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SLC9A6-related developmental and epileptic encephalopathy with spike-and-wave activation in sleep: A case report
Journal of Genetic Medicine 2022;19:100-104
Published online December 31, 2022;  https://doi.org/10.5734/JGM.2022.19.2.100
© 2022 Korean Society of Medical Genetics and Genomics.

Hye Ri Bae1,‡ and Young Ok Kim1,2,*

1Department of Pediatrics, Chonnam National University Children’s Hospital, Gwangju, Korea
2Department of Pediatrics, Chonnam National University Medical School, Gwangju, Korea
Young Ok Kim, M.D., Ph.D. https://orcid.org/0000-0002-7873-1140
Department of Pediatrics, Chonnam National University Childrens’ Hospital, 42 Jebong-ro, Dong-gu, Gwangju 61469, Korea.
Tel: +82-62-220-6646, Fax: +82-62-222-6103, E-mail: ik052@jnu.ac.kr
Current affiliation: Department of Pediatrics, Chonnam National University Childrens’ Hospital, Gwangju, Korea
Received August 28, 2022; Revised September 29, 2022; Accepted October 17, 2022.
cc This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
The gene encoding solute carrier family 9 member 6 (SLC9A6) on Xq26.3 is associated with Christianson syndrome (CS) mimicking Angelman syndrome. In CS, developmental and epileptic encephalopathy (DEE) appears in about 20%, and DEE with spike-and-wave activation in sleep (SWAS) is reported only in several cases. A 10-year-old boy with DEE showed multidrug resistant focal seizures from 6 months of age. He had progressive microcephaly, regression, global developmental delay without speech, hyperkinesia, and truncal ataxia; he had a long thin face, esotropia, and happy demeanor. Brain magnetic resonance imaging demonstrated cerebellar atrophy. Electroencephalogram at 7.5 years of age showed nearly continuous diffuse paroxysms in slow wave sleep. The seizures were responsive to corticosteroids for a while. Trio whole exome sequencing exhibited a likely pathogenic variant of SLC9A6 in the proband and his asymptomatic mother: c.1194dup (p.Leu399AlafsTer12). This is a rare case report of CS with DEE-SWAS in a Korean patient.
Keywords : Status epilepticus, Growth and development, Child, Genes, Syndrome.
Introduction

Developmental and epileptic encephalopathy (DEE) or EE with spike-wave-activation in sleep (SWAS) includes heterogeneous groups of epilepsy showing electrical status epilepticus during slow-wave sleep (ESES): EE with continuous spike-and-wave in sleep, atypical benign partial epilepsy (pseudo-Lennox syndrome), and Landau-Kleffner syndrome [1-5]. In DEE-SWAS, a nearly constant slow spike-and-wave pattern in 1.5-2 Hz is observed in non-rapid eye movement (NREM) sleep, classically occupying >85%, but is improved on awakening or in REM sleep [1,2].

The gene of solute carrier family 9 member 6 (SLC9A6), located on Xq26.3, encodes isoform 6 of the sodium/hydrogen exchanger superfamily (NHE6) abundant in the human brain [6-9]. SLC9A6 maintains cellular polarity in pre- or post-synaptic neurons and astrocytes and regulates endosomal trafficking [6-9]. The mutations of SLC9A6 leading to non-functional NHE6 seem to disturb synapse development and plasticity [6-9]. Male patients with SLC9A6 mutations present the X-linked severe neurodevelopmental syndrome of Christianson syndrome (CS) mimicking Angelman syndrome [6-10]. Some females with heterozygous variants of SLC9A6 are asymptomatic, but others have mild to moderate intellectual disability or behavioral problems [9,11].

Patients with CS have severe global developmental delay without speech, progressive or acquired microcephaly, craniofacial dysmorphism, progressive cerebellar atrophy, epilepsy, ataxia, and ophthalmoplegia [7-13]. Epilepsy is reported in most patients with CS, and about 20% belong to DEE [8,14-17]. Studies show SLC9A6 mutations in some patients with DEE-SWAS who were supposed to have CS [5,14-18]. Here, we report a non-verbal male child with DEE-SWAS who had acquired microcephaly, progressive cerebellar atrophy, mild facial dysmorphism, hyperkinesia, and ataxia. This rare case with the features of CS and DEE-SWAS had a novel frameshift mutation of SLC9A6.

This study was approved by the Human Research Ethics Committee of the Chonnam National University Hospital (IRB no. CNUH-2017-167). The Chonnam National University Hospital Biomedical Research Institute Biobank provided the biospecimens after approval from the review board. Informed consent was obtained from the proxy of the patient.

Case

A 6-month-old boy first visited our hospital for recurrent tonic deviation of his head and eyes with drooling and cyanosis, with no awareness. He had a height of 70.5 cm (50-75 percentile) and a weight of 8.21 kg (25-50 percentile) with a 41.5 cm-sized head (10 percentile). His development was normal. Brain magnetic resonance imaging (MRI) showed mild external hydrocephalus in both temporal regions. The electroencephalogram (EEG) showed no abnormality. The patient was born at a gestational age of 39 weeks after an uneventful pregnancy, weighing 2.83 kg to unrelated healthy parents. In his family, his elder sister had febrile convulsions, and each cousin of his mother and father had epileptic seizures. However, no developmental disorders were reported.

After one year of age, the patient showed flattening or regression in development and mild hypotonia. At 2 years of age, he could start to walk alone. However, he had no problems in feeding during infancy and early childhood. After one and a half years, he was diagnosed with DEE due to 1) multi-drug resistant focal tonic or tonic-clonic seizures even on carbamazepine, levetiracetam, and valproic acid; 2) progressive developmental problems; 3) focal epileptiform discharges with progressively disorganized and slow background activities. Between 4 and 5 years of age, he was transiently seizure-free after add-on therapy with topiramate.

While growing up, he had a long thin face, esotropia, happy demeanor, and progressive microcephaly. He had truncal ataxia and showed hyperkinetic movements intermittently. Brain MRI at 5 years and 5 months revealed diffuse cerebellar atrophy (Fig. 1). The intelligence quotient at 5 years and 10 months of age assessed using the fourth edition of the Korean Wechsler Preschool and Primary Scale of Intelligence, Bender-Gestalt test, House-Person-Tree test, and Social Maturation Scale, was around 30, which was suggestive of severe intellectual disability.

After 6 years, his focal seizures increased. He stared into space with his stiff right arm for a while (<5 minutes). The patient had focal or bilateral, clonic or tonic-clonic seizures during sleep. Clonazepam was added, but it was not so effective. At 7 and a half years, EEG during sleep showed nearly continuous and synchronous bifrontal or frontally-dominant generalized spikes/sharps and slow waves (Fig. 2). These continuous diffuse paroxysms occupied more than 85% of slow wave sleep. Failure to thrive and microcephaly were apparent at that time: 112.3 cm height, 17.0 kg weight, and 49.0 cm head circumference (<3 percentile in all). Prednisolone treatment for about 6 months ameliorated his seizures and EEGs. However, discontinuation of prednisolone led to recurrent clonic seizures. At 10 years and 7 months, he still had intermittent seizures, despite an additional trial of lacosamide and perampanel.

The blood samples were collected from the proband and his parents. Whole exome sequencing (WES) in trio was performed using the TruSeq Exome Kit (Illumina Inc., San Diego, CA, USA) on the HiSeq2000 platform (Illumina Inc.). WES revealed a novel variant in the proband and his mother: c.1194dup (p.Leu399AlafsTer12) on exon 10 of SLC9A6 (NM_006359.3). The results in trio were verified using Sanger sequencing (Fig. 3).

Discussion

Seizures in DEE-SWAS usually start early childhood (range, 2-12 years of age; peak, 4-5 years) accompanied by new onset or worsening cognitive and behavioral problems [1-3]. Focal or bilateral tonic-clonic seizures precede the ESES pattern in most patients with DE-SWAS, which are usually multi-drug resistant [1-3]. Improvement of the SAWS pattern is observed in adolescence, with normalized sleep architecture in addition to neuropsychiatric improvement [1,2]. Corticosteroid treatment for at least 6 months is preferred by most clinicians, as it seems to improve the ESES pattern and cognitive outcomes [3]. In addition, clobazam is another effective drug [3]. Except for SLC9A6, several genes are reported in DEE-SWAS: non-syndromic genes (GRIN2A, SCN2A, KCNQ2, KCNA2, CNKSR2, SLC6A1, and KCNB1), and syndromic genes, such as ATN1 (reported in dentatorubro-pallidoluysian atrophy), SRPX2 (in familial encephalopathy with neuroserpin inclusion bodies), and OPA3 (in Costeff syndrome) [4,5].

Male patients with CS and SLC9A6 mutations have similar clinical phenotypes to Angelman syndrome, as they have a psychomotor delay with speech deficits, happy demeanor with strabismus, acquired microcephaly, ataxic gait, hyperkinetic movements, seizures, autistic behaviors, sleep disturbance, and poor weight gain [7-13,17]. CS shows severe intellectual disability and poor weight gain (unlike AS) [7-10,17]. Although children with CS also have a happy demeanor, they have a long thin face with a prominent jaw, which is different from AS [7,17]. Studies show motor regression, progressive cerebellar atrophy, and a short life span in CS alone [7-13,17]. Cerebellar atrophy develops in 60% of CS, supposedly due to the loss of Purkinje cells [8,13]. DEE-SWAS, previously called “ESES,” based on its EEG pattern, is reported only in CS, not in AS [17].

Seizures in CS that usually begin before 3 years of age include infantile spasms and bilateral or focal tonic/tonic-clonic, myoclonic, atonic, and absence seizures in type [8,16,17]. EEGs from CS patients are mostly abnormal, showing epileptiform discharges (e.g., generalized or focal/multifocal spike-waves, hypsarrhythmia, and bilateral synchronous spike-waves patterns) in addition to the abnormal background (diffuse slowing without normal sleep architectures) [8,16-18]. Drug response to seizures varies from multi-drug resistance to relatively good with seizure freedom for more than one year [8]. Epilepsy syndromes reported in CS patients are mostly DEE, including infantile epileptic spasms syndrome, Lennox-gastaut syndrome, DEE-SWAS, and unclassified DEE [8,14-18]. In Korea, a de novo splicing mutation (c.316_325+28del) of SLC9A6 (NM_006359.2) was first reported in 2018 from a patient with unclassified early-onset epilepsy in infancy or early childhood (<3 years of age) [19]. The pathogenic variant was revealed using targeted gene sequencing covering 172 candidate genes [19]. As this panel was unavailable in our clinic, trio WES was used in our family.

DEE-SWAS in CS has been reported in less than 10 cases, of which, half the patients present an ESES pattern after 6 years of age (range, 6-8 years) [5,14-18]. In our case, the ESES pattern appeared at 7.5 years of age, 1.5 years after his focal motor seizures increased. Although a focal seizure was the main phenotype in our report, generalized or bilateral tonic-clonic seizures were more frequently observed in previous reports [5,14-18]. Cerebellar atrophy, noted in our patient after 5 years, was found in two cases after 6 years of age [14,16]. Although most seizures observed in CS and DEE-SWAS are multidrug-resistant (as in our proband), felbamate and levetiracetam were effective in one previous patient for each [17,18]. However, there is insufficient data on corticosteroid treatment, which was the most effective in our patient [5,14-18].

There is insufficient data on genotype and phenotype correlation in patients with CS and SLC9A6 mutations. The novel variant of c.1194dup (p.Leu399AlafsTer12) (in this case) was located in exon 10 of the total 16 exons of SLC9A6 (NM_006359.3). The region from exons 9 to 14 is the site encoding the transmembrane ion translocation domain interacting with the angiotensin II type 2 receptor (AGTR2) [14]. AGTR2 is associated with intellectual disability and epilepsy with unknown mechanisms [14]. More than 50% of SLC9A6 mutations in CS are from AGTR2 interacting region [14].

The clinical features in our male patient are consistent with CS features, such as global developmental delay without speech, regression, progressive microcephaly, acquired cerebellar atrophy, mild facial dysmorphism, strabismus, hyperkinesia, ataxia, and failure to thrive in addition to drug-resistant epilepsy. Results of EEGs after 7 years showed nearly continuous bilateral synchronous paroxysms in NREM sleep, compatible with DEE-SWAS. Although clonazepam was not so effective, corticosteroid treatment improved either of his seizures and the EEG pattern for a while. This rare case of CS with DEE-SWAS in a Korean patient had a novel frameshift mutation of SLC9A6.

Conflict of interest

The authors declare that they do not have any conflicts of interest.

Acknowledgements

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Republic of Korea (grant no. NRF-2017R1D1A3A03000532).

Authors’ Contributions

Conception and design: KYO. Acquisition of data: KYO, BHR. Analysis and interpretation of data: KYO. Drafting the article: KYO, BHR. Critical revision of the article: KYO. Final approval of the version to be published: all authors.

Figures
Fig. 1. Brain magnetic resonance imaging at 5 years and 5 months of age shows cerebellar atrophy in hemispheres (A, in axial T2-weighted image) and vermis (B, midsagittal T1-weighted image).
Fig. 2. Electroencephalogram during sleep at 7 years and 6 months of age shows continuous synchronous bifrontal or frontally-dominant generalized spikes/sharps and slow waves.
Fig. 3. Electropherogram of direct sequencing of SLC9A6 (NM_006359.3) in trio shows a frameshift mutation (red arrowhead) of c.1194dup (p.Leu399AlafsTer12) in the proband and his mother, but a wild-type in his father (black arrowhead).
References
  1. Specchio N, Wirrell EC, Scheffer IE, Nabbout R, Riney K, Samia P, et al. International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: position paper by the ILAE Task Force on Nosology and Definitions. Epilepsia 2022;63:1398-442.
    Pubmed CrossRef
  2. Gardella E, Cantalupo G, Larsson PG, Fontana E, Bernardina BD, Rubboli G, et al. EEG features in encephalopathy related to status epilepticus during slow sleep. Epileptic Disord 2019;21(S1):22-30.
  3. van den Munckhof B, Arzimanoglou A, Perucca E, van Teeseling HC, Leijten FSS, Braun KPJ, et al; RESCUE ESES Study Group. Corticosteroids versus clobazam in epileptic encephalopathy with ESES: a European multicentre randomised controlled clinical trial (RESCUE ESES*). Trials 2020;21:957.
    Pubmed KoreaMed CrossRef
  4. Kessi M, Peng J, Yang L, Xiong J, Duan H, Pang N, et al. Genetic etiologies of the electrical status epilepticus during slow wave sleep: systematic review. BMC Genet 2018;19:40.
    Pubmed KoreaMed CrossRef
  5. Gong P, Xue J, Jiao X, Zhang Y, Yang Z. Genetic etiologies in developmental and/or epileptic encephalopathy with electrical status epilepticus during sleep: cohort study. Front Genet 2021;12:607965.
    Pubmed KoreaMed CrossRef
  6. Parsons MP, Raymond LA. Extrasynaptic NMDA receptor involvement in central nervous system disorders. Neuron 2014;82:279-93.
    Pubmed CrossRef
  7. Gilfillan GD, Selmer KK, Roxrud I, Smith R, Kyllerman M, Eiklid K, et al. SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome. Am J Hum Genet 2008;82:1003-10.
    Pubmed KoreaMed CrossRef
  8. Pescosolido MF, Stein DM, Schmidt M, El Achkar CM, Sabbagh M, Rogg JM, et al. Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome. Ann Neurol 2014;76:581-93.
    Pubmed KoreaMed CrossRef
  9. Masurel-Paulet A, Piton A, Chancenotte S, Redin C, Thauvin-Robinet C, Henrenger Y, et al. A new family with an SLC9A6 mutation expanding the phenotypic spectrum of Christianson syndrome. Am J Med Genet A 2016;170:2103-10.
    Pubmed CrossRef
  10. Tan WH, Bird LM, Thibert RL, Williams CA. If not Angelman, what is it? A review of Angelman-like syndromes. Am J Med Genet A 2014;164A:975-92.
    Pubmed CrossRef
  11. Sinajon P, Verbaan D, So J. The expanding phenotypic spectrum of female SLC9A6 mutation carriers: a case series and review of the literature. Hum Genet 2016;135:841-50.
    Pubmed CrossRef
  12. Padmanabha H, Saini AG, Sahu JK, Singhi P. Syndrome of X linked intellectual disability, epilepsy, progressive brain atrophy and large head associated with SLC9A6 mutation. BMJ Case Rep 2017;2017:bcr2017222050.
    Pubmed KoreaMed CrossRef
  13. Bosemani T, Zanni G, Hartman AL, Cohen R, Huisman TA, Bertini E, et al. Christianson syndrome: spectrum of neuroimaging findings. Neuropediatrics 2014;45:247-51.
    Pubmed CrossRef
  14. Zanni G, Barresi S, Cohen R, Specchio N, Basel-Vanagaite L, Valente EM, et al. A novel mutation in the endosomal Na+/H+ exchanger NHE6 (SLC9A6) causes Christianson syndrome with electrical status epilepticus during slow-wave sleep (ESES). Epilepsy Res 2014;108:811-5.
    Pubmed CrossRef
  15. Mathieu ML, de Bellescize J, Till M, Flurin V, Labalme A, Chatron N, et al. Electrical status epilepticus in sleep, a constitutive feature of Christianson syndrome? Eur J Paediatr Neurol 2018;22:1124-32.
    Pubmed CrossRef
  16. Ikeda A, Yamamoto A, Ichikawa K, Tsuyusaki Y, Tsuji M, Iai M, et al. Epilepsy in Christianson syndrome: two cases of Lennox-Gastaut syndrome and a review of literature. Epilepsy Behav Rep 2019;13:100349.
    Pubmed KoreaMed CrossRef
  17. Liu X, Xie L, Fang Z, Jiang L. Case report: novel SLC9A6 splicing variant in a Chinese boy with Christianson syndrome with electrical status epilepticus during sleep. Front Neurol 2022;12:796283.
    Pubmed KoreaMed CrossRef
  18. Coorg R, Weisenberg JL. Successful treatment of electrographic status epilepticus of sleep with felbamate in a patient with SLC9A6 mutation. Pediatr Neurol 2015;53:527-31.
    Pubmed CrossRef
  19. Rim JH, Kim SH, Hwang IS, Kwon SS, Kim J, Kim HW, et al. Efficient strategy for the molecular diagnosis of intractable early-onset epilepsy using targeted gene sequencing. BMC Med Genomics 2018;11:6.
    Pubmed KoreaMed CrossRef


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