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Clinical Electrophysiology

Editor-in-Chief

Dr. David J. Wilber.

J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 2 , N O . 3 , 2 0 1 6

ª 2 0 1 6 B Y T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y F O U N D A T I O N

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Comorbid Epilepsy and DevelopmentalDisorders in Congenital Long QTSyndrome With Life-ThreateningPerinatal Arrhythmias
Aya Miyazaki, MD,a Heima Sakaguchi, MD,a Takeshi Aiba, MD,b Akira Kumakura, MD,c Michio Matsuoka, MD,a
Yosuke Hayama, MD,a Yuriko Shima, MD,a Nobuyuki Tsujii, MD,a Osamu Sasaki, MD,a Ken-ichi Kurosaki, MD,a

Jun Yoshimatsu, MD,d Yoshihiro Miyamoto, MD,e Wataru Shimizu, MD,b,f Hideo Ohuchi, MDa

ABSTRACT

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OBJECTIVES Given the association of long QT syndrome (LQTS) and neurological disorders, we speculated that the

more severe LQTS phenotype, perinatal LQTS, would exhibit more frequent comorbid neurodevelopmental anomalies

than LQTS without perinatal arrhythmias (nonperinatal LQTS).

BACKGROUND Congenital LQTS with life-threatening perinatal arrhythmias (perinatal LQTS) has a poor life prognosis.

METHODS Twenty-one consecutive LQTS patients diagnosed before 1 year of age at our institution and 3 previously

reported perinatal LQTS patients with neurological seizures were enrolled. In total, the clinical course was evaluated in

24 patients.

RESULTS Among 21 infantile LQTS patients, 5 of 6 with perinatal LQTS (83%) were diagnosed with epilepsy

and 4 (67%) with developmental disorders, but none with nonperinatal LQTS were. The total development

quotient by Kinder Infant Development Scale scores was 17 to 72 (median 67) in 5 epileptic perinatal LQTS.

In the 8 perinatal LQTS patients with neurological disorders, including 3 previously reported cases, epileptic

seizures occurred at 2 days to 2.5 years of age and 5 had developmental disorders. Mutations in these

8 patients were located in the transmembrane loop of KCNH2, and D3/S4-S5 linker, D4/S4, or the D4/S6

segment of SCN5A.

CONCLUSIONS A high comorbidity of neurodevelopmental anomalies was observed in perinatal LQTS. Mutations in

patients with neurological comorbidities were in loci linked to LQTS with a severe cardiac phenotype. These observations

indicate the possibility that neurological disorders in perinatal LQTS are manifested as neurological phenotypes asso-

ciated with severe cardiac phenotypes, while we could not completely exclude another possibility that those were

caused by a brain perfusion injury. (J Am Coll Cardiol EP 2016;2:266–76) © 2016 by the American College of Cardiology

Foundation.

m the aDepartment of Pediatric Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan; bDepartment of Car-

vascular Medicine, Division of Arrhythmias and Electrophysiology, National Cerebral and Cardiovascular Center, Osaka, Japan;

epartment of Pediatrics, Kitano Hospital, The Tazuke Kofukai Medical Research Institute, Osaka, Japan; dDepartment of Peri-

tology, National Cerebral and Cardiovascular Center, Osaka, Japan; eDepartment of Preventive Cardiology, Department of

ventive Medicine and Epidemiologic Informatics, National Cerebral and Cardiovascular Center, Osaka, Japan; and the fDe-

rtment of Cardiovascular Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan. Drs. Aiba, Miyamoto,

d Shimizu were supported in part by the Research Grant for Cardiovascular Diseases (H26-040) from the Ministry of Health,

bour and Welfare, Japan. All other authors have reported that they have no relationships relevant to the contents of this paper

disclose.

nuscript received September 10, 2015; revised manuscript received October 22, 2015, accepted October 29, 2015.

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AB BR E V I A T I O N S

AND ACRONYM S

AVB = atrioventricular block

CT = computed tomography

DQ = development quotient

ECG = electrocardiogram

EEG = electroencephalogram

KIDS = Kinder Infant

Development Scale

LQTS = long QT syndrome

MRI = magnetic resonance

imaging

QTc = corrected QT

J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 2 , N O . 3 , 2 0 1 6 Miyazaki et al.J U N E 2 0 1 6 : 2 6 6 – 7 6 Neurological Comorbidity in Perinatal LQTS

267

C ongenital long QT syndrome (LQTS) patientswho experience aborted cardiac arrest in thefirst year of life are at very high risk for near-

fatal or fatal cardiac events during the next 10 years oflife (1). Especially, LQTS cases with torsade de pointes(TdP) and 2:1 atrioventricular block (AVB) during theperinatal period have poorer prognoses than LQTScases without these arrhythmias (2–5). Current thera-pies, such as b-blockers, mexiletine, and pacemakerdevice implantations, have reduced the mortalityand resulted in relatively favorable prognoses forperinatal LQTS (1,3,6). However, aborted cardiac ar-rest and sudden death still occur in this group despitetreatment (1,3,4).

SEE PAGE 277

TdP = torsade de pointes

As with LQTS, Mendelian epilepsies and cardiacarrhythmias may also arise from mutations in ionchannels or related signaling molecules, some due tomutations in the same genes associated with LQTS(7). In the brain, as in the myocardium, inheriteddysfunction of ion channels (channelopathies) candestabilize excitable tissue, leading to paroxysmalclinical events (7). The possible association of epi-lepsy arising from the same channelopathies as LQTSwas recently examined (8–10). Abnormal corticalelectroencephalographic (EEG) activity was identifiedmore frequently in subjects with LQTS secondary topotassium channel mutations than in healthy con-trols (8). In addition, 15% of the patients with LQTSwho presented with seizures or seizure-like episodeshad EEG-identified epileptiform activity (9).Furthermore, mutations in KCNH2 or SCN5A wereidentified in 6 of 68 patients with sudden unexpecteddeath in epilepsy (10).

A comorbidity of epilepsy and/or developmentaldisorders has been observed in perinatal LQTS pa-tients who survived life-threatening ventricular ar-rhythmias. However, to the best of our knowledge,only 3 case reports have been previously published(11–13). Therefore, we hypothesized that perinatalLQTS patients, the most severe phenotype of LQTS(1,3,4), would have higher incidences of neurologicalmanifestations of channelopathies, such as epilepsyor developmental disorders. In this study, we evalu-ated the clinical and neurological findings in infantileLQTS patients with or without perinatal arrhythmias.

METHODS

PATIENTS. Twenty-four consecutive patients diag-nosed with LQTS before 1 year of age at the NationalCerebral and Cardiovascular Center from November1998 to August 2015 were considered for this study.

LQTS was diagnosed by genetic testing or acorrected QT (QTc) interval $470 ms with afamily history of LQTS, calculated withBazett’s formula (14) on the resting electro-cardiogram (ECG). Three patients who wereless than 1 year old at the last follow-up wereexcluded and the remaining 21 were enrolledin this study. Four sibling pairs wereincluded, and 1 patient was previouslydescribed (Patient #3) (15). Among the 21 pa-tients, 6 had life-threatening arrhythmicevents during the perinatal period, such asTdP or 2:1 AVB due to QTc prolongation. Weclassified these 6 patients as perinatal LQTS,and the other 15 as nonperinatal LQTS.
Further, we added the data of the clinical featuresand genetic analyses from 3 previously reported caseswith perinatal LQTS and epileptic seizures (11–13). Atotal of 24 patients were examined. We assert that allprocedures contributing to this work complied withthe relevant national guidelines on human experi-mentation (Japan) and with the Helsinki Declarationof 1975 (as revised in 2008), and were approved by theinstitutional ethics committees (M25-132).
CLINICAL CHARACTERISTICS. The following parameterswere assessed: gender, age at the initial presentation,family history of LQTS, gene mutations, ECG findingsat the initial presentation, syncope or life-threateningarrhythmias during follow-up, medical treatments forLQTS, comorbid epilepsy, developmental outcomes,and other neurological disorders. Syncope wasdistinguished from epileptic seizures by a rapid onsetwithout warning, shorter duration, and no postictalphase.

The ECG findings at the initial presentation werecompared between 9 perinatal and 15 nonperinatalLQTS patients, including the 3 previously reportedcases. The incidence of life-threatening arrhythmias,epilepsy, and developmental disorders during thefollow-up was evaluated in our 6 perinatal LQTS and15 nonperinatal LQTS patients.

DEVELOPMENTAL OUTCOME. The developmentaloutcomes were assessed using the Kinder InfantDevelopment Scale (KIDS) (16,17) in 14 patients fromour institution. In the perinatal LQTS group, the KIDSwas available only in 5 patients with comorbidepileptic seizures. KIDS type B, C, and T were used asappropriate. Type B was designed for assessing infantchildren 12 to 23 months of age. It included 142 itemsand yields subscales for 9 developmental domains:physical motor, manipulation, language reception,language expression, concept, social relationshipswith children, social relationships with adults,

TABLE 1 Clinical Cha

Patient # Sex G

1 M

2 F

3 M

4 M

5 M

6 F

7 M

8 M

9 M

10 F

11 M

12 F

13 F Un

14 M

15 M

16 M

17 M

18 M

19 F

20 M

21 F

22* M

23* M

24* F

Patients #1 and #8, #10 an

AVB ¼ atrioventricular btachycardia; PVC ¼ premat

Miyazaki et al. J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 2 , N O . 3 , 2 0 1 6

Neurological Comorbidity in Perinatal LQTS J U N E 2 0 1 6 : 2 6 6 – 7 6

268

training, and feeding. Type C was designed for chil-dren 36 to 83 months of age. It included 133 items andyield subscales for the same developmental domainsexcept for feeding. Type T was designed for assessingdevelopmentally delayed children 36 to 83 months ofage. It included 282 items and yield subscales for the9 developmental domains of type B. Type T was alsouseful for assessing severe developmentally delayedchildren of up to 12 years old. Each item was scored aspass (1 point) or fail (0) by the parents and the scoreswere summed for each subscale. The overall devel-opmental age from the total score and those for allsubscales were determined using a conversion chart(16). Development quotients (DQs) for the total and allsubscales were then calculated using the followingformula.

DQ ¼ development age=calendar age� 100

A total DQ under 70 was defined as a develop-mental disorder. DQs were compared between 5

racteristics of LQTS Patients Under 1 Year of Age

enotype Gene Mutation

Age atthe Initial

Presentation(days)

HR(beats/min)

QTc(ms)

LQT3 SCN5A N406K 2 120 566

LQT2 KCNH2 T623I 0 93 606

LQT3 SCN5A G1631D 0 150 538

LQT3 SCN5A P1332L 1 158 584

LQT2 KCNH2 S624R 0 58 686

LQT2 KCNH2 T613M 0 115 582

LQT1 KCNQ1 A341V 57 150 506

LQT3 SCN5A N406K 60 136 452

LQT1 KCNQ1 A341V 0 97 559

LQT2 KCNH2 W563C 0 143 494

LQT1 KCNQ1 G325R 0 115 582

LQT2 KCNH2 T65P 321 130 472

identified - - 0 120 566

LQT7 KCNJ2 G300V 0 136 543

LQT1 KCNQ1 R174C 0 136 513

LQT7 KCNJ2 G300V 0 120 509

LQT2 KCNH2 W563C 0 125 520

LQT1 KCNQ1 A344E 38 150 493

LQT1 KCNQ1 L563P 316 120 453

LQT2 KCNH2 T65P 0 136 482

LQT1 KCNQ1 R174H 0 120 509

LQT3LQT6

SCN5AKCNE2

R1623QI57T

0 N/A 535

LQT3 SCN5A M1766L 1 81 513

LQT2 KCNH2 T613M 0 67 607

d #17, #12 and #20, and #14 and #16 were siblings. *Patients #22, #23, and #24 were prev

lock; BB ¼ b-blocker; FH ¼ family history; HR ¼ heart rate; LQTS ¼ long QT syndrome; Mex ¼ure ventricular contraction; TdP ¼ torsade de pointes; Ver ¼ verapamil; VT ¼ ventricular ta

epileptic perinatal LQTS and 9 nonperinatal LQTSpatients.

NEUROLOGICAL EVALUATION. Epilepsy was diag-nosed by pediatric neurologists, based on the defini-tions of a seizure and epilepsy by the Task Force ofthe International League Against Epilepsy in 2005(18). An epileptic seizure is a transient occurrence ofsigns and/or symptoms due to abnormal excessive orsynchronous neuronal activity in the brain. Epilepsyis a disorder of the brain characterized by andenduring a predisposition to generate epileptic sei-zures, and by the neurobiologic, cognitive, psycho-logical, and social consequence of this condition. Thedefinition of epilepsy requires the occurrence of atleast 1 epileptic seizure. We evaluated the neurolog-ical examination, blood tests, and electroencephalo-grams to diagnose epilepsy in all our patients withclinical seizures. We eliminated the possibility ofepilepsy imitators such as syncope due to

Medications at theInitial Presentation

ClinicalPresentation

Arrhythmias Duringthe Neonatal Period

- Frequent PVC TdP

Transplacental(BB, Ver, Mg)

FH 2:1AVB

- Fetal TdP TdP

- NSVT TdP, VT

Transplacental(Mex, Mg)

Fetal TdP, fetal AVB 2:1 AVB

Transplacental(BB, Mex, Mg)

Fetal TdP Wenckebach AVB

- FH -

- FH -

Transplacental (BB) FH -

Transplacental (Mg) FH -


- FH -

Transplacental (Mg) FH bradycardia -

Transplacental (BB, Ver) FH -




- FH -

- FH -



N/A Irregular fetal heartrhythm

TdP

N/A Irregular fetal heartrhythm

TdP

N/A Fetal bradycardia 2:1 AVB, TdP

iously reported cases (11–13).

mexiletine; Mg ¼ magnesium; N/A ¼ not available; NSVT ¼ nonsustained ventricularchycardia.

FIGURE 1 Electrocardiography Findings at the Initial Presentation

The heart rate (A) and corrected QT interval (B) are compared between perinatal long QT

syndrome (LQTS) and nonperinatal LQTS cases. Thirteen patients were administered

antiarrhythmic agents transplacentally at the initial presentation (Table 1). Perinatal LQTS

cases are represented by pink and LQTS cases without perinatal arrhythmias by blue.


269

arrhythmias by monitoring the electrocardiogramsduring the seizures. Computed tomography (CT) ormagnetic resonance imaging (MRI) was performed inpatients with epilepsy or syncope to determine thepresence and extent of hypoxic ischemic encepha-lopathy, brain hemorrhages, and cerebral infarctions.For the 3 previously reported cases, the data con-cerning the neurological findings were obtained fromtheir reports.

GENETIC ANALYSIS. The protocol for the geneticanalysis was approved by the Institutional EthicsCommittee and performed under its guidelines (M24-031-4). The genomic DNA was isolated from wholeblood using a DNA analyzer (QIAGEN GmbH, Hilden,Germany) (19). Genetic screening for KCNQ1, KCNH2,and SCN5A (and if necessary KCNE1, KCNE2, andKCNJ2) mutations was performed by directsequencing (ABI 3730 DNA Analyzer, Life Technolo-gies, Carlsbad, California). The cDNA sequencenumbering was based on the GenBank referencesequence.

STATISTICAL ANALYSIS. Statistical analysis was notperformed to compare the clinical findings betweenperinatal LQTS and nonperinatal LQS, because of thesmall number population (n ¼ 24) including 4 siblingpairs.

RESULTS

CLINICAL CHARACTERISTICS. The clinical charac-teristics are shown in Table 1. Patients #1 to #6 wereperinatal LQTS patients from our institution, and 22to 24 were previously reported perinatal LQTS pa-tients with neurological seizures. Three of the 9perinatal LQTS cases had TdP in utero as documentedby magnetocardiography. One patient was deliveredin our hospital because of maternal LQTS and theother 5 were transferred from other institutions orconsulted because of frequent premature ventricularcontractions, nonsustained ventricular tachycardia,or fatal arrhythmias. All 15 nonperinatal LQTS pa-tients (Patients #7 to #21) were examined because ofmaternal or paternal LQTS but presented withoutsymptoms. Thirteen patients in total were trans-placentally administered antiarrhythmic agents, 2 forfetal TdP (Patient #5 and #6) and 11 for maternalLQTS.

The heart rate and QTc at the initial presentationwere compared between 9 perinatal and 15 non-perinatal LQTS patients in Figure 1. The heart rate was58 to 158 (median 104) beats/min and 97 to 150 (me-dian 130) beats/min, and the QTc was 513 to 686(median 582) ms and 452 to 582 (median 509) ms in

perinatal and nonperinatal LQTS, respectively. TheECGs from our 6 perinatal LQTS patients are shown inFigure 2.

CLINICAL COURSE OF INFANTILE LQTS. Twenty-two patients were alive at the last follow-up and 2patients with perinatal LQTS (Patients #4 and #23)died suddenly due to arrhythmias (Table 2). All 9perinatal LQTS cases have been taking antiarrhythmicagents since their perinatal periods. Conventionalpacemaker devices were implanted during theneonatal period in 5 patients (Patients #2, #5, #6, #22,and #24) and 4 were later upgraded to an implantablecardioverter-defibrillator. Patient #3 was implantedwith an implantable cardioverter-defibrillator at0.9 years old. Despite treatment, syncope or life-threatening arrhythmias still occurred after theneonatal period in 7 patients. In the nonperinatalLQTS group, 1 unmedicated patient (Patient #8) hadsyncope at 13.5 years of age.

FIGURE 2 Electrocardiograms From Perinatal LQTS Patients

(A to F) Representative electrocardiograms from Patients #1 to #6, respectively. HR ¼ hazard ratio; LQTS ¼ long QT syndrome; QTc ¼ corrected QT.



270

COMPARISON OF THE CLINICAL FINDINGS AND KIDS

BETWEEN PERINATAL LQTS AND NONPERINATAL

LQTS IN 21 INFANTILE LQTS PATIENTS FROM OUR

INSTITUTION. Among our 21 infantile LQTS patients,the age at the last follow-up was 1.0 to 16.8 (median8.1) years in the 6 perinatal LQTS and 1.0 to 16.6(median 3.8) years in the 15 nonperinatal LQTS pa-tients. During the follow-up, syncope or life-threatening arrhythmias occurred in 5 perinatalLQTS patients (83%) and 1 nonperinatal LQTS patient(7%). Further, 5 perinatal LQTS patients (83%) werediagnosed with epilepsy and 4 (67%) with develop-mental disorders, while neither disorder wasobserved in the nonperinatal LQTS group. Among theperinatal LQTS patients, Patients #2, #3, #5, and #6had all symptoms, such as syncope or life-threateningarrhythmias, epilepsy, and developmental disorders,while Patient #1 had no symptoms during the follow-up (Figure 3). There were no family members withepilepsy or developmental disorders.

A type B KIDS was performed in 4 patients, type Cin 5 patients, and type T in 5 patients (Table 2). Thetotal and 9 subscales were compared between peri-natal LQTS patients with epilepsy and nonperinatalLQTS cases in Figure 4. The total DQ was 17 to 72(median 67) in 5 epileptic perinatal LQTS, while itwas 73 to 129 (median 100) in 9 nonperinatal LQTS.

NEUROLOGICAL FINDINGS. No patients in eithergroup had symptoms of cerebral palsy except for 2previously reported cases without any informationabout it (Patients #23 and #24). The neurologicalfindings of 8 perinatal LQTS patients with neurolog-ical disorders are shown in Table 3. The age at theonset of the epileptic seizures ranged from 2 days to2.5 years of age and 5 had developmental disorders(Table 3). Epileptic seizures occurred under mex-iletine or lidocaine in 7 patients, excluding Patient#22. Five patients had interictal EEG abnormalities(Figure 5), while 2 had none (Patients #2 and #24) andthe remaining 1 had no data. Six patients had unre-markable findings on cerebral imaging (CT in 3 ratherthan MRI due to device implantations), while therewere no data for 2 previously reported cases.GENETIC CHARACTERISTICS. The LQT genotype waseither LQT2 or LQT3 in all perinatal LQTS patients. Inthe nonperinatal LQTS patients, the genotype wasmore variable, either LQT1, LQT2, LQT3, or LQT7(Table 1). Among 9 perinatal LQTS cases, 7 were pro-bands. Five had a de novo mutation and 4 hadinherited mutations.

The locations of the gene mutations in 8 perinatalLQTS patients with neurological disorders are shownin Figure 6. The KCNH2 mutation in Patients #2, #6,and #24 (T613M, T623I) was previously reported

FIGURE 3 Pedigrees of LQTS Patients With Perinatal Arrhythmias

(A to F) Pedigrees of Patients #1 to #6, respectively. LQTS ¼ long QT syndrome; Pt ¼ patient.


271

without functional assays (20,21), and the S624R inPatient #5 was a novel mutation. The other 4 SCN5Amutations (P1332L, R1623Q, G1631D, M1766L) in theperinatal LQTS patients were previously reportedwith detailed functional assays (12,15,22,23). In the 6perinatal LQTS cases with epileptic seizures, themutations were located in the transmembrane loop ofKCNH2 (T613M, T623I, S 624R) and the D4/S4segment of SCN5A (R1623Q, G1631D).

DISCUSSION

We showed a high incidence of comorbid epilepsyand/or developmental disorders in perinatal LQTSpatients, while neither disorder was observed in thenonperinatal LQTS patients. In addition, the total DQwas 17 to 72 (median 67) in 5 epileptic perinatal LQTS.In the 8 perinatal LQTS patients with neurologicaldisorders including 3 previously reported cases,epileptic seizures occurred between 2 days and 2.5years of age and 5 had developmental disorders.We found no evidence of hypoxic ischemic braininjury in any of these patients. The mutations in pa-tients with neurological comorbidities were in locipreviously linked to LQTS with a severe cardiacphenotype. These findings indicate the possibility

that neurological disorders are observed in perinatalLQTS as a neurological phenotype associated withthe most severe cardiac phenotype of LQTS, life-threatening arrhythmias, during the perinatal period.CLINICAL CHARACTERISTICS AND CLINICAL COURSE IN

PERINATAL AND INFANTILE LQTS. Life-threateningcardiac events are rare during infancy in LQTS pa-tients. Of 3,323 LQTS patients in an internationalregistry, sudden cardiac death occurred in only20 (0.6%), aborted cardiac arrest in 16 (0.4%), andsyncope in 34 (1%) during the first year of life (1).However, these patients are known to be at a veryhigh risk of aborted cardiac arrest or sudden death inthe years to come, especially those with LQTS plusTdP or 2:1 AVB during the perinatal period (1–5).

In the present study, during the follow-up, morearrhythmic events were observed in the perinatalLQTS patients despite more intensive treatment.Notably, perinatal LQTS had a high incidence of epi-lepsy (83%) and developmental disorders (67%),while neither disorder was observed in the non-perinatal LQTS patients. Moreover, the total DQ byKIDS was revealed to be low, 17 to 72 (median 67), in 5epileptic perinatal LQTS.

Previous relatively large-scale studies on perinatalLQTS did not report the rates of epilepsy and/or

FIGURE 4 Development Quotient for the Total and Each Subscale of the KIDS Battery for Perinatal LQTS and Nonperinatal LQTS Patients

Development quotient for the total (A), physical motor (B), manipulation (C), language reception (D), language expression (E), concept (F), socialization with other

children (G), socialization with adults (H), training (I), and feeding (J) were compared between perinatal long QT syndrome (LQTS) patients with epilepsy (pink) and

nonperinatal LQTS cases (blue). KIDS ¼ Kinder Infant Development Scale.



272

developmental disorders (1,3,4,6), possibly becauseof the brief follow-up data in patients with rare phe-notypes associated with early mortality. In addition,these reports were mostly retrospective analysesfrom registry data or questionnaire surveys ratherthan prospective studies with clinical monitoring.NEUROLOGICAL FINDINGS. While the channelop-athy could lead directly to neurological dysfunction,an alternative possibility is that the neurologicaldisorder in perinatal LQTS arises secondary to hyp-oxic ischemic injury from perinatal arrhythmias.However, the clinical manifestations of the patientsin the present study differed from that of the patientswith intrapartum hypoxic ischemia. The main symp-tom of the patients with intrapartum hypoxic

ischemia is cerebral palsy, and learning difficulties inthese patients generally occur in conjunction with CPassociated with severe motor disability and extensivebrain damage observed by cerebral imaging (24). Inthis study, none of perinatal LQTS patients withneurological disorders had cerebral palsy and or anyremarkable findings in the cerebral imaging. MRI isthe most sensitive and specific imaging modality forexamining infants with hypoxic-ischemic brain in-juries (25). Also, cerebral CT can reveal the atrophicchanges of the brain in the chronic phase of hypoxic-ischemic encephalopathy, but it is hard to detectsmall brain damage (25). In the present study, at least3 patients were confirmed to have no findings ofhypoxic ischemic brain injury by MRI, and another

TABLE 3 Neurological Findings in 8 Perinatal LQTS Patients With Neurological Comorbidities

Patient #LQTType

CerebralPalsy

EpilepticSeizure

DevelopmentalDisorder

Age at theOnset ofEpilepticSeizures

AntiepilepticDrugs at the

Last Follow-Up

Age at theTime of the

EEGEEG

Localization

Age at theTime of theCerebralImaging

CerebralImages

2 LQT2 - þ þ 1.6 yrs Clonazedpam,Gabapentin

2.0, 3.6, 4.6 yrs No apparentparoxysmaldischarge

6.6 yrs CT; unremarkable

3 LQT3 - þ þ 0.4 yrs Topiramate 1.7 yrs Bilateral frontal 0.7 yrs MRI;unremarkable

4 LQT3 - þ - 2.5 yrs Levetiracetam 4.4 yrs Left occipital 4.5 yrs MRI;unremarkable

5 LQT2 - þ þ 54 days Zonisamide 54 days Bilateral frontal 0.1, 0.3 yrs CT; unremarkable

6 LQT2 - þ þ 0.7 yrs None 0.7 yrs Bilateral frontal 0.6, 0.7 yrs CT; unremarkable

22* LQT3 - þ þ 4 days Valproic acid,Clobazam

5 days Centrotemporal 5 days MRI;unremarkable

23* LQT3 N/A þ N/A 2 days Phenobarbital N/A N/A N/A N/A

24* LQT2 N/A þ N/A 7 days None 7 days No apparentparoxysmaldischarge

N/A N/A

*Patients #22, #23 and #24 were previously reported cases (11–13).

CT ¼ computed tomography; EEG ¼ electroencephalogram; LQTS ¼ long QT syndrome; MRI ¼ magnetic resonance imaging; N/A ¼ not available.

TABLE 2 Clinical Findings During Follow-Up in LQTS Patients Under 1 Year of Age

Patient # GenotypeAge at the

Last Follow-Up

Syncope orLife-ThreateningArrhythmias Afterthe Neonatal Period

Age at the Timeof Syncope or

Life-ThreateningArrhythmias Afterthe Neonatal Period

AADs atthe LastFollow-Up PMI

EpilepticSeizure

DevelopmentDisorder

KIDSType

Age atKIDS(yrs)

TotalDQ

1 LQT3 16.8 yrs - BB, Mex - - - N/A

2 LQT2 8.9 yrs TdP 6.6 yrs BB, Mex, Ver ICD (VVI) þ þ T 7.5 18

3 LQT3 8.3 yrs TdP, ACA 2, 4, 11 months, 1.9,2.0, 4.2, 4.8,5.4, 7.6 yrs

BB, Mex, Ver ICD(DDD)

þ þ T 6.7 17

4 LQT3 8.0 yrs SCD 8.0 years BB, Mex - þ - T 6.6 72

5 LQT2 2.5 yrs TdP 48 days BB, Mex ICD(DDD)

þ þ T 1.3 69

6 LQT2 1.0 yrs VT 4 months BB, Mex PM (VVI) þ þ T 1.0 67

7 LQT1 16.6 yrs - BB - - - N/A

8 LQT3 15.1 yrs syncope 13.5 yrs BB, Mex, Ver - - - N/A

9 LQT1 7.8 yrs - BB - - - C 6.6 73

10 LQT2 7.1 yrs - BB - - - C 5.8 106

11 LQT1 6.3 yrs - BB - - - C 4.9 102

12 LQT2 6.2 yrs - - - - - C 4.9 102

13 N/A 5.6 yrs - - - - - C 4.4 100

14 LQT7 3.8 yrs - - - - - N/A

15 LQT1 3.4 yrs - - - - - B 2.9 91

16 LQT7 2.5 yrs - - - - - N/A

17 LQT2 3.7 yrs - - - - - B 2.4 83

18 LQT1 2.7 yrs - - - - - B 1.4 129

19 LQT1 1.6 yrs - - - - - B 1.6 100

20 LQT2 1.0 yrs - - - - - N/A

21 LQT1 1.0 yrs - - - - - N/A

22* LQT3 5 yrs VT 45 days, 1.5 yrs BB ICD þ þ N/A

23* LQT3 1.3 yrs SCD 1.3 yrs BB, Mex - þ N/A N/A

24* LQT2 11 days N/A BB, Mex ICD(DDD)

þ N/A N/A

*Patients #22, #23, and #24 were previously reported cases (11–13).

AAD ¼ antiarrhythmic drug; ACA ¼ aborted cardiac arrest; DQ ¼ development quotients; ICD ¼ implantable cardioverter-defibrillator; KIDS ¼ Kinder Infant Development Scale; PMI ¼ pacemaker im-plantation; PM ¼ conventional pacemaker; SCD ¼ sudden cardiac death; VF ¼ ventricular fibrillation; other abbreviations as in Table 1.


273

FIGURE 5 Electroencephalograms From Perinatal LQTS Patients

(A to D) Representative electroencephalograms (EEGs) from Patients #3 (6.7 years of age), #4 (4.4 years of age), #5 (0.1 years of age), and #6 (0.7 years of age),

respectively. The red boxes indicate focal abnormal EEG changes. The EEG leads are as follows: FP, most frontal leads; F, frontal; T, temporal; C, central; P, parietal; O,

occipital; and A, ear. Leads with uneven numbers are EEG registrations from the left side and even numbers from the right side. LQTS ¼ long QT syndrome.



274

3 did not exhibit any atrophic changes of the brainobserved on CT. These finding support our hypothe-sis that neurological disorders in perinatal LQTS aremanifested as a neurological phenotype. Neverthe-less, still we could not completely deny the possibil-ity that these were caused by a hypoxic ischemicbrain injury, because childhood survivors of perinatalhypoxic ischemia was reported to be at risk forcognitive deficits even in the absence of functionalmotor disorders (24).

Another possibility is additional mutations at epi-lepsy susceptibility loci (26). While genetic testing forknown epilepsy-associated mutations was not per-formed, in our 5 patients no family members hadany neurological symptoms, and Patient #21 was re-ported to have no mutations of epilepsy susceptibilitygenes (11).

GENOTYPE-NEUROLOGICAL PHENOTYPE CORRELATION.

LQTS patients with arrhythmias during the perinatalperiod have predominantly LQT2 or LQT3 (3). Indeed,all 9 perinatal LQTS patients in the present study hadLQT2 or LQT3, 8 of which exhibited neurologicalcomorbidities.

A clinical association between LQTS and epilepsywas recently reported in older LQTS patients. EEGabnormalities were found in 71% of individuals withLQT1 or LQT2 (8). Further, the seizure incidence wassignificantly higher in LQT2 than LQT1 or LQT3 pa-tients (9). In a large cohort of Australian cases ofsudden unexpected death in epilepsy, genetic anal-yses revealed 6 nonsynonymous variants in KCNH2and SCN5A among 68 patients (10).

KCNH2 and SCN5A are expressed not only in theheart, but also in brain. A correlation between

FIGURE 6 Locations of the Gene Mutations in 8 Perinatal LQTS Patients With

Neurological Comorbidities

The upper and lower figures show the predicted topology of the Kv11.1 cardiac potassium

channel a-subunit and the Nav1.5 cardiac sodium channel a-subunit, respectively. The pink

solid circles indicate the mutations in patients with perinatal long QT syndrome (LQTS)

with epilepsy and/or developmental disorders from our institution. The blue solid circle

indicates the mutation in a previously reported case of perinatal LQTS and neurological

seizures.


275

mutations in these genes and neurological pheno-types has been proposed but there have been nomolecular investigations. LQT2 is caused by loss-of-function mutations in KCNH2, encoding the a-sub-unit of the Kv11.1 potassium channel that conductsthe IKr current (27). Expression of KCNH2 transcriptshave been detected within hippocampal astrocytes,cerebellar Purkinje cells, and vestibular nucleusneurons (28). These IKr currents are important forspatial buffering of extracellular potassium ions byastrocytes during high neuronal activity. Kv11.1 mu-tations could affect the potassium ion bufferingproperties of astrocytes, leading to epilepsy (9,28).Alternatively, LQT3 is caused by mutations in theNav1.5 sodium channel a-subunit gene SCN5A, whichincrease the persistent inward sodium current (27).SCN5A expression has been detected in the rat limbicforebrain (29). Persistent depolarization by abnor-mally prolonged sodium currents in limbic cortexneurons due to SCA5A mutations would elicitepileptiform bursting, synchronous network activa-tion, and seizures (11,29).

Among 7 mutations in 8 perinatal LQTS patientswith neurological disorders, T613M in KCNH2, andR1623Q and G1631D in SCN5A were reported as mu-tations in life-threatening perinatal LQTS(4,15,20,23). Further, in 6 of 8 patients, the muta-tions were located in the transmembrane loop ofKCNH2 (T613M, T623I, S 624R) and the D4/S4segment (R1623Q, G1631D) of SCN5A. Mutations inthe transmembrane loop of KCNH2 are correlatedwith a severe LQTS cardiac phenotype (30), andmutations in the SCN5A D4/S4 segment, a compo-nent of the voltage-sensor important for activationand inactivation, are correlated with severe perinatalLQTS (15). Another 1 of the remaining 2 mutations,the P1332L mutation in the D3/S4-S5 linker, was alsocorrelated with a severe cardiac phenotype, but witha good response to mexiletine (22). Based on thesefindings, we speculated that the channelopathyassociated with the most severe cardiac phenotypealso conferred susceptibility to a “neurologicalphenotype,” such as epilepsy and/or developmentaldisorders.

STUDY LIMITATIONS. There were several limitationsto this study. First, the static analysis was not avail-able because of the small sample size. Second, 5perinatal LQTS patients with comorbid neurologicaldisorders were not examined by MRI because of de-vice implantations. Even when the findings of thepresent study are supported our hypothesis, still thepossibility that the neurological disorders were theresult of a perfusion injury due to hemodynamically

compromising arrhythmias could not be completelyexcluded. Third, functional assays were not availablefor the 3 KCNH2 mutations. Fourth, the EEG and KIDSwere performed at various ages. Finally, we did nottest for mutations in epilepsy susceptibility genes.Nevertheless, these findings strongly suggest thatcertain mutations associated with severe LQTS (withlife-threatening cardiac arrhythmias in the perinatalperiod) may also enhance the susceptibility toneurological disorders, such as epilepsy and/ordevelopmental disorders.

CONCLUSIONS

In this study of LQTS patients diagnosed in infancy,8 with perinatal arrhythmias, including 3 previouslyreported cases, exhibited a comorbid neurologicalphenotype. We found no evidence of hypoxicischemic brain injury in any of these patients. Inaddition, the total DQ scores on the KIDS wasrevealed to be low, 17 to 72 (median 67), in 5 epilepticperinatal LQTS. The mutations in the perinatal LQTSwith epilepsy cases were located in ion channel geneloci associated with a severe cardiac phenotype.Although we could not completely deny the

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE: Cur-

rent therapies have resulted in relatively favorable life

prognoses in perinatal LQTS. Based on our findings

that they have a high comorbidity of neurological

disorders, the improvement of their developmental

prognoses should be considered as the next step of

the medical treatment.

TRANSLATIONAL OUTLOOK: Further larger pro-

spective studies with a more detailed neurological

evaluation are needed to define the etiology of co-

morbid neurological disorders in perinatal LQTS.



276

possibility that the neurological disorders were theresult of a brain perfusion injury, our findings sug-gested that channel dysfunction leading to a mostsevere cardiac phenotype may also confer suscepti-bility to a neurological phenotype. Further study isneeded to define the etiology of the neuro-developmental anomalies in perinatal LQTS.

ACKNOWLEDGMENT The authors wish to expresstheir gratitude to Mr. John Martin for his assistance inpreparing the manuscript.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Aya Miyazaki, Department of Pediatric Cardiology,National Cerebral and Cardiovascular Center, 5-7-1Fujishirodai, Suita, Osaka 565-8565, Japan. E-mail:[email protected].

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KEY WORDS developmental disorder,epilepsy, perinatal LQTS

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