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KCNMA1 mutation in children with paroxysmal dyskinesia and epilepsy: Case report and literature review

Abstract

Patients with KCNMA1 gene mutation present with paroxysmal dyskinesia and/or epilepsy. We describe a male with heterozygous mutation c.3158A>G, (p.N1053S) in KCNMA1 gene, displaying paroxysmal dyskinesia and moderate mental retardation. We also review 20 reported cases with KCNMA1 mutation. We summarize that there is clinical heterogeneity in these patients. The onset age of episodic events ranges from 20 days to 15 years old. 6/21 (29%) patients merely had epilepsy, 10/21(48%) patients had paroxysmal dyskinesia only, and 5/21 (24%) had both epilepsy and paroxysmal dyskinesia. Seizure types were various, including absence, generalized tonic–clonic seizures, and myoclonic seizures. Paroxysmal dyskinesia was nonkinesigenic, but can be induced by alcohol, fatigue or stress. Most patients had variable degrees of mental retardation. The clinical outlook for this condition is in general not good. Epilepsy or non-epileptic events were resistant in most patients. Most patients presented with mild to severe intellectual disability and developmental delay.

1Introduction

KCNMA1 gene encodes α-subunit of the large conductance calcium-sensitive potassium channel (Kca1.1) [1]. Kca1.1 has a wide distribution in central nervous system, especially in excitatory neurons of cortex and hippocampus. It plays important roles in regulating neuronal excitability [1–3]. In 2005, KCNMA1 gene was first reported as a pathogenic gene in a large family with autosomal dominant paroxysmal nonkinesigenic dyskinesia and generalized epilepsy [4]. Since then, several KCNMA1 gene mutations in twenty patients have been described [5, 6]. Here, to delineate the clinical characteristics of the disease caused by KCNMA1 gene mutation further, one patient with a de novo KCNMA1 gene mutation is described. Besides, the reports associated with diseases caused by KCNMA1 gene mutations are summarized.

2Case report

The 3.5-year-old boy is the first child of nonconsanguineous Chinese parents. Pregnancy was uneventful. He has a normal birth and an early development. Head circumference was 33 cm at birth. At 16 months old, he developed episodes of sudden weakness of lower limbs, occasionally accompanied by rolling his eyes, lasting one to ten seconds. It occurred 10–20 times per day, with higher frequency with fatigue or excitement. Symptoms were not trigged by starvation. Before coming to our hospital, he was treated with valproate (VPA) at 16 months old with no response. When oxcarbazepine (OXC) was added to his therapy, the frequency of episodic events increased. Consequently, OXC was stopped. At 3 years of age, lamotrigine (LTG) was added, but there was still no response. Then clonazepam (CLZ) was administrated, and the frequency of paroxysmal dyskinesia was reduced to 3–5 times per day, and the longest interval could be up to three weeks.

Development is moderately delayed. He could control his head at 3 months, sit independently at 6 months, walk alone at 2 years old and say single words at 3 years old. Head circumference was 48 cm at his age of 2 years and 11 months. There was no family history of epilepsy or dyskinesia with him.

Electroencephalogram (EEG) at age of 2 years and 11 months showed generalized spike wave complexes. Episodic events presented during the EEG test; there were no epileptic discharges simultaneously. MRI at age of 16 months revealed no anomalies. Lumbar puncture was performed so as to exclude GLUT1-deficiency syndrome. Routine CSF test was unremarkable. Glucose level of CSF (2.66 mmol/L, ref 2.5∼4.5 mmol/L) and serum (6.28 mmol/L, ref 3.9∼6.9 mmol/L) were normal.

A gene panel consisting of 380 genes (Additional files 1) related with epilepsy and/orparoxysmal dyskinesia was performed on the proband. In total, 34 variants (Additional file 2) were discovered, of which 32 variants were reported polymorphisms. Pathogenicity of one heterozygous variant in ACY1 gene was ruled out, as it is inherited as autosomal recessive pattern. Consequently, the mutation (c.3158A>G, p.N1053S) in KCNMA1 gene deserved most attention. PCR-Sanger sequencing was used to confirm the mutation and parental origin, which revealed de novo occurrence (Fig. 1). It was a known pathogenic mutation, which had been reported previously in a patient with paroxysmal dyskinesia and developmental delay [6]. The clinical information of patients with KCNMA1 mutation is summarized in Table 1.

Fig.1

Sequence chromatogram showing one base pair substitution in KCNMA1 gene (A) and conservation of the altered amino acid shown in the ClustalW alignments (B).

Sequence chromatogram showing one base pair substitution in KCNMA1 gene (A) and conservation of the altered amino acid shown in the ClustalW alignments (B).
Table 1

Clinical features of patients with KCNMA1 gene mutation

PatientsDu et al. [4]Zhang et al. [6]Tabarki et al. [5]Our study
Sex10 M, 6 FMMFFM
Age of onset6 mo- 15 y20 d7 mo8 mo8 mo16 mo
E and PD4 with E alone, 5 with E+PD, 7 with PD alonePDPDEEPD
Seizure type4 with Ab, 2 with Ab and GTCSNoNoMyoclonic seizures evolving to tonicand GTCSMyoclonic seizures evolving to tonicand GTCSNo
PDInvoluntary dystonic or choreiform movements of the mouth, tongue and extremities1) Sudden onset of asymmetric limbdystonic posture, sometimes with nystagmus and strabismus, lasted several minutes to half an hour, and occurring once a week initially to 2–7 times per day after 1 year.2) Sudden decrease in voluntary movement of limbs, with hypotonia and occasional esotropia and yawning, lasting as long as 1 hour, and occurringonce to twice a day.Paroxysmal dystonic postures, lasting several seconds to minutes, and occurring 3–5 times per day to once a week.NoNoSudden weakness of lower limbs, occasionally accompanied by rolling his eyes, and occurring 10–20 timesper day
TriggersAlcohol, fatigue and stressNoNoNoNoFatigue or agitation
DevelopmentNASevere delayMild delaySevere delaySevere delayModerate delay
EEGGeneralized spike wave complexes (the proband)NormalNormalLennox–Gastaut patternMild backgroundslowingGeneralized spike wave complexes
MRINANormalNormalCerebellar atrophyCerebellar atrophyNormal
TreatmentSeizure frequency was reduced from daily to monthly with VPA and LTG in the proband; seizures and PD partially responsive to CLZ in other two patientsNo response to OXC, VPA, LEVControlled by CLZControlled by VPAControlled by VPA, LEVAggravated by OXC; VPA, LTG were not effective; frequency of episodic events was decreased after CLZ was added.
Mutation (NM_1161352)c.1301A>G (heterozygous)c.2650G>A (heterozygous)c.3158A>G (heterozygous)c.2026dupT (homozygous)c.2026dupT (homozygous)c. 3158A>G (heterozygous)
AA changedD434GE884KN1053SY676Lfs*7Y676Lfs*7N1053S

M, male; F, female; mo, months; y, year; E, epilepsy; PD, paroxysmal dyskinesia; Ab, absence; GTCS, generalized tonic clonic seizures; NA, not available; OXC, oxcarbazepine; VPA, valproate; LEV, levetiracetam; CLZ, clonazepam; LTG, lamotrigine.

3Discussion

KCNMA1 gene, which is located at 10q22.3, encodes the alpha-subunit of the KCa1.1, consisting of seven transmembrane domains (S0–S6) at the N terminus, and an extensive C-terminal cytosolic domain which confers Ca2 + sensitivity to the channel. There are two putative high affinity Ca2 + binding sites, RCK domain and Ca2 + bowl, respectively [7, 8]. Kca1.1 has a wide distribution in central nervous system, and prominent expression is observed in excitatory neurons of cortex and hippocampus. It plays vital roles in driving action potential repolarization, mediating fast phase of AHP (after hyperpolarization potential), and regulating neurotransmitter release and dendritic excitability [1–3].

Since 2005, KCNMA1 gene has been associated with early onset epilepsy, paroxysmal dyskinesia and developmental delay [4]. To date, three publications with 21 patients (13 males and 8 females), have been found with KCNMA1 gene mutations, including two pedigrees (16 and 2 affected members, respectively) and three sporadic patients [4–6]. The age of onset ranged from 20 days after birth to 15 years old. Among the 18 patients with detailed clinical description, 33% (6/18) of patients had the onset of episodes within one year after birth, 55% (10/18) patients had symptoms between 2∼7 years old, and 17% (2/18) after age of 7 years.

The pathology associated with KCNMA1 mutations can manifest in patients as paroxysmal dyskinesia or epilepsy only, or both [4–6]. 10/21 (48%) had paroxysmal dyskinesia only, 6/21 (29%) had epilepsy only, 5/21 (24%) had both epilepsy and paroxysmal dyskinesia, including one patient who had paroxysmal dyskinesia within 6 months after birth and seizures attacks at age of 3 years, while the other four patients had epilepsy and paroxysmal dyskinesia simultaneously. Among 11 patients with epilepsy, 4 had absence seizure, 2 had absence seizures accompanied by GTCS (generalized tonic clonic seizures) occasionally, 2 had myoclonic seizures or myoclonic seizures evolving to tonicand GTCS, and 3 had epilepsy with no description about seizure types. Paroxysmal dyskinesia was nonkinesigenic, but in some patients it can be induced by alcohol, fatigue or stress. Patients presented different degrees of mental retardation. EEG abnormity was observed in patients with or without epilepsy, including generalized spike wave complexes, Lennox–Gastaut pattern, and mild background slowing.

There are not so many related reports on the treatments of patients with KCNMA1 mutations. In Zhang’s report, one patient with paroxysmal dyskinesia only was controlled by CLZ [6]. In Tabarki’s report, the seizure-free state was achieved in two patients with epilepsy only, by VPA and VPA combined with levetiracetam (LEV), respectively [5]. Three patients with both paroxysmal dyskinesia and epilepsy were partially responsive to antiepileptic drugs (Table 1) [4]. For our patient, OXC aggravated his paroxysmal events, while VPA and LTG had poor curative effective. He was partially responsive to CLZ, and the frequency of episodic events was reduced after CLZ was added. In vitro functional analysis revealed that gain of function of the BK channel leads to greater macroscopic potassium conductance, which results in more rapid repolarization of action potentials. Enhancing this repolarization leads to faster removal of inactivation of sodium channels, hence the neurons fire more frequently [5]. Consequently, considering previous reports and our study, sodium-channel blockers might be effective. Moreover, activation of inhibitory GABAB receptors by CLZ is effective as well.

The missense mutation (c.3158A>G, p.N1053S) identified in this study was previously mentioned by Zhang et al. [6]. Both patients merely presented with paroxysmal dyskinesia and developmental delay, while without epilepsy. But phenotype of patient in this study was a bit more severe (Table 1), which indicated the clinical heterogeneity of disorders caused by KCNMA1 mutations.

Including this study, four mutations of KCNMA1 were identified to be associated with epilepsy and/or paroxysmal dyskinesia. The majority of patients were heterozygous and the mutations were inherited as autosomal dominant. But patients with homozygous mutation in KCNMA1 gene were also reported, while the mutation was inherited from their heterozygous parents. Those parents were second cousins and had normal phenotype (Table 1) [5, 6]. All the mutations were located in the C-terminal of Kca1.1 (Fig. 2). D434G was located in the RCK domain, and the functional analysis revealed that the D434G speeds up channel activation and enhances Ca2 + sensitivity, suggesting a gain-of-function of Kca1.1 channel [4]. The functional impact of other mutations on BK channel activity remains unknown. The mutated N1053S identified in this study was located nearby S10, which might change the spatial conformation of the channel [6]. On the other hand, previous reports also indicated loss-of-function of KCNMA1 gene was pathogenic. Besides, Tabarki et al. described two siblings with homozygous truncated mutation in KCNMA1 gene, which presented with epilepsy and severe psychomotor retardation [5]. Kcnma1 homozygous knockout mice displayed severe motor dysfunction and cerebellar ataxia [9]. Taking all the above studies together, we could conclude that both gain-of-function and loss-of-function of Kca1.1 were responsible for epilepsy and movement disorders.

Fig.2

Simplified schematic of the large-conductance Ca2 +-activated K+ channel and KCNMA1mutations ever identified.

Simplified schematic of the large-conductance Ca2 +-activated K+ channel and KCNMA1mutations ever identified.

Our report summarized the mutation spectrum of KCNMA1and phenotypic profile of KCNMA1 gene related disorders. More mutations reports and function researches in the future might help to figure out the structure-function relationships of Kca1.1 and the mechanisms of its pathogenesis in neurological disorders.

Appendices

Additional file 1.

380 genes in the panel related with epilepsy accompanied with/without paroxysmal dyskinesia

ABCC8CEP152EIF2B1HPMTHFRPPT1SLC9A6
ACADSBCHI3L1EIF2B2HRASNDNPRICKLE1SLC9A9
ACTBCHRNA2EIF2B3HSD17B10NDUFA1PRICKLE2SNIP1
ACY1CHRNA3EIF2B4HSD17B4NDUFA11PROCSNRPN
ADKCHRNA4EIF2B5HTR2ANDUFAF1PRODHSOBP
ADSLCHRNA5ELP4HTTNDUFAF2PRRT2SPAST
AFG3L2CHRNA7EMX2ICCANDUFAF3PTPN22SPTAN1
AKT1CHRNB2EPB41L1IDH2NDUFAF4PUS1SPTLC2
ALDH7A1CLCN2EPM2AIDSNDUFB3QDPRSRPX2
ALG1CLN3ERBB4IER3IP1NDUFS1RAB39BSTRADA
ALG11CLN5ERLIN2IFNGNDUFS2RANBP2STS
ALG3CLN6EVCIL6NDUFS4RELNSTXBP1
AMACRCLN8FADDINSNDUFS6ROGDISUOX
AMTCNTNAP2FAM123BKCNA1NDUFV1RPIASYN1
APOL2COG7FASTKD2KCNJ10NDUFV2RTN4RSYN2
APOL4COH1FCGR2BKCNJ11NEU1RYR1SYNGAP1
APPCOMTFKTNKCNMA1NF1SCARB2SYP
ARG1COX6B1FLNAKCNQ1NHLRC1SCN1ATBC1D24
ARHGAP31CPA6FOLR1KCNQ2NHSSCN1BTBP
ARHGEF9CPS1FOXG1KCNQ3NOTCH3SCN2ATCF4
ARSACSTBFOXRED1KCTD7NR3C1SCN8ATMEM165
ARSECTSAGABRA1KDM5CNRXN1SCN9ATPP1
ARXCTSDGABRB3KIF11NTNG1SCZD1TREM2
ASAH1CYB5R3GABRDKIF1ANUBPLSCZD11TREX1
ATICD2HGDHGABRG2KRASOFD1SCZD12TSC1
ATN1DAOGAMTL2HGDHOPHN1SCZD2TSC2
ATP1A2DAOAGBALBRPAFAH1B1SCZD3TSEN2
ATP2A2DBHGCKLGI1PAHSCZD5TSEN34
ATP6AP2DCXGCSHLIASPAK3SCZD6TSEN54
ATRXDHFRGLB1LMX1BPANK2SCZD7TUBGCP6
ATXN10DISC1GLDCMAGI1PCDH19SCZD8TYROBP
BANK1DISC2GLRA1MAGI2PDHA1SERPINI1UBE3A
BOLA3DMPKGOSR2MAN1B1PGK1SETBP1XK
BRP44LDNAJC5GPHNMANBAPHF6SGCEZDHHC15
C10orf2DNASE1GPR48MAPK10PHGDHSHHZEB2
C12orf62DOCK6GPR98MCCC2PIGLSIAT9ZFYVE26
C20orf7DPYDGRIN1MCPH1PIGVSIX3ZNF41
C2orf64DRD2GRIN2AMECP2PLA2G6SLC17A5STK11
C4ADRD3GSSMEF2CPLCB1SLC19A3HCN2
CACNA1HDTNBP1GYS1MFSD8PLP1SLC20A2SCN3A
CACNB4DXS423EHAX1MLC1PNKPSLC25A15GABRA6
CACNG2EBPHFEMOCS1PNPOSLC25A22CAPS
CASRECM1HLA-DQA1MOCS2POLGSLC26A4SYNE1
CCM1EFHC1HLA-DQB1MOCS3POMGNT1SLC2A1VLDLR
CDKL5EHMT1HNF1BMR1PPOXSLC46A1VPS13
ABCB7ATP2B3AXKFMR1NOP56POLG1TBP
AFG3L2ATPXBEANFXNNPHP1PPP2R2BTDP1
AHI1ATTPC10orf2ITPR1PANR2PRKCGTGM6
APTXATXN1CA8JPH3PDYNRPGRIP1LTMEM216
ARL13BATXN10CABC1KCNA1PEX1SACSTTBK2
ARXATXN2CACNA1AKCNC3PEX2SETXTTBK2
ATCAYATXN3CACNB4KCNJ10PEX26SIL1TTPA
ATMATXN7CC2D2AMPZPLEKHG4SLC1A3ADH3
ATN1ATXN8OSFGF14MRE11APMP22SPTBN2ATP13A2
AAOPDADH1C

Additional file 2.

Variants identified by NGS panel

GeneTranscriptBase changeAA changeHeterohomodbSNPMAFSIFTPolyPhen-2
ACY1NM_001198898.1c.584-9C>THeteroUncertain Significance
APOL2NM_145637.2c.733A>Gp.V245VHomors1327600Benign
ATP1A2NM_000702.3c.1704C>Tp.F568FHeterors178467140.0278Benign
CASRNM_000388.3c.2244G>Cp.P758PHomors20364000.0272Benign
CNTNAP2NM_014141.5c.3716-6C>GHeterors77025884Likely Benign
CPS1NM_001122633.2c.13_14insTCTp.I5_K6insFHeterors38350470.477Benign
CPS1NM_001122633.2c.204C>Tp.G68GHeterors5298365560.0002Uncertain Significance
CPS1NM_001122633.2c.1048A>Gp.T344AHeterors1047883BenignDamaging
DNAJC5NM_025219.2c.144C>Tp.P48PHeterors1139870770.0278Benign
DTNBP1NM_001271667.1c.268+7281C>AHomors69264010.0281Benign
HTTNM_002111.7c.7182A>Cp.L2394LHomors28577900.0152Benign
KCNA1NM_000217.2c.1296C>Gp.S432SHeterors760666810.025Benign
KCNQ1NM_000218.2c.54C>Tp.I145IHeterors18001700.009Likely Benign
KRASNM_004985.4c.451-5617G>Ap.R161RHomors43622220.0024Benign
LGI1NM_001308275.1c.657T>Cp.F171FHomors11118200.0226Benign
MCPH1NM_024596.3c.1175A>Gp.D344GHomors25155690.0056BenignTolerated
NDUFAF3NM_199070.1c.166+8G>AHeterors5548622070.0002Uncertain Significance
NHSNM_001291868.1c.566-12_566-11insTHomors5901624Benign
NR3C1NM_001018074.1c.1764C>Tp.H491HHeterors61940.0198Benign
PDHA1NM_001173456.1c.958A>Cp.M251LHomors22291370.0495BenignTolerated
PRICKLE2NM_198859.3c.816T>Cp.D272DHomors276730.0162Benign
PRRT2NM_145239.2c.751T>Cp.L251LHomors111505730.0082Benign
RANBP2NM_006267.4c.8253G>Ap.E2751EHomors8265800.0128Benign
RELNNM_173054.2c.3060C>Tp.D1020DHeterors1158861700.0022Uncertain Significance
RELNNM_173054.2c.1888A>Cp.S630RHeterors1157342140.0172Likely BenignDamaging
SLC46A1NM_080669.5c.4417delAHomors58198440Benign
SPTAN1NM_001195532.1c.1330G>Ap.V444IHeterors773586500.0176Likely BenignTolerated
SPTAN1NM_001195532.1c.5085A>Gp.L1690LHomors14155680.0152Benign
TCF4NM_001243226.2c.28G>Cp.P10PHomors6113260.0032Benign
TUBGCP6NM_020461.3c.4861G>Cp.L1621LHomors48388640.0012Benign
TYROBPNM_198125.2c.130G>Tp.V44LHeterors777823210.0232BenignActivating
ZFYVE26NM_015346.3c.6405G>Ap.L2135LHeterors763274470.017Benign
ZFYVE26NM_015346.3c.453C>Tp.S151SHeterors753911130.016Benign
KCNMA1NM_1161352c.3158A>Gp.N1053SHeteroPathogenicDamaging

Acknowledgments

We truly thank and appreciate the patients and their parents for their cooperation in this study. This study was financially supported by 985 Peking University and Clinical HospitalCooperation Project (2013-1-06), and Technology innovation talents special fund of Harbin Science and Technology Bureau (2016RAXYJ089).

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