complexes. increased synthase reference Mitochondrial were citrate the Isolated limits. IV the of normal and of activity biopsy. its II normal muscle above complexes the also patient’s by of was the activities activity of isolated II+III fragment (cytochrome while complexes III frozen ranges, spectropho- dehydrogenase), normal a assessed (NADH their from was I complexes prepared activities of homogenate complexes activities chain a respiratory on (RRFs) mitochondrial tometrically fibers of red evaluation ragged noted. Quantitative No were 3B). fibers network (Fig. negative Mitochondrial diffuse COX 3A). was no aggregation and (Fig. Reac- mitochondrial observed stain. excessive frequently immunohistochemical with on was fragmentation expression proliferation normal showed mitochondrial a (COX), showed subsarcolemmal in synthase enzymes, oxidase tive ATP oxidative c variation lipid 3A). of cytochrome Intramyocellular mild assessment (Fig. and Histochemical activities showed dehydrogenase myofibers. normal density. muscle succinate and disintegrating reductase, skeletal size of NADH-tetrazolium in the clusters including both of increased multifocal excessively pathol- studies and were mitochondrial Pathological fibrosis globules on mutation minimal pathogenic function. size, this and chain of myofibers WES impact respiratory the sequencing. evaluate and Sanger to ogy by lab. performed was confirmed Centogene copy, biopsy the muscle second by A the validated of and 2 performed exon were in sequencing > :pY4C ffcigtectltcdmi n eepredominantly were and domain catalytic the affecting p.Y144C) G: 3 bc 1 ,adV(T ytae eewithin were synthase) (ATP V and ), Posted on Authorea 1 Apr 2020 — CC BY 4.0 — https://doi.org/10.22541/au.158575904.44855209 — This a preprint and has not been peer reviewed. Data may be preliminary. lani . ag . a,H,E-atb .W,Fqi,E . ae,M . og .C (2018). C. L. Wong, . interpre- . variants . significance. and A., evolutionary spectra, M. and molecular Saleh, functional, and A., biochemical, structural, In E. clinical, on Faqeih, of W., Deficiency. based review FARS2 A. tation cases, El-Hattab, new (2019). H., deficiency; Dai, C. FARS2 J., L.-J. Wang, Wong, M., & Almannai, W., A. El-Hattab, E., views Faqeih, gene M., FARS2 in Almannai, refractoriness, presenting medical patients to in diagnosis. progressing two differential that References: seizures other the indicate focal the in considered and with with conjuction be mutations adolescence reported should in FARS2 the early mutation findings of of or Our few expression childhood a 2013). phenotypic Tyynismaa, late that the note & Konovalova to expand neuropathological 2012; interesting the cases al., including is this et (AHD) it disease of (Elo regard, Alpers-Huttenlocher suggestive that findings. of is In criteria characteristic (poly)spikes the A 2018). fulfilled superimposed mutations al., 2020). FARS2 disorders with types Thomas, et delta related seizure & Westrhenen (Lim high-amplitude (van Other POLG seizures rhythmic continua. diagnosis. myoclonic of as as partialis presentation known well epilepsia as common pattern to origin EEG most progression adolescence occipital during frequent of The second seizures refractory with 2016). the focal seizures 2020). and al., with include motor years Thomas, et 2-4 course focal bimodal Walker of & a of downhill ages 2019; (Lim has consist the a Zhang, status which between adulthood being (AHD), & refractory be early common disease (Chen most super to and Alpers-Huttenlocher the infections of a onset, appear recurrent that seizure to of from at there age reminiscent evolving later status, is years before presentation of few clinical initially years This a episode are few death seizures the a and Those to for seizures phenotype 2). treatment Subsequent third (Table AED a adolescence on epilepticus. of or bilateral controlled to presence childhood progressing well the late sometimes indicate relatively seizures during motor strongly appearing aware reports seizures focal previous her of tonic-clonic consisting two since mutations the and FARS2 deterioration. with controlled with cognitive associated well conjunction of relatively evidence in far clinical case so no seizures Our clonic are is intraoperative aware but there by focal ago, hemisphere The guided but months contralateral months. resection continua 14 the three prefronto-insular surgery, partialis of from the period recurred epilepsia case, a only refractory our for then the freedom In seizure treat a in 2016). to In resulted progressive al., electrocorticography attempted treatment. the et was (Walker anesthetic of callosotomy success despite because seizures without corpus operation electrographic a life-saving the case, a of as previous worsening 2019; surgery and al., epilepsy deterioration et emergency hemodynamic (Almannai an IV underwent beta-oxidation. - patient acids I biochemi- Our impairment, fatty complexes whose mitochondrial mitochondrial of the subjects of denotes activity further some disruption the deposits, a for in lipid intramyocellular triggering reduction except Excessive slight normal of 2016). a al., be activities et of mitochondria. Walker to biochemical evidence dysfunctional showed reported to enhanced mechanism studies was observed compensatory cal activity The the complexes highlights other further 2019). ETC two II+III Previously, in al., and reported et early IV, also II, an (Almannai was histo- complexes proliferation our mutation as by mitochondrial FARS2 mitochondria indicated of as with findings of mechanism disintegration patients proliferation structural pathological compensatory ongoing This reactive Those the a for studies. compensate of logical triggering to mitochondria. aggregation deficiency order in of bioenergetic excessive mechanism proliferation defense a and from denote subsarcolemmal disruption years likely mitochon- to network 20 most functional mitochondrial addition and of diffuse organizational in age showed by mitochondria, the biopsy characterized muscle at patient’s impairment died . our drial 2019) patient to of Zhang, the studies progressed & histochemical that and (Chen Broad seizures controlled infection tonic-clonic respiratory 2019) poorly controlled a bilateral Zhang, well remained following & to remained subsequently failure (Chen focal that pulmonary agents seizures with age anesthetic His presented of with controlled years he eventually . 12 when epilepticus at years status onset convulsive 17 an generalized of with age seizures the tonic-clonic until generalized of history a ® [Internet] nvriyo ahntn Seattle. Washington, of University : 4 o ee ea,125 Metab, Genet Mol 3,281-291. (3), GeneRe- Posted on Authorea 1 Apr 2020 — CC BY 4.0 — https://doi.org/10.22541/au.158575904.44855209 — This a preprint and has not been peer reviewed. Data may be preliminary. akr .A,Mhe,K . okn,K . aly .H,Sete,D . ba . hbr,R. Thibert, . . . M., Ibba, A., FARS2-Linked D. of Sweetser, Phenotypes H., Recognized D. the Oakley, mit- Expand W., non-fatal Mutations Heterozygous K. and Disease. FARS2 Compound Hopkins, Novel in P., (2016). Mutations K. L. (2015). Mohler, S. A., Naidu, M. Walker, & A., siblings. two D. in Batista, syndrome. Ferrier, dysfunction R., Alpers’ W., ochondrial McClellan, POLG1 N. Teunissen, in J., markers A., H. EEG M. Vernon, Specific S. (2018). Salm, W. der P. van K. B., Geleijns, Munckhof, 129 . den . van . H., A., C. E. F. Cats, Alkuraya, A., . candidate Westrhenen, . novel van reveals . population A., consanguineous Kentab, a H., in Alkhalidi, diseases genes. 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