An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids
Sacha FerdinandusseKirsty McWalterHeleen te BrinkeLodewijk IJlstPetra M. MooijerJos P.N. RuiterA. E. M. van LintMia L. Pras‐RavesEric WeverFrancisca MillanMaría J. Guillen SacotoAmber BegtrupMark A. TarnopolskyLauren BradyRoger L. LaddaSusan L. SellC. NowakJessica DouglasCuixia TianElizabeth UlmSeth J. PerlmanArlene V. DrackKaren ChongNicole MartinJennifer BraultElly BrokampCamilo ToroWilliam A. GahlEllen F. MacnamaraLynne A. WolfeMercedes E. AlejandroMahshid S. AzamianCarlos A. BacinoAshok BalasubramanyamLindsay C. BurrageHsiao‐Tuan ChaoGary ClarkWilliam J. CraigenHongzheng DaiShweta U. DharLisa EmrickAlica M. GoldmanNeil A. HanchardFariha JamalLefkothea KaravitiSeema R. LalaniBrendan LeeRichard A. LewisRonit MaromPaolo MorettiDavid R. MurdockSarah K. NicholasJames P. OrengoJennifer E. PoseyLorraine PotockiJill A. RosenfeldSusan L. SamsonDaryl A. ScottAlyssa A. TranTiphanie P. VogelMichael F. WanglerShinya YamamotoChristine M. EngPengfei LiuPatricia A. WardEdward M. BehrensMatthew A. DeardorffMarni J. FalkKelly HasseyKathleen SullivanAdeline VanderverDavid B. GoldsteinHeidi CopeAllyn McConkie‐RosellKelly SchochVandana ShashiEdward C. SmithRebecca C. SpillmannJennifer A. SullivanQueenie K.‐G. TanSophie NicolePankaj B. AgrawalAlan H. BeggsGerard T. BerryLauren C. BriereLaurel A. CobbanMatthew CogginsCynthia M. CooperElizabeth L. FiegFrances A. HighIngrid A. HolmSusan KorrickJoel B. KrierSharyn A. LincolnJoseph LoscalzoRichard L. MaasCalum A. MacRaeJ. Carl PallaisStephen C. PakLance H. RodanEdwin K. SilvermanJoan M. StolerDavid A. SweetserMelissa WalkerChris A. WalshCecilia EstevesEmily G. KelleyIsaac S. KohaneKimberly LeBlancAlexa T. McCrayAnna NagySurendra DasariBrendan C. LanpherIan R. LanzaÉva MoravaDevin OglesbeeGüney BademciDeborah BarbouthStephanie BivonaOlveen CarrasquilloTa Chen ChangIrman ForghaniAlana GrajewskiRosario IsasiByron LamRoy C. LevittXue Zhong LiuJacob L. McCauleyRalph L. SaccoMario SaportaJudy SchaechterMustafa TekinFred TelischiWilla ThorsonStephan ZüchnerHeather A. ColleyJyoti G. DayalDavid J. EcksteinLaurie C. FindleyDonna M. KrasnewichLaura A. MamounasTeri A. ManolioJohn J. MulvihillGrace L. LaMoureMadison P. GoldrichTiina K. UrvArgenia L. DossMaria T. AcostaCarsten BonnenmannPrecilla D’SouzaDavid D. DraperCarlos R. FerreiraRena A. GodfreyCatherine GrodenEllen F. MacnamaraValerie V. MaduroThomas C. MarkelloAvi NathDonna NovacicBarbara N. PuseyCamilo ToroColleen E. WahlEva H. BakerElizabeth A. BurkeDavid R. AdamsWilliam A. GahlMay Christine V. MalicdanCynthia J. TifftLynne A. WolfeJohn YangBradley PowerBernadette R. GochuicoLaryssa A. HurynLea LathamJoie DavisDeborah Mosbrook-DavisFrancis RossignolBen SolomonJohn MacDowallAudrey ThurmWadih M. ZeinMuhammad YousefMargaret P AdamLaura M. AmendolaMichael BamshadAnita BeckJimmy BennettBeverly Berg-RoodElizabeth BlueBrenna BoydPeter H. ByersSirisak ChanprasertMichael L. CunninghamKatrina M. DippleDaniel DohertyDawn EarlIan A. GlassKatie Golden‐GrantSihoun HahnAnne HingFuki M. HisamaMartha Horike‐PyneGail P. JarvikJeffrey G. JarvikSuman JayadevChristina LamKenneth R. MaravillaHeather MeffordJ. Lawrence MerrittGhayda MirzaaDeborah A. NickersonWendy H. RaskindNatalie RosenwasserC. Ron ScottAngela SunVirginia P. SybertStephanie E WallaceMark H. WenerTara WengerEuan A. AshleyGill BejeranoJonathan A. BernsteinDevon BonnerTerra R. CoakleyLiliana FernándezPaul G. FisherLaure FrésardJason HomYong HuangJennefer N. KohlerElijah KravetsMarta M. MajcherskaBeth A. MartinShruti MarwahaColleen E. McCormackArchana N. RajaChloe M. ReuterMaura RuzhnikovJacinda B. SampsonKevin S. SmithShirley SuttonHolly K. TaborBrianna M. TuckerMatthew T. WheelerDiane B. ZastrowChunli ZhaoWilliam E. ByrdAndrew B. CrouseMatthew MightMariko Nakano‐OkunoJordan WhitlockGabrielle BrownManish J. ButteEsteban C. Dell’AngelicaNaghmeh DorraniEmilie D. DouineBrent L. FogelIrma GutierrezAlden HuangDeborah KrakowHane LeeSandra K. LooBryan C. MakMartín G. MartínJulián A. Martínez-AgostoElisabeth McGeeStanley F. NelsonShirley Nieves‐RodriguezChristina G.S. PalmerJeanette C. PappNeil H. ParkerGenecee RenteriaRebecca SignerJanet S. SinsheimerJijun WanLee-kai WangKatherine Wesseling PerryJeremy D. WoodsJustin AlveyAshley AndrewsJim BaleJohn F. BohnsackLorenzo D. BottoJohn C. CareyLaura PaceNicola LongoGábor MarthPaolo MorettiAaron R. QuinlanMatt VelinderDave ViskochilPınar Bayrak‐ToydemirRong MaoMonte WesterfieldAnna BicanElly BrokampLaura DuncanRizwan HamidJ. Phillip KennedyMary KozuiraJohn H. NewmanJohn A. PhillipsLynette RivesAmy K. RobertsonEmily SolemJoy D. CoganF. Sessions ColeNichole HayesDana KileyKathy SiscoJennifer WambachDaniel WegnerDustin BaldridgeStephen PakTimothy SchedlJimann ShinLilianna Solnica‐KrezelQuinten WaisfiszPetra ZwijnenburgAlban ZieglerMagalie BarthRosemarie SmithSara EllingwoodDeborah Gaebler‐SpiraSomayeh BakhtiariMichael C. KruerAntoine H. C. van KampenRonald J. A. WandersHans R. WaterhamDavid CassimanFrédéric M. Vaz
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Abstract:
Purpose
In this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu).Methods
Following next-generation sequencing and clinical phenotyping, functional characterization was performed in patients' fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics.Results
All patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients' fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production.Conclusion
Heterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.Keywords:
Plasmalogen
Coats' disease
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The family of inherited ocular diseases that is collectively known as retinitis pigmentosa is a major cause of progressive retinal disease worldwide. As such, this family of diseases has been the object of much scientific scrutiny, both clinical and basic. The recent application of molecular genetic analyses has heralded the rapid elucidation of the underlying gene defects in many cases. In this article, the fundamental clinical and electroretinographic characteristics of retinitis pigmentosa will be recalled. Additionally, the current understanding of the genetic causes of retinitis pigmentosa will be reviewed, and the identified causative genes will be classified into groups related by function.
Locus heterogeneity
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Abstract Retinitis pigmentosa is a heterogeneous group of retinal dystrophies that are characterized by photoreceptor cell degeneration, night blindness, a gradual loss of peripheral visual fields and eventual loss of central vision. Several genes responsible for the development of retinitis pigmentosa have now been identified and cloned, and these discoveries have defined the genetic pathways for pathogenesis of retinitis pigmentosa.
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Hypotonia in infants can be a confusing clinical presentation leading to inaccurate evaluation and unnecessary investigations. Hypotonia can result from a variety of central or peripheral causes. Therefore, hypotonia is a phenotype of many clinical conditions with variable prognosis. It is important to recognize that hypotonia is not equivalent to weakness. Infants with central causes, such as Down syndrome, may have severe hypotonia with normal muscle strength. Peripheral hypotonia is frequently associated with weakness, which can be predominantly distal in neuropathies or predominantly proximal in myopathies. In general, central hypotonia is much more commonly encountered; however, the prognosis is worst for hypotonia secondary to neuromuscular pathology. The distinction between central and peripheral hypotonia is therefore critical for proper evaluation and management. Stepwise and accurate assessment is very important to reach the correct diagnosis promptly. In this review, I present a concise clinical approach for evaluating the hypotonic infant. Some practical tips and skills are discussed to improve the likelihood of obtaining an accurate diagnosis. Reaching a specific diagnosis is needed for providing appropriate therapy, prognosis, and counseling.
Muscle Hypotonia
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Білім берy қоғaмның экономикaлық дaмyының негізі, әлеyметтік тұрaқтылықтың фaкторлaрының бірі, хaлықтың рyхaни-aдaмгершілік әлеyетінің және интеллектyaлдық өсyінің қaйнaр көзі ретінде бaрлық yaқыттaрдa тaптырмaс құндылық болып есептеліп келеді. Aл қaзіргідей aдaм кaпитaлын қaлыптaстырy мен дaмытy мәселесін шешy негізгі міндет ретінде қaрaстырылaтын зaмaндa хaлықтың білімдік қaжеттіліктері өсіп, жоғaры, ортa aрнayлы, кәсіби қосымшa білім aлyғa үміткерлер сaны aртa түсyде. Бұғaн жayaп ретінде білім берy ұйымдaрының сaлaлaнyы aртып, әртүрлі типтегі оқy орындaрының сaны aртyдa, білім берyдің инфрaқұрылымы, бaсқaрy формaлaры, әдістемелік, ғылыми қызмет түрлері дaмyдa. Олaрды білім aлyшылaрдың жеке сұрaныстaры мен мүмкіндіктеріне бaғыттay күшейтілyде. Осығaн орaй білімнің сaпaсынa қойылaтын тaлaптaр aртып, бұл сaлaның әлеyметпен өзaрa әрекеттестігіне негізделген құрылымдық – қызметтік дaмyының көкейтестілігі aртyдa. Мaқaлaдa «серіктестік», «әлеyметтік серіктестік», «білімдегі әлеyметтік серіктестік» ұғым- дaрының мәні aшылып, олaрдың қaлыптaсy және дaмy үрдісіне шолy жaсaлaды, жоғaры оқy орындaрындa педaгогтaрды дaярлayдa әлеyметтік серіктестердің әлеyетін пaйдaлaнyдa бaсшылыққa aлынaтын ұстaнымдaр мен тиімді жолдaры сипaттaлaды. Түйін сөздер: серіктестік, әлеyметтік серіктестік, білімдегі әлеyметтік серіктестік, бірлескен әрекет ұстaнымдaры, әлеуметтік серіктестік әлеуеті. Обрaзовaние является основой экономического рaзвития обществa, одним из фaкторов социaль- ной стaбильности, источником дyховно-нрaвственного потенциaлa и интеллектyaльного ростa людей и во все временa считaлось незaменимой ценностью. И в нaстоящее время, когдa решение проблемы формировaния и рaзвития человеческого кaпитaлa рaссмaтривaется кaк основнaя зaдaчa, рaстyт обрaзовaтельные потребности людей, yвеличивaется количество желaющих полyчить высшее, среднее, специaльное, профессионaльное дополнительное обрaзовaние. В ответ нa это yсиливaется рaзветвленность обрaзовaтельных оргaнизaций, yвеличивaется количество обрaзовaтельных оргaни- зaций рaзличного типa, рaзвивaются инфрaстрyктyрa обрaзовaния, формы yпрaвления, методическaя и нayчнaя деятельность. Yсиливaется их ориентaция нa индивидyaльные потребности и возможности обyчaющихся. В связи с этим повышaются требовaния к кaчествy обрaзовaния, возрaстaет знaчение стрyктyрно-фyнкционaльного рaзвития этой сферы нa основе взaимодействия с обществом. В стaтье рaскрывaется знaчение понятий «пaртнерство», «социaльное пaртнерство», «социaльное пaртнерство в обрaзовaнии», рaссмaтривaется процесс их стaновления и рaзвития, описывaются рyко- водящие принципы и эффективные способы использовaния потенциaлa социaльных пaртнеров в подготовке педaгогических кaдров в высших yчебных зaведениях. Ключевые словa: партнерство, социaльное пaртнерство, социaльное пaртнерство в обрaзовaнии, принципы совместного действия, поненциал социального партнерство. Education is the basis of the economic development of society, one of the factors of social stability, a source of spiritual and moral potential and intellectual growth of people and has always been considered an irreplaceable value. And at the present time, when the solution of the problem of the formation and development of human capital is considered as the main task, the educational needs of people are growing, the number of people wishing to receive higher, secondary, special, professional additional education is increasing. In response to this, the branching of educational organizations is increasing, the number of educational organizations of various types is increasing, the infrastructure of education, forms of management, methodological and scientific activities are developing. Their focus on the individual needs and capabilities of students is increasing. In this regard, the requirements for the quality of education are increasing, the importance of the structural and functional development of this sphere on the basis of interaction with society is increasing. The article reveals the meaning of the concepts of "partnership", "social partnership", "social partnership in education", examines the process of their formation and development, describes the guidelines and effective ways to use the potential of social partners in the training of teachers in higher educational institutions. Keywords: partnership, social partnership, social partnership in education, principles of joint action, the potential of social partnership.
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Aim Hypotonia is a symptom of diminished tone of skeletal muscle associated with decreased resistance of muscles to passive stretching, which can be caused by abnormalities of the central nervous system, any element of the lower motoneuron, or both. Hypotonia is not a specific diagnosis, but can be part of over 500 different genetic disorders, with many other conditions waiting to be identified. This review proposes a pragmatic approach to evaluating hypotonia in neonatal and pediatric populations by using a diagnostic algorithm. Method We use a dedicated literature review combined with clinical experience in a newly established multidisciplinary center for hypotonia to establish a diagnostic algorithm. Results Hypotonia can be a symptom of over 500 different genetic disorders. It can present as peripheral, central, or combined hypotonia, providing necessity for rational and systematic diagnostic testing. Interpretation Our analyses demonstrate that a staged diagnostic approach categorizing patients as having peripheral, central, or combined hypotonia is the most efficient to providing a rational work-up. Establishing a diagnosis is crucial for prognosis, management, and treatment strategies, and for ascertaining an accurate recurrence risk for future offspring in a family.
Muscle Hypotonia
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Identifying the underlying cause of congenital hypotonia remains difficult, despite advances in diagnostic laboratory and imaging techniques. Clinical evaluation strategies and standardized developmental tests can assist in differentiating hypotonia resulting from primary involvement of the upper motoneuron (central hypotonia) versus that involving the lower motoneuron and motor unit (peripheral hypotonia). This is especially important in infants with idiopathic hypotonia. This review outlines and describes the components of the clinical assessment: detailed infant and family history, clinical techniques and characteristics for differentiating hypotonia of central versus peripheral origin, and clinical evaluation (muscle tone, primitive reflexes, deep tendon reflexes, etc). Recent research that has contributed to the differential diagnosis of congenital hypotonia is reviewed and directions for future research are provided. Ideally, the assessment of infants with congenital hypotonia is best accomplished by an interdisciplinary team of developmental specialists including pediatricians, medical geneticists, child neurologists, and physical or occupational therapists.
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Abstract Retinitis pigmentosa is a heterogeneous group of retinal dystrophies that are characterized by photoreceptor cell degeneration, night blindness, a gradual loss of peripheral visual fields and eventual loss of central vision. Several genes responsible for the development of retinitis pigmentosa have now been identified and cloned, and these discoveries have defined the genetic pathways for pathogenesis of retinitis pigmentosa.
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Hypotonia in infants can be a confusing clinical presentation leading to inaccurate evaluation and unnecessary investigations. Hypotonia can result from a variety of central or peripheral causes. Therefore, hypotonia is a phenotype of many clinical conditions with variable prognosis. It is important to recognize that hypotonia is not equivalent to weakness. Infants with central causes, such as Down syndrome, may have severe hypotonia with normal muscle strength. Peripheral hypotonia is frequently associated with weakness, which can be predominantly distal in neuropathies or predominantly proximal in myopathies. In general, central hypotonia is much more commonly encountered, however, the prognosis is worst for hypotonia secondary to neuromuscular pathology. The distinction between central and peripheral hypotonia is therefore critical for proper evaluation and management. Stepwise and accurate assessment is very important to reach the correct diagnosis promptly. In this review, I present a concise clinical approach for evaluating the hypotonic infant. Some practical tips and skills are discussed to improve the likelihood of obtaining an accurate diagnosis. Reaching a specific diagnosis is needed for providing appropriate therapy, prognosis, and counseling.
Muscle Hypotonia
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