Timothy syndrome is a rare disorder caused by CACNA1C gene mutations and characterized by multi-organ system dysfunctions, including ventricular arrhythmias, syndactyly, dysmorphic facial features, intermittent hypoglycemia, immunodeficiency, developmental delay, and autism. Because of the low morbidity and high mortality at a young age, it remains a huge challenge to establish a diagnosis and treatment system to manage Timothy syndrome patients. Here, we aim to provide a detailed review of Timothy syndrome, discuss the mechanisms underlying dysfunctional Cav1.2 due to CACNA1C mutations, and provide some new emerging evidences in treating Timothy syndrome from cell to bedside, promoting the management of this rare disease.
Impact statement
The knowledge of Timothy syndrome (TS) caused by dysfunctional Cav1.2 channel due to CACNA1C mutations is rapidly evolving as novel technologies of electrophysiology are introduced and our understanding of the mechanisms of TS develops. In this review, we focus on the TS-related dysfunctional Cav1.2 and the underlying mechanisms. We update TS-related CACNA1C mutations in a precise way over the past 20 years and summarize all reported TS patients based on their clinical presentations and molecular mechanisms, respectively. We hope this review will provide a new comprehensive way to better understand the electrophysiological mechanisms underlying TS from cell to bedside, promoting the management of TS in practice.
SplawskiITimothyKWDecherNKumarPSachseFBBeggsAHSanguinettiMCKeatingMT.Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proc Natl Acad Sci U S A2005;
102:8089–96; discussion 6–8
2.
KosakiROnoHTerashimaHKosakiK.Timothy syndrome-like condition with syndactyly but without prolongation of the QT interval. Am J Med Genet A2018;
176:1657–61
3.
SplawskiITimothyKWSharpeLMDecherNKumarPBloiseRNapolitanoCSchwartzPJJosephRMCondourisKTager-FlusbergHPrioriSGSanguinettiMCKeatingMT.Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell2004;
119:19–31
4.
GaoYXueXHuDLiuWYuanYSunHLiLTimothyKWZhangLLiCYanGX.Inhibition of late sodium current by mexiletine: a novel pharmotherapeutical approach in timothy syndrome. Circ Arrhythm Electrophysiol2013;
6:614–22
5.
ReichenbachHMeisterEMTheileH.[The heart-hand syndrome. A new variant of disorders of heart conduction and syndactylia including osseous changes in hands and feet]. Kinderarztl Prax1992;
60:54–6
6.
MarksMLWhislerSLClericuzioCKeatingM.A new form of long QT syndrome associated with syndactyly. J Am Coll Cardiol1995;
25:59–64
7.
MarksMLTrippelDLKeatingMT.Long QT syndrome associated with syndactyly identified in females. Am J Cardiol1995;
76:744–5
8.
GershonESGrennanKBusnelloJBadnerJAOvsiewFMemonSAlliey-RodriguezNCooperJRomanosBLiuC.A rare mutation of CACNA1C in a patient with bipolar disorder, and decreased gene expression associated with a bipolar-associated common SNP of CACNA1C in brain. Mol Psychiatry2014;
19:890–4
9.
JinWDLiangXGLiZJLiuGZHaoJH.A case report of Timothy syndrome. J Clin Cardiol2016;
32:99–100
10.
HanBNiuNZhangYLiWZZhaoLJYiYCZhangJJZhuangXJHanXZ.A case report of Timothy syndrome. Chin J Cadiac Arrhyth2014;
18:28–9
11.
GettysKFGastonGR.Timothy syndrome: a life-threatening syndactyly association: a.case report. JBJS Case Connect2014;
4:e48–e3
12.
PapineauSDWilsonS.Dentition abnormalities in a Timothy syndrome patient with a novel genetic mutation: a case report. Pediatr Dent2014;
36:245–9
13.
ShuJLiYJuRYanGX.Two types of T wave alternans in long-QT syndrome. J Cardiovasc Electrophysiol2014;
25:910–2
14.
BoczekNJMillerEMYeDNesterenkoVVTesterDJAntzelevitchCCzosekRJAckermanMJWareSM.Novel Timothy syndrome mutation leading to increase in CACNA1C window current. Heart Rhythm2015;
12:211–9
15.
CostainGRocheSLSchererSWSilversidesCKBassettAS.Rare copy number variations in an adult with transposition of the great arteries emphasize the importance of updated genetic assessments in syndromic congenital cardiac disease. Int J Cardiol2016;
203:516–8
16.
PhilippLRRodriguezFH.3rd.Cardiac arrest refractory to standard intervention in atypical Timothy syndrome (LQT8 type 2). Proc (Bayl Univ Med Cent)2016;
29:160–2
17.
KawaidaMAbeTNakanishiTMiyaharaYYamagishiHSakamotoMYamadaT.A case of Timothy syndrome with adrenal medullary dystrophy. Pathol Int2016;
66:587–92
18.
BaurandAFalcon-EicherSLaurentGVillainEBonnetCThauvin-RobinetCJacquotCEicherJCGourraudJBSchmittSBezieauSGiraudMDumontSKuentzPProbstVBurguetAKyndtFFaivreL.Incomplete Timothy syndrome secondary to a mosaic mutation of the CACNA1C gene diagnosed using next-generation sequencing. Am J Med Genet A2017;
173:531–6
19.
WalshMATurnerCTimothyKWSellerNHaresDLJamesAFHancoxJCUzunOBoyceDStuartAGBrennanPSartonCMcGuireKNewbury-EcobRAMcLeodK.A multicentre study of patients with Timothy syndrome. Europace2018;
20:377–85
20.
DufendachKATimothyKAckermanMJBlevinsBPflaumerAEtheridgeSPerryJBlomNATempleJChowdhuryDSkinnerJRJohnsrudeCBratincsakABosJMShahM.Clinical outcomes and modes of death in Timothy syndrome: a multicenter international study of a rare disorder. JACC Clin Electrophysiol2018;
4:459–66
21.
Corona-RiveraJRBarrios-PrietoENieto-GarciaRBloiseRPrioriSNapolitanoCBobadilla-MoralesLCorona-RiveraAZapata-AldanaEPena-PadillaCRivera-VargasJChavana-NaranjoE.Unusual retrospective prenatal findings in a male newborn with Timothy syndrome type 1. Eur J Med Genet2015;
58:332–5
22.
Lo Ansm WildeAAvan ErvenLBlomNA.Syndactyly and long QT syndrome (CaV1.2 missense mutation G406R) is associated with hypertrophic cardiomyopathy. Heart Rhythm2005;
2:1365–8
23.
GillisJBurashnikovEAntzelevitchCBlaserSGrossGTurnerLBabul-HirjiRChitayatD.Long QT, syndactyly, joint contractures, stroke and novel CACNA1C mutation: expanding the spectrum of Timothy syndrome. Am J Med Genet A2012;
158a:182–7
24.
AnHSChoiEYKwonBSKimGBBaeEJNohCIChoiJYParkSS.Sudden cardiac arrest during anesthesia in a 30-month-old boy with syndactyly: a case of genetically proven Timothy syndrome. J Korean Med Sci2013;
28:788–91
25.
EtheridgeSPBowlesNEArringtonCBPilcherTRopeAWildeAAAldersMSaarelEVTavernierRTimothyKWTristani-FirouziM.Somatic mosaicism contributes to phenotypic variation in Timothy syndrome. Am J Med Genet A2011;
155a:2578–83
26.
DufendachKAGiudicessiJRBoczekNJAckermanMJ.Maternal mosaicism confounds the neonatal diagnosis of type 1 Timothy syndrome. Pediatrics2013;
131:e1991–5
27.
HanDTanHSunCLiG.Dysfunctional Nav1.5 channels due to SCN5A mutations. Exp Biol Med2018;
243:852–63
28.
BoczekNJBestJMTesterDJGiudicessiJRMiddhaSEvansJMKampTJAckermanMJ.Exome sequencing and systems biology converge to identify novel mutations in the L-type calcium channel, CACNA1C, linked to autosomal dominant long QT syndrome. Circ Cardiovasc Genet2013;
6:279–89
29.
FukuyamaMWangQKatoKOhnoSDingWGToyodaFItohHKimuraHMakiyamaTItoMMatsuuraHHorieM.Long QT syndrome type 8: novel CACNA1C mutations causing QT prolongation and variant phenotypes. Europace2014;
16:1828–37
30.
BoczekNJYeDJinFTesterDJHusebyABosJMJohnsonAJKanterRAckermanMJ.Identification Functional Characterization of a novel CACNA1C-mediated cardiac disorder characterized by prolonged QT intervals with hypertrophic cardiomyopathy, congenital heart defects, and sudden cardiac death. Circ Arrhythm Electrophysiol2015;
8:1122–32
31.
SutphinBSBoczekNJBarajas-MartinezHHuDYeDTesterDJAntzelevitchCAckermanMJ.Molecular and functional characterization of rare CACNA1C variants in sudden unexplained death in the young. Congenit Heart Dis2016;
11:683–92
32.
LandstromAPBoczekNJYeDMiyakeCYDe la UzCMAllenHDAckermanMJKimJJ.Novel long QT syndrome-associated missense mutation, L762F, in CACNA1C-encoded L-type calcium channel imparts a slower inactivation tau and increased sustained and window current. Int J Cardiol2016;
220:290–8
33.
SeoSHKimSYChoSIParkHLeeSChoiJMKimMJLeeJSAhnKJSongMKBaeEJParkSSSeongMW.Application of multigene panel sequencing in patients with prolonged rate-corrected QT interval and no pathogenic variants detected in KCNQ1, KCNH2, and SCN5A. Ann Lab Med2018;
38:54–8
34.
OzawaJOhnoSSaitoHSaitohAMatsuuraHHorieM.A novel CACNA1C mutation identified in a patient with Timothy syndrome without syndactyly exerts both marked loss- and gain-of-function effects. Heart Rhythm Case Rep2018;
4:273–7
35.
HennesseyJABoczekNJJiangYHMillerJDPatrickWPfeifferRSutphinBSTesterDJBarajas-MartinezHAckermanMJAntzelevitchCKanterRPittGS.A CACNA1C variant associated with reduced voltage-dependent inactivation, increased CaV1.2 channel window current, and arrhythmogenesis. PLoS One2014;
9:e106982
36.
HiippalaATallilaJMyllykangasSKoskenvuoJWAlastaloTP.Expanding the phenotype of Timothy syndrome type 2: an adolescent with ventricular fibrillation but normal development. Am J Med Genet A2015;
167a:629–34
37.
DiepVSeaverLH.Long QT syndrome with craniofacial, digital, and neurologic features: is it useful to distinguish between Timothy syndrome types 1 and 2?Am J Med Genet A2015;
167a:2780–5
38.
CatterallWAPerez-ReyesESnutchTPStriessnigJ.International union of pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels. Pharmacol Rev2005;
57:411–25
39.
Franzini-ArmstrongCProtasiFRameshV.Shape, size, and distribution of Ca(2+) release units and couplons in skeletal and cardiac muscles. Biophys J1999;
77:1528–39
40.
PriestBTGarciaMLMiddletonREBrochuRMClarkSDaiGDickIEFelixJPLiuCJReiseterBSSchmalhoferWAShaoPPTangYSChouMZKohlerMGSmithMMWarrenVAWilliamsBSCohenCJMartinWJMeinkePTParsonsWHWaffordKAKaczorowskiGJ.A disubstituted succinamide is a potent sodium channel blocker with efficacy in a rat pain model. Biochemistry2004;
43:9866–76
41.
AbernethyDRSoldatovNM.Structure-functional diversity of human L-type Ca2+ channel: perspectives for new pharmacological targets. J Pharmacol Exp Ther2002;
300:724–8
42.
TsengGNBoydenPA.Multiple types of Ca2+ currents in single canine Purkinje cells. Circ Res1989;
65:1735–50
ShistikEIvaninaTPuriTHoseyMDascalN.Ca2+ current enhancement by alpha 2/delta and beta subunits in Xenopus oocytes: contribution of changes in channel gating and alpha 1 protein level. J Physiol1995;
489:55–62
OrreniusSZhivotovskyBNicoteraP.Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol2003;
4:552–65
49.
BarrettCFTsienRW.The Timothy syndrome mutation differentially affects voltage- and calcium-dependent inactivation of CaV1.2 L-type calcium channels. Proc Natl Acad Sci U S A2008;
105:2157–62
50.
ChengEPYuanCNavedoMFDixonRENieves-CintronMScottJDSantanaLF.Restoration of normal L-type Ca2+ channel function during Timothy syndrome by ablation of an anchoring protein. Circ Res2011;
109:255–61
51.
ErxlebenCLiaoYGentileSChinDGomez-AlegriaCMoriYBirnbaumerLArmstrongDL.Cyclosporin and Timothy syndrome increase mode 2 gating of CaV1.2 calcium channels through aberrant phosphorylation of S6 helices. Proc Natl Acad Sci U S A2006;
103:3932–7
52.
DixonREYuanCChengEPNavedoMFSantanaLF.Ca2+ signaling amplification by oligomerization of L-type Cav1.2 channels. Proc Natl Acad Sci U S A2012;
109:1749–54
53.
DickIEJoshi-MukherjeeRYangWYueDT.Arrhythmogenesis in Timothy syndrome is associated with defects in Ca(2+)-dependent inactivation. Nat Commun2016;
7:10370
54.
FallonJLBakerMRXiongLLoyREYangGDirksenRTHamiltonSLQuiochoFA.Crystal structure of dimeric cardiac L-type calcium channel regulatory domains bridged by Ca2+* calmodulins. Proc Natl Acad Sci U S A2009;
106:5135–40
55.
NavedoMFChengEPYuanCVotawSMolkentinJDScottJDSantanaLF.Increased coupled gating of L-type Ca2+ channels during hypertension and Timothy syndrome. Circ Res2010;
106:748–56
56.
DixonREChengEPMercadoJLSantanaLF.L-type Ca2+ channel function during Timothy syndrome. Trends Cardiovasc Med2012;
22:72–6
57.
AiXCurranJWShannonTRBersDMPogwizdSM.Ca2+/calmodulin-dependent protein kinase modulates cardiac ryanodine receptor phosphorylation and sarcoplasmic reticulum Ca2+ leak in heart failure. Circ Res2005;
97:1314–22
58.
OuaredRLarrabideIBrinaOBouillotPErcegGYilmazHLovbladKOMendes PereiraV.Computational fluid dynamics analysis of flow reduction induced by flow-diverting stents in intracranial aneurysms: a patient-unspecific hemodynamics change perspective. J Neurointervent Surg2016;
8:1288–93
59.
ThielWHChenBHundTJKovalOMPurohitASongLSMohlerPJAndersonME.Proarrhythmic defects in Timothy syndrome require calmodulin kinase II. Circulation2008;
118:2225–34
60.
YarotskyyVGaoGPetersonBZElmslieKS.The Timothy syndrome mutation of cardiac CaV1.2 (L-type) channels: multiple altered gating mechanisms and pharmacological restoration of inactivation. J Physiol2009;
587:551–65
61.
DepilKBeylSStary-WeinzingerAHohausATiminEHeringS.Timothy mutation disrupts the link between activation and inactivation in Ca(V)1.2 protein. J Biol Chem2011;
286:31557–64
62.
AlmagorLChomsky-HechtOBen-MochaAHendin-BarakDDascalNHirschJA.Ca(V)1.2 I-II linker structure and Timothy syndrome. Channels2012;
6:468–72
63.
BidaudILoryP.Hallmarks of the channelopathies associated with L-type calcium channels: a focus on the Timothy mutations in Ca(v)1.2 channels. Biochimie2011;
93:2080–6
64.
DrumBMDixonREYuanCChengEPSantanaLF.Cellular mechanisms of ventricular arrhythmias in a mouse model of Timothy syndrome (long QT syndrome 8). J Mol Cell Cardiol2014;
66:63–71
65.
AibaTHeskethGGLiuTCarlisleRVilla-AbrilleMCO'RourkeBAkarFGTomaselliGF.Na+ channel regulation by Ca2+/calmodulin and Ca2+/calmodulin-dependent protein kinase II in guinea-pig ventricular myocytes. Cardiovasc Res2010;
85:454–63
66.
SchlotthauerKBersDM.Sarcoplasmic reticulum Ca(2+) release causes myocyte depolarization. Underlying mechanism and threshold for triggered action potentials. Circ Res2000;
87:774–80
67.
KatraRPLauritaKR.Cellular mechanism of calcium-mediated triggered activity in the heart. Circ Res2005;
96:535–42
68.
MarbanERobinsonSWWierWG.Mechanisms of arrhythmogenic delayed and early afterdepolarizations in ferret ventricular muscle. J Clin Invest1986;
78:1185–92
69.
WeissJNGarfinkelAKaragueuzianHSChenPSQuZ.Early afterdepolarizations and cardiac arrhythmias. Heart Rhythm2010;
7:1891–9
70.
YatesDYatesACollyerT.A life-threatening complication of the arterial tourniquet in Timothy syndrome. Paediatr Anaesth2007;
17:492–5
71.
ShengXNakadaTKobayashiMKashiharaTShibazakiTHoriuchi-HiroseMGomiSHiroseMAoyamaTYamadaM.Two mechanistically distinct effects of dihydropyridine nifedipine on CaV1.2 L-type Ca(2)(+) channels revealed by Timothy syndrome mutation. Eur J Pharmacol2012;
685:15–23
72.
CheliVTSantiago GonzalezDAZamoraNNLamaTNSpreuerVRasmussonRLBettGCPanagiotakosGPaezPM.Enhanced oligodendrocyte maturation and myelination in a mouse model of Timothy syndrome. Glia2018;
66:2324–39
73.
BaderPLFaiziMKimLHOwenSFTadrossMRAlfaRWBettGCTsienRWRasmussonRLShamlooM.Mouse model of Timothy syndrome recapitulates triad of autistic traits. Proc Natl Acad Sci U S A2011;
108:15432–7
74.
BettGCLisAWersingerSRBaizerJSDuffeyMERasmussonRL.A mouse model of timothy syndrome: a complex autistic disorder resulting from a point mutation in Cav1.2. N A J Med Sci2012;
5:135–40
75.
EhlingerDGCommonsKG.Altered Cav1.2 function in the Timothy syndrome mouse model produces ascending serotonergic abnormalities. Eur J Neurosci2017;
46:2416–25
76.
SekeraERRudolphHLCarroSDMoralesMJBettGCLRasmussonRLWoodTD.Depletion of stercobilin in fecal matter from a mouse model of autism spectrum disorders. Metabolomics2017;
13:132
77.
RendallARFordALPerrinoPAHolly FitchR.Auditory processing enhancements in the TS2-neo mouse model of Timothy Syndrome, a rare genetic disorder associated with autism spectrum disorders. Adv Neurodev Disord2017;
1:176–89
78.
BaiJWangKLiuYLiYLiangCLuoGDongSYuanYZhangH.Computational cardiac modeling reveals mechanisms of ventricular arrhythmogenesis in long QT syndrome type 8: CACNA1C R858H mutation linked to ventricular fibrillation. Front Physiol2017;
8:771
79.
BaiJWangKLiQYuanYZhangH.Pro-arrhythmogenic effects of CACNA1C G1911R mutation in human ventricular tachycardia: insights from cardiac multi-scale models. Sci Rep2016;
6:31262
80.
BettGCKaplanADLisACimatoTRTzanakakisESZhouQMoralesMJRasmussonRL.Electronic “expression” of the inward rectifier in cardiocytes derived from human-induced pluripotent stem cells. Heart Rhythm2013;
10:1903–10
PascaSPPortmannTVoineaguIYazawaMShcheglovitovAPascaAMCordBPalmerTDChikahisaSNishinoSBernsteinJAHallmayerJGeschwindDHDolmetschRE.Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat Med2011;
17:1657–62
84.
SicouriSTimothyKWZygmuntACGlassAGoodrowRJBelardinelliLAntzelevitchC.Cellular basis for the electrocardiographic and arrhythmic manifestations of Timothy syndrome: effects of ranolazine. Heart Rhythm2007;
4:638–47
85.
TianYVoineaguIPascaSPWonHChandranVHorvathSDolmetschREGeschwindDH.Alteration in basal and depolarization induced transcriptional network in iPSC derived neurons from Timothy syndrome. Genome Med2014;
6:75
86.
YazawaMHsuehBJiaXPascaAMBernsteinJAHallmayerJDolmetschRE.Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature2011;
471:230–4
87.
MartinezRASteinJLKrostagARNelsonAMMarkenJSMenonVMayRCYaoZKaykasAGeschwindDHGrimleyJS.Genome engineering of isogenic human ES cells to model autism disorders. Nucleic Acids Res2015;
43:e65
88.
SongLAwariDWHanEYUche-AnyaEParkSHYabeYAChungWKYazawaM.Dual optical recordings for action potentials and calcium handling in induced pluripotent stem cell models of cardiac arrhythmias using genetically encoded fluorescent indicators. Stem Cells Transl Med2015;
4:468–75
89.
Tunca SahinGErgulY.A case report: is mexiletine usage effective in the shortening of QTC interval and improving the T-wave alternans in Timothy syndrome? Ann Noninvasive Electrocardiol2018;
23:e12522
90.
DhalaAASinghAK.Rare cause of infranodal block. Card Electrophysiol Clin2016;
8:743–5
91.
SeppRHateganLBacsiACseklyeJKornyeiLBorbasJSzellMForsterTNagyIHegedusZ.Timothy syndrome 1 genotype without syndactyly and major extracardiac manifestations. Am J Med Genet A2017;
173:784–9
92.
FrohlerSKieslichMLangnickCFeldkampMOpgen-RheinBBergerFWillJCChenW.Exome sequencing helped the fine diagnosis of two siblings afflicted with atypical Timothy syndrome (TS2). BMC Med Genet2014;
15:48
93.
ErgulYOzyilmazIHaydinSGuzeltasATuzcuV.A rare association with suffered cardiac arrest, long QT interval, and syndactyly: Timothy syndrome (LQT-8). Anatol J Cardiol2015;
15:672–4
94.
KrauseUGravenhorstVKriebelTRuschewskiWPaulT.A rare association of long QT syndrome and syndactyly: Timothy syndrome (LQT 8). Clin Res Cardiol2011;
100:1123–7
95.
JacobsAKnightBPMcDonaldKTBurkeMC.Verapamil decreases ventricular tachyarrhythmias in a patient with Timothy syndrome (LQT8). Heart Rhythm2006;
3:967–70
96.
LiGZhangL.The role of mexiletine in the management of long QT syndrome.J Electrocardiol2018;
51:1061–2
97.
ShimizuW.T wave alternans: from cell to clinical. J Cardiovasc Electrophysiol2001;
12:428–30
98.
GuoDYoungLPatelCJiaoZWuYLiuTKoweyPRYanGX.Calcium-activated chloride current contributes to action potential alternations in left ventricular hypertrophy rabbit. Am J Physiol Heart Circ Physiol2008;
295:H97–h104
99.
ShahDPBaez-EscuderoJLWeisbergILBeshaiJFBurkeMC.Ranolazine safely decreases ventricular and atrial fibrillation in Timothy syndrome (LQT8). Pacing Clin Electrophysiol2012;
35:e62–4
100.
YarotskyyVElmslieKS.Roscovitine, a cyclin-dependent kinase inhibitor, affects several gating mechanisms to inhibit cardiac L-type (Ca(V)1.2) calcium channels. Br J Pharmacol2007;
152:386–95
101.
SongLParkSEIsseroffYMorikawaKYazawaM.Inhibition of CDK5 alleviates the cardiac phenotypes in Timothy syndrome. Stem Cell Rep2017;
9:50–7
102.
NathanATAntzelevitchCMontenegroLMVetterVL.Case scenario: anesthesia-related cardiac arrest in a child with Timothy syndrome. Anesthesiology2012;
117:1117–26
103.
WhyteSDBookerPDBuckleyDG.The effects of propofol and sevoflurane on the QT interval and transmural dispersion of repolarization in children. Anesth Analg2005;
100:71–7
104.
HunekeRFasslJRossaintRLuckhoffA.Effects of volatile anesthetics on cardiac ion channels. Acta Anaesthesiol Scand2004;
48:547–61
