Advertisement

A cross-sectional study of the neuropsychiatric phenotype of CACNA1C-related disorder

      Highlights:

      • CACNA1C-related disorder (CRD) is a rare genetic disorder with a high risk of neurodevelopmental disorders and risk of cardiac arrhythmia.
      • Among 24 individuals with CRD we found high rates of developmental delay, neurologic, and psychiatric symptoms, including a 37.5% prevalence of epilepsy.
      • Whether or not an individual had cardiac symptoms did not change these risks.
      • These findings suggest that individuals with CRD should be screened and receive care for these common symptoms.

      Abstract

      Background

      CACNA1C encodes the voltage gated L-type calcium channel CaV1.2. A specific gain of function pathogenic variant in CACNA1C causes Timothy syndrome type 1 (TS1) with cardiac long QT syndrome, syndactyly, and neuropsychiatric symptoms. Our previous work found that the TS1 mutation alters neuronal activity-dependent signaling and interneuron migration. Recent case series highlighted a broader spectrum of CACNA1C-related disorder (CRD) that includes isolated cardiac disease, isolated neurologic deficits, and TS, but it is unknown how the clinical presentation of other CRD variants relate to neural defects. We surveyed individuals with CRD to define the neuropsychiatric and developmental phenotype in an effort to guide future research into the role of calcium channels in neural development.

      Methods

      Caregivers of and individuals with CRD completed an online survey of pre- and perinatal events, cardiac events, developmental milestones, neuropsychiatric symptoms, and neuropsychiatric diagnoses. Multiple Mann-Whitney tests were used for comparison of categorical values and Fisher’s exact test for comparison of categorical variables between participants with and without cardiac arrhythmia.

      Results

      Twenty-four participants with germline CACNA1C variants including TS1 completed the survey. The most common neuropsychiatric symptoms and/or diagnoses were developmental delay in 92%, incoordination in 71%, hypotonia in 67%, autism spectrum disorder in 50% (autistic features in 92%), seizures in 37.5%, and attention deficit hyperactivity disorder in 21% of participants. There were no significant differences in symptoms between participants with and without arrhythmia.

      Conclusions

      In our CRD cohort there was an increased prevalence of multiple neuropsychiatric symptoms compared with the general population. These findings indicate the key role of CaV1.2 in brain development and the clinical importance of screening and therapeutically addressing neuropsychiatric symptoms in all individuals with CRD. Future directions include deep phenotyping of neuropsychiatric symptoms and efforts to relate these symptoms to cellular defects.

      List of abbreviations:

      ADHD (attention deficit hyperactivity disorder), ASD (autism spectrum disorder), CRD (CACNA1C-related disorder), LQTS (long QT interval syndrome), LTCC (L-type calcium channel), OCD (obsessive compulsive disorder), TS (Timothy syndrome), TS1 (Timothy syndrome type 1), TS2 (Timothy syndrome type 2)

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Pediatric Neurology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Flavell S.W.
        • Greenberg M.E.
        Signaling mechanisms linking neuronal activity to gene expression and plasticity of the nervous system.
        Annu Rev Neurosci. 2008; 31: 563-590https://doi.org/10.1146/annurev.neuro.31.060407.125631
        • Greer P.L.
        • Greenberg M.E.
        From synapse to nucleus: calcium-dependent gene transcription in the control of synapse development and function.
        Neuron. 2008; 59: 846-860https://doi.org/10.1016/j.neuron.2008.09.002
        • Cross-Disorder Group of the Psychiatric Genomics Consortium
        Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.
        Lancet. 2013; 381: 1371-1379https://doi.org/10.1016/S0140-6736(12)62129-1
        • Green E.K.
        • Grozeva D.
        • Jones I.
        • et al.
        The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia.
        Mol Psychiatry. 2010; 15: 1016-1022https://doi.org/10.1038/mp.2009.49
        • Ferreira M.A.R.
        • O’Donovan M.C.
        • Meng Y.A.
        • et al.
        Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder.
        Nat Genet. 2008; 40: 1056-1058https://doi.org/10.1038/ng.209
        • Moskvina V.
        • Craddock N.
        • Holmans P.
        • et al.
        Gene-wide analyses of genome-wide association data sets: evidence for multiple common risk alleles for schizophrenia and bipolar disorder and for overlap in genetic risk.
        Mol Psychiatry. 2009; 14: 252-260https://doi.org/10.1038/mp.2008.133
        • Schizophrenia Working Group of the Psychiatric Genomics Consortium
        Biological insights from 108 schizophrenia-associated genetic loci.
        Nature. 2014; 511: 421-427https://doi.org/10.1038/nature13595
        • Hamshere M.L.
        • Walters J.T.R.
        • Smith R.
        • et al.
        Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC.
        Mol Psychiatry. 2013; 18: 708-712https://doi.org/10.1038/mp.2012.67
        • Splawski I.
        • Timothy K.W.
        • Sharpe L.M.
        • et al.
        Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism.
        Cell. 2004; 119: 19-31https://doi.org/10.1016/j.cell.2004.09.011
        • Mio C.
        • Passon N.
        • Baldan F.
        • et al.
        CACNA1C haploinsufficiency accounts for the common features of interstitial 12p13.33 deletion carriers.
        Eur J Med Genet. 2020; 63103843https://doi.org/10.1016/j.ejmg.2020.103843
        • Quintela I.
        • Eirís J.
        • Gómez-Lado C.
        • et al.
        Copy number variation analysis of patients with intellectual disability from North-West Spain.
        Gene. 2017; 626: 189-199https://doi.org/10.1016/j.gene.2017.05.032
        • Roberts J.L.
        • Hovanes K.
        • Dasouki M.
        • Manzardo A.M.
        • Butler M.G.
        Chromosomal microarray analysis of consecutive individuals with autism spectrum disorders or learning disability presenting for genetic services.
        Gene. 2014; 535: 70-78https://doi.org/10.1016/j.gene.2013.10.020
        • Kaplanis J.
        • Samocha K.E.
        • Wiel L.
        • et al.
        Evidence for 28 genetic disorders discovered by combining healthcare and research data.
        Nature. 2020; 586: 757-762https://doi.org/10.1038/s41586-020-2832-5
        • Splawski I.
        • Timothy K.W.
        • Decher N.
        • et al.
        Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations.
        Proc Natl Acad Sci U S A. 2005; 102 (; discussion 8086-8088): 8089-8096https://doi.org/10.1073/pnas.0502506102
        • Fröhler S.
        • Kieslich M.
        • Langnick C.
        • et al.
        Exome sequencing helped the fine diagnosis of two siblings afflicted with atypical Timothy syndrome (TS2).
        BMC Med Genet. 2014; 15: 48https://doi.org/10.1186/1471-2350-15-48
        • Gillis J.
        • Burashnikov E.
        • Antzelevitch C.
        • et al.
        Long QT, syndactyly, joint contractures, stroke and novel CACNA1C mutation: expanding the spectrum of Timothy syndrome.
        Am J Med Genet A. 2012; 158A: 182-187https://doi.org/10.1002/ajmg.a.34355
        • Krause U.
        • Gravenhorst V.
        • Kriebel T.
        • Ruschewski W.
        • Paul T.
        A rare association of long QT syndrome and syndactyly: Timothy Syndrome (LQT 8).
        Clin Res Cardiol. 2011; 100: 1123-1127https://doi.org/10.1007/s00392-011-0358-4
        • Boczek N.J.
        • Miller E.M.
        • Ye D.
        • et al.
        Novel Timothy syndrome mutation leading to increase in CACNA1C window current.
        Heart Rhythm. 2015; 12: 211-219https://doi.org/10.1016/j.hrthm.2014.09.051
        • Hennessey J.A.
        • Boczek N.J.
        • Jiang Y.H.
        • et al.
        A CACNA1C variant associated with reduced voltage-dependent inactivation, increased CaV1.2 channel window current, and arrhythmogenesis.
        PLoS One. 2014; 9e106982https://doi.org/10.1371/journal.pone.0106982
        • Boczek N.J.
        • Ye D.
        • Jin F.
        • et al.
        Identification and 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 Electrophysiol. 2015; 8: 1122-1132https://doi.org/10.1161/CIRCEP.115.002745
        • Boczek N.J.
        • Best J.M.
        • Tester D.J.
        • et al.
        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 Genet. 2013; 6: 279-289https://doi.org/10.1161/CIRCGENETICS.113.000138
        • Landstrom A.P.
        • Boczek N.J.
        • Ye D.
        • et al.
        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 Cardiol. 2016; 220: 290-298https://doi.org/10.1016/j.ijcard.2016.06.081
        • Wemhöner K.
        • Friedrich C.
        • Stallmeyer B.
        • et al.
        Gain-of-function mutations in the calcium channel CACNA1C (Cav1.2) cause non-syndromic long-QT but not Timothy syndrome.
        J Mol Cell Cardiol. 2015; 80: 186-195https://doi.org/10.1016/j.yjmcc.2015.01.002
        • Mellor G.J.
        • Panwar P.
        • Lee A.K.
        • et al.
        Type 8 long QT syndrome: pathogenic variants in CACNA1C-encoded Cav1.2 cluster in STAC protein binding site.
        Europace. 2019; 21: 1725-1732https://doi.org/10.1093/europace/euz215
        • Fukuyama M.
        • Ohno S.
        • Wang Q.
        • et al.
        L-type calcium channel mutations in Japanese patients with inherited arrhythmias.
        Circ J. 2013; 77: 1799-1806https://doi.org/10.1253/circj.cj-12-1457
        • Liu X.
        • Shen Y.
        • Xie J.
        • et al.
        A mutation in the CACNA1C gene leads to early repolarization syndrome with incomplete penetrance: A Chinese family study.
        PLoS One. 2017; 12e0177532https://doi.org/10.1371/journal.pone.0177532
        • Rodan L.H.
        • Spillmann R.C.
        • Kurata H.T.
        • et al.
        Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations.
        Genet Med. Published online June. 2021; 23https://doi.org/10.1038/s41436-021-01232-8
        • Bozarth X.
        • Dines J.N.
        • Cong Q.
        • et al.
        Expanding clinical phenotype in CACNA1C related disorders: From neonatal onset severe epileptic encephalopathy to late-onset epilepsy.
        Am J Med Genet A. 2018; 176: 2733-2739https://doi.org/10.1002/ajmg.a.40657
        • Iossifov I.
        • O’Roak B.J.
        • Sanders S.J.
        • et al.
        The contribution of de novo coding mutations to autism spectrum disorder.
        Nature. 2014; 515: 216-221https://doi.org/10.1038/nature13908
        • Deciphering Developmental Disorders Study
        Prevalence and architecture of de novo mutations in developmental disorders.
        Nature. 2017; 542: 433-438https://doi.org/10.1038/nature21062
        • Han D.
        • Xue X.
        • Yan Y.
        • Li G.
        Dysfunctional Cav1.2 channel in Timothy syndrome, from cell to bedside.
        Exp Biol Med (Maywood). 2019; 244: 960-971https://doi.org/10.1177/1535370219863149
        • Bauer R.
        • Timothy K.W.
        • Golden A.
        Update on the Molecular Genetics of Timothy Syndrome.
        Front Pediatr. 2021; 9668546https://doi.org/10.3389/fped.2021.668546
      1. Frankenburg W, Dodds J. DENVER II Training Manual. Published online 1992.

        • Jacobs A.
        • Knight B.P.
        • McDonald K.T.
        • Burke M.C.
        Verapamil decreases ventricular tachyarrhythmias in a patient with Timothy syndrome (LQT8).
        Heart Rhythm. 2006; 3: 967-970https://doi.org/10.1016/j.hrthm.2006.04.024
        • Gershon E.S.
        • Grennan K.
        • Busnello J.
        • et al.
        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 Psychiatry. 2014; 19: 890-894https://doi.org/10.1038/mp.2013.107
        • Moon A.L.
        • Haan N.
        • Wilkinson L.S.
        • Thomas K.L.
        • Hall J.
        CACNA1C: Association With Psychiatric Disorders, Behavior, and Neurogenesis.
        Schizophr Bull. 2018; 44: 958-965https://doi.org/10.1093/schbul/sby096
        • Moon A.L.
        • Brydges N.M.
        • Wilkinson L.S.
        • Hall J.
        • Thomas K.L.
        Cacna1c Hemizygosity Results in Aberrant Fear Conditioning to Neutral Stimuli.
        Schizophr Bull. Published online January. 2020; 7: sbz127https://doi.org/10.1093/schbul/sbz127
        • Tigaret C.M.
        • Lin T.C.E.
        • Morrell E.R.
        • et al.
        Neurotrophin receptor activation rescues cognitive and synaptic abnormalities caused by hemizygosity of the psychiatric risk gene Cacna1c.
        Mol Psychiatry. 2021; 26: 1748-1760https://doi.org/10.1038/s41380-020-01001-0
        • Bader P.L.
        • Faizi M.
        • Kim L.H.
        • et al.
        Mouse model of Timothy syndrome recapitulates triad of autistic traits.
        Proc Natl Acad Sci U S A. 2011; 108: 15432-15437https://doi.org/10.1073/pnas.1112667108
        • Paşca S.P.
        • Portmann T.
        • Voineagu I.
        • et al.
        Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome.
        Nat Med. 2011; 17: 1657-1662https://doi.org/10.1038/nm.2576
        • Birey F.
        • Andersen J.
        • Makinson C.D.
        • et al.
        Assembly of functionally integrated human forebrain spheroids.
        Nature. 2017; 545: 54-59https://doi.org/10.1038/nature22330
        • Birey F.
        • Li M.Y.
        • Gordon A.
        • et al.
        Dissecting the molecular basis of human interneuron migration in forebrain assembloids from Timothy syndrome.
        Cell Stem Cell. 2022; 29 (e7): 248-264https://doi.org/10.1016/j.stem.2021.11.011