Pediatric Neurology 53 (2015) 527e531
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observations
Successful Treatment of Electrographic Status Epilepticus of Sleep With Felbamate in a Patient With SLC9A6 Mutation Rohini Coorg MD a, b, c,1, Judith L.Z. Weisenberg MD a, * a
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri Department of Pediatrics, Baylor College of Medicine, Houston, Texas c Department of Neurology, Baylor College of Medicine, Houston, Texas b
abstract BACKGROUND: Mutations of SLC9A6 may cause an X-linked clinical syndrome first described by Christianson in 1999
in which affected males exhibited profound intellectual disability, autism, drug-resistant epilepsy, ophthalmoplegia, mild craniofacial dysmorphism, microcephaly, and ataxia. METHODS: We describe a child with an SLC9A6 mutation and an electroencephalographic pattern consistent with electrographic status epilepticus of sleep. RESULTS: Our patient’s electrographic status epilepticus of sleep resolved after treatment with felbamate. Following treatment, he remained seizure-free but did not make significant or lasting gains in language. CONCLUSION: Our report extends the clinical epilepsy phenotype in children with SLC9A6 mutations to include electrographic status epilepticus of sleep. In addition, felbamate was an effective treatment for electrographic status epilepticus of sleep in our patient. Keywords: epilepsy, SLC9A6, ESES, felbamate, Christianson syndrome
Pediatr Neurol 2015; 53: 527-531 Ó 2015 Elsevier Inc. All rights reserved.
Introduction
Mutations in SLC9A6 may cause an X-linked clinical syndrome first described by Christianson in 1999 in which affected males exhibited profound intellectual disability, autism, epilepsy, ophthalmoplegia, mild craniofacial dysmorphisms, microcephaly, and ataxia.1 Some carrier females had mild intellectual disability.1 Subsequent reports expanded the phenotype in males to include acquired microcephaly and a happy demeanor suggestive of Angelman syndrome,2 initial hypotonia with development of spasticity,3 retinitis pigmentosum,4 stereotyped, repetitive hand movements, and dystonia.5 Seizures typically begin within the first two years of life, are medically refractory, and have multiple semiologies: Article History: Received April 24, 2015; Accepted in final form July 14, 2015 * Communications should be addressed to: Dr. Weisenberg; Department of Neurology; Box 8111; Washington University School of Medicine; 660 South Euclid Avenue; St. Louis, MO 63110. E-mail addresses: [email protected], [email protected] 1
Present address: Department of Pediatrics and Neurology; 6701 Fannin; Suite 1250; Houston, TX 77030. 0887-8994/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2015.07.007
generalized tonic-clonic1-3 with and without photosensitivity,1 atypical absence,3 and focal with complex motor and autonomic features.2 The interictal electroencephalograph (EEG) may be normal, have focal epileptiform discharges,1 or contain abnormalities consistent with a diagnosis of LennoxeGastaut syndrome.3 Prominent alpha frequency activity or a fast posterior dominant rhythm of 10-14 Hz may occur.2,3 To date, children with an SLC9A6 mutation and an EEG pattern consistent with electrographic status epilepticus of sleep (ESES) or the clinical syndrome of continuous spike-waves during sleep (CSWS) have not been described in the literature. Magnetic resonance imaging of the brain may reveal cerebellar atrophy.1,2 Neuropathology of two patients who died after the fourth decade revealed widespread neuronal and glial cell tau deposition with tangles in the basal ganglia, entorhinal cortex, and dentate nucleus.5 Diseasecausing mutations in SLC9A6 result in abnormal function of an endosomal sodium-proton exchanger6 that may be amenable to targeted treatment.7 Here, we describe a child with an SLC9A6 mutation who developed an EEG pattern consistent with ESES that resolved after treatment with felbamate.
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R. Coorg, J.L.Z. Weisenberg / Pediatric Neurology 53 (2015) 527e531
Patient Description Our patient presented at 8 years of age with microcephaly, autism, global developmental delay, and epilepsy. He was born at term via spontaneous vaginal delivery after a normal pregnancy without complications. His birth weight, length, and head circumference were reportedly within normal percentiles and he had a normal reported newborn course. His seizures began at one year of life and consisted of abrupt activity cessation and apnea with unilateral (either right or left side) arm extension. At this time, acquired microcephaly was documented with height and weight in the tenth percentile and head circumference below the first percentile. His family elected not to start an antiepileptic medication at the onset. Between ages 1 and 4, seizures occurred every six months. All seizures lasted 45 seconds or less and were accompanied by postictal lethargy. At four years of age, he had an episode of status epilepticus arising from sleep with a seizure described as whole body stiffening and jerking. This resolved after approximately one hour and after multiple doses of lorazepam and fosphenytoin. Carbamazepine was initiated but he continued to have seizures occurring biannually over the next two years. At eight years of age, he was transitioned to levetiracetam, which was discontinued after three months because of intolerable behavioral side effects. Valproate was then initiated and increased to 21 mg/kg/day. He had experienced global developmental delay since infancy without motor or language regression. He gained appropriate motor milestones until nine months of age and eventually walked at 18 months of age. He ran at five years of age. He was right-handed. He began speaking at three years of age and was unable to speak sentences. By eight years, he had a four- to five-word vocabulary at any given time but did not retain words. He had limited use of a communication device. His family history was significant for two paternal great-uncles with childhood-onset epilepsy of unknown etiology. He had normal hearing and vision testing. In addition to seizures, he had insomnia and behavioral difficulties before five years of age. Physical examination at eight years of life revealed height in the third percentile, weight in the twenty-fifth percentile, and head circumference below the first percentile. His general physical examination was otherwise normal. He had no dysmorphic facial features. On neurological examination, he had minimal eye contact and remained hyperfocused on a video game. He said “hello” after prompting but was otherwise nonverbal. Motor examination was significant for diffuse hypotonia, normal muscle bulk and strength, and a wide-based gait. No dysmetria or ataxia was noted while reaching for toys with each hand.
Diagnostic evaluation and clinical course
Extensive evaluation revealed normal complete blood count, chemistry panel, and liver enzymes. Metabolic studies, including ammonia, lactate, plasma amino acids, acylcarnitine profile, urine organic acids, urine creatine metabolites, urine sulfites, purines, and urine pyrimidines were all normal. Fragile X testing was normal. Methylation and DNA sequencing of UBE3A for Angelman syndrome were normal. Chromosomal microarray (Affymetrix whole genome SNP 6.0) and karyotype were normal. Cerebrospinal fluid, lactate, pyruvate, amino acids, and neurotransmitter metabolites were normal. Magnetic resonance imaging of the brain with and without contrast at 12 and 28 months of life were each reported as normal. Initial EEG at 12 months was reported to show diffuse generalized discharges that were more frequent during sleep. Subsequent routine awake and asleep EEGs at 2 and 4 years, respectively, showed a 9-Hz posterior dominant rhythm. The EEG at 4 years of age also showed mild diffuse slowing and bifrontal and occasional right central sharp waves. A 24-hour continuous video-EEG
at 8 years showed frontally predominant generalized spike and wave interictal epileptiform discharges during wakefulness and sleep. Notably, the generalized discharges composed more than 85% of the slow wave sleep recording, a pattern consistent with ESES (Fig 1). He continued to have generalized tonic-clonic seizures annually between 4 and 9 years of age. Given the results of the continuous video-EEG, valproate was transitioned to clobazam and titrated to 20 mg twice daily (1.7 mg/kg/day). Clobazam was initiated to obtain seizure control and treat ESES. One month later, a repeat 24hour continuous video-EEG study was unchanged. Given the lack of response to clobazam and persistent seizures, felbamate was added and titrated to 43 mg/kg/day. Clinically, his parents reported a transient period when the patient was able to speak one or two words and improved behavior. Four months later, a routine awake and asleep EEG showed generalized beta frequency activity without interictal epileptiform discharges and overnight video-EEG confirmed resolution of ESES (Fig 2). He had no further seizures after the initiation of felbamate at 8 years of age. SCN1A gene sequencing revealed a maternally inherited heterozygous variant resulting in an amino acid change of threonine to isoleucine, an unlikely explanation for our patient’s severe clinical symptoms. SLC9A6 gene sequencing at eight years of age showed a hemizygous c.1710G>A (p.W570X) mutation in exon 14 in SLC9A6 resulting in substitution of tryptophan to a premature termination codon. This was not a previously reported change but was interpreted as disease-causing. At 12 years, he remains seizure-free on approximately 40 mg/kg/d of felbamate. Clobazam was continued because of behavioral worsening during weaning, and his most recent EEG showing rare bilateral frontal and independent right central epileptiform discharges during sleep. Despite full seizure control since 8 years of age and resolution of ESES on EEG, he had only transient gains in language. At nine years, he developed a reported 15-word vocabulary and then became nonverbal over a six-month period. At age 12 years, he continues to have minimal language use with a three- to four-word vocabulary, behavioral challenges, and insomnia. Discussion
This child constitutes the first known instance of a disease-causing mutation in SLC9A6 and ESES. Of nearly equal interest is the resolution of ESES on overnight EEG following a moderate dose of felbamate. Although this association does not imply causation in our patient, this has been reported previously in one developmentally normal child with acquired epileptic aphasia, in which normal speech recurred following initiation of felbamate.8 Our patient, on the other hand, had minimal language acquisition after treatment but had full seizure control with significantly fewer interictal discharges on EEG. It is unknown whether other individuals with an SLC9A6 mutation have reached full seizure control on felbamate. SLC9A6 encodes a sodium-hydrogen exchanger protein, NHE6, in recycling endosomal membranes of cells6 and dysfunction of these exchanger proteins may contribute indirectly to neuronal hyperexcitability and epilepsy7 or an
R. Coorg, J.L.Z. Weisenberg / Pediatric Neurology 53 (2015) 527e531
529
FIGURE 1. Electroencephalograph during slow wave sleep at 8 years of age with findings consistent with electrographic status epilepticus of sleep.
Angelman syndrome-like phenotype.9 In general, there is a paucity of information about specific epilepsy phenotypes on otherwise well-characterized genetic syndromes in the literature. Specifically, the relationship between SLC9A6 and manifestations of epilepsy including the development of ESES is unknown. The definition of ESES itself has varied, with studies describing an EEG pattern with interictal epileptiform discharges interrupting a minimum of anywhere from 50% to 90% of slow wave sleep activity.10 Continuous spike-waves during slow wave sleep and Landau-Kleffner syndrome, an acquired epileptic aphasia in otherwise normally developing children,11 are examples of clinical syndromes associated with an encephalopathy and ESES on EEG.10 Associations with early developmental lesions and genetic predispositions have been described in the literature, but the exact mechanisms behind ESES and CSWS remain poorly understood.12 Previous characterizations of patients with SLC9A6 mutations have identified interictal epileptiform abnormalities on routine EEG studies, but overnight EEG monitoring has not been reported.1,3 This child’s course suggests that an overnight EEG study should be considered in other patients with SLC9A6 mutations to evaluate for ESES, especially in the context of language delay or regression.
As may be expected with a heterogeneous definition, standard treatment for ESES and CSWS is not wellestablished. The use of felbamate in these circumstances, aside from the single case report mentioned previously, has not been examined in the literature. This may be due to a general reluctance to use this medication given early reports of aplastic anemia and fatal hepatotoxicity despite established long-term safety.13 Felbamate has many proposed mechanisms,14,15 but whether any one or all of these effects led to full seizure control and resolution of ESES in our patient is unclear. Much remains unknown about the disease-causing mutations in SLC9A6 and the downstream effects of this disease may be uniquely tempered by felbamate’s properties. In addition, the response of our patient, in combination with that of the previous case,8 suggests that felbamate should also be considered in patients with drug-resistant ESES not associated with SLC9A6 mutations. Although this child represents an example of successful diagnosis after targeted genetic testing, many years passed before our patient was able to achieve a diagnosis. It is unclear whether his language function would have improved had effective epilepsy and ESES treatment been initiated earlier. Whole genomic sequencing may increase the yield of diagnosing rare genetic diseases, especially
530
R. Coorg, J.L.Z. Weisenberg / Pediatric Neurology 53 (2015) 527e531
FIGURE 2. Electroencephalograph 4 months later, after addition of felbamate. Note: the presence of beta frequency activity is likely because of clobazam.
those with atypical phenotypes. As more knowledge accrues regarding the downstream molecular effects of genetic changes, therapies may be created and tailored toward targeting specific mechanisms of diseases and, more immediately, existing therapies may be used in novel ways. Drs. Coorg and Weisenberg would like to acknowledge the patient and his family. In addition, they would like to acknowledge Dr. Michael Wong for his comments on the manuscript. Author contributions: Dr. Coorg prepared the first draft of the manuscript. Dr. Weisenberg provided mentorship and revised the manuscript in detail. Declarations of conflicting interest: Dr. Coorg: None. Dr. Weisenberg: None. Funding: Dr. Coorg: None. Dr. Weisenberg: NINDS. Ethical approval: IRB approval was not obtained nor indicated. Permission to submit this case report was obtained from the patient’s family.
References 1. Christianson AL, Stevenson RE, van der Meyden CH, et al. X linked severe mental retardation, craniofacial dysmorphology, epilepsy, opthalmoplegia and cerebellar atrophy in a large South African kindred is localized to Xq24-q27. J Med Genet. 1999;36:758-766. 2. Gilfillan GD, Selmer KK, Roxrud I, et al. SLC9A6 mutations cause Xlinked mental retardation, microcephaly, epilepsy and ataxia, a phenotype mimicking Angelman syndrome. Am J Med Genet. 2008; 82:1003-1010.
3. Schroer RJ, Holden KR, Tarpey PS, et al. Natural history of Christianson syndrome. Am J Med Genet A. 2010;152A:2775-2783. 4. Mignot C, Héron D, Bursztyn J, et al. Novel mutation in SLC9A6 gene in a patient with Christianson syndrome and retinitis pigmentosum. Brain Dev. 2012;35:172-176. 5. Garben JY, Neurmann M, Trojanowski JQ, et al. A mutation affecting the sodium/proton exchanger, SLC9A6, causes mental retardation with tau deposition. Brain. 2010;133:1391-1402. 6. Brett CI, Wei Y, Donowitz M, et al. Human Na(þ)/H(þ) exchanger isoform 6 is found in recycling endosomes of cells, not in mitochondria. Am J Physiol Cell Physiol. 2002;282: C1031-C1041. 7. Ouyang Q, Lizarraga SB, Schmidt M, et al. Christianson Syndrome protein NHE6 modulates TrkB endosomal signaling required for neuronal circuit development. Neuron. 2013;80:97-112. 8. Glauser TA, Olberding LS, Titanic MK, et al. Felbamate in the treatment of acquired epileptic aphasia. Epilepsy Res. 1995;20: 85-89. 9. Takahashi Y, Hosoki K, Matsushita M, et al. A loss-of-function mutation in the SLC9A6 gene causes X-linked mental retardation resembling Angelman syndrome. Am J Med Genet B Neuropsychiatr Genet. 2011;156B:799-807. 10. Scheltens-de Boer M. Guidelines for EEG in encephalopathy related to ESES/CSWS in children. Epilepsia. 2009;50(Suppl 7):13-17. 11. Landau WM, Kleffner FR. Syndrome of acquired aphasia with convulsive disorder in children. Neurology. 1957;7:523-530. 12. Sanchez Fernandez I, Chapman KE, Peters JM, et al. Continuous spikes and waves during sleep: electroclinical presentation and suggestions for management. Epilepsy Res Treat. 2013;2013: 583531.
R. Coorg, J.L.Z. Weisenberg / Pediatric Neurology 53 (2015) 527e531 13. White JR, Leppik IE, Beattie JL, et al. Long-term use of felbamate: clinical outcomes and effect of age and concomitant antiepileptic drug use on its clearance. Epilepsia. 2009;50:2390-2396. 14. Rho JM, Donevan SD, Rogawski MA. Mechanism of action of the anticonvulsant felbamate: opposing effects on N-Methyl-D-
531
aspartate and gamma-aminobutyric acid A receptors. Ann Neurol. 1993;35:229-234. 15. White HS. Comparative anticonvulsant and mechanistic profile of the established and newer antiepileptic drugs. Epilepsia. 1999; 40(Suppl 5):S2-S10.
Memory can redeem the past, it can transfigure history, however painful, into another pattern. T. S. Eliot Four Quartets
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observations
Successful Treatment of Electrographic Status Epilepticus of Sleep With Felbamate in a Patient With SLC9A6 Mutation Rohini Coorg MD a, b, c,1, Judith L.Z. Weisenberg MD a, * a
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri Department of Pediatrics, Baylor College of Medicine, Houston, Texas c Department of Neurology, Baylor College of Medicine, Houston, Texas b
abstract BACKGROUND: Mutations of SLC9A6 may cause an X-linked clinical syndrome first described by Christianson in 1999
in which affected males exhibited profound intellectual disability, autism, drug-resistant epilepsy, ophthalmoplegia, mild craniofacial dysmorphism, microcephaly, and ataxia. METHODS: We describe a child with an SLC9A6 mutation and an electroencephalographic pattern consistent with electrographic status epilepticus of sleep. RESULTS: Our patient’s electrographic status epilepticus of sleep resolved after treatment with felbamate. Following treatment, he remained seizure-free but did not make significant or lasting gains in language. CONCLUSION: Our report extends the clinical epilepsy phenotype in children with SLC9A6 mutations to include electrographic status epilepticus of sleep. In addition, felbamate was an effective treatment for electrographic status epilepticus of sleep in our patient. Keywords: epilepsy, SLC9A6, ESES, felbamate, Christianson syndrome
Pediatr Neurol 2015; 53: 527-531 Ó 2015 Elsevier Inc. All rights reserved.
Introduction
Mutations in SLC9A6 may cause an X-linked clinical syndrome first described by Christianson in 1999 in which affected males exhibited profound intellectual disability, autism, epilepsy, ophthalmoplegia, mild craniofacial dysmorphisms, microcephaly, and ataxia.1 Some carrier females had mild intellectual disability.1 Subsequent reports expanded the phenotype in males to include acquired microcephaly and a happy demeanor suggestive of Angelman syndrome,2 initial hypotonia with development of spasticity,3 retinitis pigmentosum,4 stereotyped, repetitive hand movements, and dystonia.5 Seizures typically begin within the first two years of life, are medically refractory, and have multiple semiologies: Article History: Received April 24, 2015; Accepted in final form July 14, 2015 * Communications should be addressed to: Dr. Weisenberg; Department of Neurology; Box 8111; Washington University School of Medicine; 660 South Euclid Avenue; St. Louis, MO 63110. E-mail addresses: [email protected], [email protected] 1
Present address: Department of Pediatrics and Neurology; 6701 Fannin; Suite 1250; Houston, TX 77030. 0887-8994/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2015.07.007
generalized tonic-clonic1-3 with and without photosensitivity,1 atypical absence,3 and focal with complex motor and autonomic features.2 The interictal electroencephalograph (EEG) may be normal, have focal epileptiform discharges,1 or contain abnormalities consistent with a diagnosis of LennoxeGastaut syndrome.3 Prominent alpha frequency activity or a fast posterior dominant rhythm of 10-14 Hz may occur.2,3 To date, children with an SLC9A6 mutation and an EEG pattern consistent with electrographic status epilepticus of sleep (ESES) or the clinical syndrome of continuous spike-waves during sleep (CSWS) have not been described in the literature. Magnetic resonance imaging of the brain may reveal cerebellar atrophy.1,2 Neuropathology of two patients who died after the fourth decade revealed widespread neuronal and glial cell tau deposition with tangles in the basal ganglia, entorhinal cortex, and dentate nucleus.5 Diseasecausing mutations in SLC9A6 result in abnormal function of an endosomal sodium-proton exchanger6 that may be amenable to targeted treatment.7 Here, we describe a child with an SLC9A6 mutation who developed an EEG pattern consistent with ESES that resolved after treatment with felbamate.
528
R. Coorg, J.L.Z. Weisenberg / Pediatric Neurology 53 (2015) 527e531
Patient Description Our patient presented at 8 years of age with microcephaly, autism, global developmental delay, and epilepsy. He was born at term via spontaneous vaginal delivery after a normal pregnancy without complications. His birth weight, length, and head circumference were reportedly within normal percentiles and he had a normal reported newborn course. His seizures began at one year of life and consisted of abrupt activity cessation and apnea with unilateral (either right or left side) arm extension. At this time, acquired microcephaly was documented with height and weight in the tenth percentile and head circumference below the first percentile. His family elected not to start an antiepileptic medication at the onset. Between ages 1 and 4, seizures occurred every six months. All seizures lasted 45 seconds or less and were accompanied by postictal lethargy. At four years of age, he had an episode of status epilepticus arising from sleep with a seizure described as whole body stiffening and jerking. This resolved after approximately one hour and after multiple doses of lorazepam and fosphenytoin. Carbamazepine was initiated but he continued to have seizures occurring biannually over the next two years. At eight years of age, he was transitioned to levetiracetam, which was discontinued after three months because of intolerable behavioral side effects. Valproate was then initiated and increased to 21 mg/kg/day. He had experienced global developmental delay since infancy without motor or language regression. He gained appropriate motor milestones until nine months of age and eventually walked at 18 months of age. He ran at five years of age. He was right-handed. He began speaking at three years of age and was unable to speak sentences. By eight years, he had a four- to five-word vocabulary at any given time but did not retain words. He had limited use of a communication device. His family history was significant for two paternal great-uncles with childhood-onset epilepsy of unknown etiology. He had normal hearing and vision testing. In addition to seizures, he had insomnia and behavioral difficulties before five years of age. Physical examination at eight years of life revealed height in the third percentile, weight in the twenty-fifth percentile, and head circumference below the first percentile. His general physical examination was otherwise normal. He had no dysmorphic facial features. On neurological examination, he had minimal eye contact and remained hyperfocused on a video game. He said “hello” after prompting but was otherwise nonverbal. Motor examination was significant for diffuse hypotonia, normal muscle bulk and strength, and a wide-based gait. No dysmetria or ataxia was noted while reaching for toys with each hand.
Diagnostic evaluation and clinical course
Extensive evaluation revealed normal complete blood count, chemistry panel, and liver enzymes. Metabolic studies, including ammonia, lactate, plasma amino acids, acylcarnitine profile, urine organic acids, urine creatine metabolites, urine sulfites, purines, and urine pyrimidines were all normal. Fragile X testing was normal. Methylation and DNA sequencing of UBE3A for Angelman syndrome were normal. Chromosomal microarray (Affymetrix whole genome SNP 6.0) and karyotype were normal. Cerebrospinal fluid, lactate, pyruvate, amino acids, and neurotransmitter metabolites were normal. Magnetic resonance imaging of the brain with and without contrast at 12 and 28 months of life were each reported as normal. Initial EEG at 12 months was reported to show diffuse generalized discharges that were more frequent during sleep. Subsequent routine awake and asleep EEGs at 2 and 4 years, respectively, showed a 9-Hz posterior dominant rhythm. The EEG at 4 years of age also showed mild diffuse slowing and bifrontal and occasional right central sharp waves. A 24-hour continuous video-EEG
at 8 years showed frontally predominant generalized spike and wave interictal epileptiform discharges during wakefulness and sleep. Notably, the generalized discharges composed more than 85% of the slow wave sleep recording, a pattern consistent with ESES (Fig 1). He continued to have generalized tonic-clonic seizures annually between 4 and 9 years of age. Given the results of the continuous video-EEG, valproate was transitioned to clobazam and titrated to 20 mg twice daily (1.7 mg/kg/day). Clobazam was initiated to obtain seizure control and treat ESES. One month later, a repeat 24hour continuous video-EEG study was unchanged. Given the lack of response to clobazam and persistent seizures, felbamate was added and titrated to 43 mg/kg/day. Clinically, his parents reported a transient period when the patient was able to speak one or two words and improved behavior. Four months later, a routine awake and asleep EEG showed generalized beta frequency activity without interictal epileptiform discharges and overnight video-EEG confirmed resolution of ESES (Fig 2). He had no further seizures after the initiation of felbamate at 8 years of age. SCN1A gene sequencing revealed a maternally inherited heterozygous variant resulting in an amino acid change of threonine to isoleucine, an unlikely explanation for our patient’s severe clinical symptoms. SLC9A6 gene sequencing at eight years of age showed a hemizygous c.1710G>A (p.W570X) mutation in exon 14 in SLC9A6 resulting in substitution of tryptophan to a premature termination codon. This was not a previously reported change but was interpreted as disease-causing. At 12 years, he remains seizure-free on approximately 40 mg/kg/d of felbamate. Clobazam was continued because of behavioral worsening during weaning, and his most recent EEG showing rare bilateral frontal and independent right central epileptiform discharges during sleep. Despite full seizure control since 8 years of age and resolution of ESES on EEG, he had only transient gains in language. At nine years, he developed a reported 15-word vocabulary and then became nonverbal over a six-month period. At age 12 years, he continues to have minimal language use with a three- to four-word vocabulary, behavioral challenges, and insomnia. Discussion
This child constitutes the first known instance of a disease-causing mutation in SLC9A6 and ESES. Of nearly equal interest is the resolution of ESES on overnight EEG following a moderate dose of felbamate. Although this association does not imply causation in our patient, this has been reported previously in one developmentally normal child with acquired epileptic aphasia, in which normal speech recurred following initiation of felbamate.8 Our patient, on the other hand, had minimal language acquisition after treatment but had full seizure control with significantly fewer interictal discharges on EEG. It is unknown whether other individuals with an SLC9A6 mutation have reached full seizure control on felbamate. SLC9A6 encodes a sodium-hydrogen exchanger protein, NHE6, in recycling endosomal membranes of cells6 and dysfunction of these exchanger proteins may contribute indirectly to neuronal hyperexcitability and epilepsy7 or an
R. Coorg, J.L.Z. Weisenberg / Pediatric Neurology 53 (2015) 527e531
529
FIGURE 1. Electroencephalograph during slow wave sleep at 8 years of age with findings consistent with electrographic status epilepticus of sleep.
Angelman syndrome-like phenotype.9 In general, there is a paucity of information about specific epilepsy phenotypes on otherwise well-characterized genetic syndromes in the literature. Specifically, the relationship between SLC9A6 and manifestations of epilepsy including the development of ESES is unknown. The definition of ESES itself has varied, with studies describing an EEG pattern with interictal epileptiform discharges interrupting a minimum of anywhere from 50% to 90% of slow wave sleep activity.10 Continuous spike-waves during slow wave sleep and Landau-Kleffner syndrome, an acquired epileptic aphasia in otherwise normally developing children,11 are examples of clinical syndromes associated with an encephalopathy and ESES on EEG.10 Associations with early developmental lesions and genetic predispositions have been described in the literature, but the exact mechanisms behind ESES and CSWS remain poorly understood.12 Previous characterizations of patients with SLC9A6 mutations have identified interictal epileptiform abnormalities on routine EEG studies, but overnight EEG monitoring has not been reported.1,3 This child’s course suggests that an overnight EEG study should be considered in other patients with SLC9A6 mutations to evaluate for ESES, especially in the context of language delay or regression.
As may be expected with a heterogeneous definition, standard treatment for ESES and CSWS is not wellestablished. The use of felbamate in these circumstances, aside from the single case report mentioned previously, has not been examined in the literature. This may be due to a general reluctance to use this medication given early reports of aplastic anemia and fatal hepatotoxicity despite established long-term safety.13 Felbamate has many proposed mechanisms,14,15 but whether any one or all of these effects led to full seizure control and resolution of ESES in our patient is unclear. Much remains unknown about the disease-causing mutations in SLC9A6 and the downstream effects of this disease may be uniquely tempered by felbamate’s properties. In addition, the response of our patient, in combination with that of the previous case,8 suggests that felbamate should also be considered in patients with drug-resistant ESES not associated with SLC9A6 mutations. Although this child represents an example of successful diagnosis after targeted genetic testing, many years passed before our patient was able to achieve a diagnosis. It is unclear whether his language function would have improved had effective epilepsy and ESES treatment been initiated earlier. Whole genomic sequencing may increase the yield of diagnosing rare genetic diseases, especially
530
R. Coorg, J.L.Z. Weisenberg / Pediatric Neurology 53 (2015) 527e531
FIGURE 2. Electroencephalograph 4 months later, after addition of felbamate. Note: the presence of beta frequency activity is likely because of clobazam.
those with atypical phenotypes. As more knowledge accrues regarding the downstream molecular effects of genetic changes, therapies may be created and tailored toward targeting specific mechanisms of diseases and, more immediately, existing therapies may be used in novel ways. Drs. Coorg and Weisenberg would like to acknowledge the patient and his family. In addition, they would like to acknowledge Dr. Michael Wong for his comments on the manuscript. Author contributions: Dr. Coorg prepared the first draft of the manuscript. Dr. Weisenberg provided mentorship and revised the manuscript in detail. Declarations of conflicting interest: Dr. Coorg: None. Dr. Weisenberg: None. Funding: Dr. Coorg: None. Dr. Weisenberg: NINDS. Ethical approval: IRB approval was not obtained nor indicated. Permission to submit this case report was obtained from the patient’s family.
References 1. Christianson AL, Stevenson RE, van der Meyden CH, et al. X linked severe mental retardation, craniofacial dysmorphology, epilepsy, opthalmoplegia and cerebellar atrophy in a large South African kindred is localized to Xq24-q27. J Med Genet. 1999;36:758-766. 2. Gilfillan GD, Selmer KK, Roxrud I, et al. SLC9A6 mutations cause Xlinked mental retardation, microcephaly, epilepsy and ataxia, a phenotype mimicking Angelman syndrome. Am J Med Genet. 2008; 82:1003-1010.
3. Schroer RJ, Holden KR, Tarpey PS, et al. Natural history of Christianson syndrome. Am J Med Genet A. 2010;152A:2775-2783. 4. Mignot C, Héron D, Bursztyn J, et al. Novel mutation in SLC9A6 gene in a patient with Christianson syndrome and retinitis pigmentosum. Brain Dev. 2012;35:172-176. 5. Garben JY, Neurmann M, Trojanowski JQ, et al. A mutation affecting the sodium/proton exchanger, SLC9A6, causes mental retardation with tau deposition. Brain. 2010;133:1391-1402. 6. Brett CI, Wei Y, Donowitz M, et al. Human Na(þ)/H(þ) exchanger isoform 6 is found in recycling endosomes of cells, not in mitochondria. Am J Physiol Cell Physiol. 2002;282: C1031-C1041. 7. Ouyang Q, Lizarraga SB, Schmidt M, et al. Christianson Syndrome protein NHE6 modulates TrkB endosomal signaling required for neuronal circuit development. Neuron. 2013;80:97-112. 8. Glauser TA, Olberding LS, Titanic MK, et al. Felbamate in the treatment of acquired epileptic aphasia. Epilepsy Res. 1995;20: 85-89. 9. Takahashi Y, Hosoki K, Matsushita M, et al. A loss-of-function mutation in the SLC9A6 gene causes X-linked mental retardation resembling Angelman syndrome. Am J Med Genet B Neuropsychiatr Genet. 2011;156B:799-807. 10. Scheltens-de Boer M. Guidelines for EEG in encephalopathy related to ESES/CSWS in children. Epilepsia. 2009;50(Suppl 7):13-17. 11. Landau WM, Kleffner FR. Syndrome of acquired aphasia with convulsive disorder in children. Neurology. 1957;7:523-530. 12. Sanchez Fernandez I, Chapman KE, Peters JM, et al. Continuous spikes and waves during sleep: electroclinical presentation and suggestions for management. Epilepsy Res Treat. 2013;2013: 583531.
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Memory can redeem the past, it can transfigure history, however painful, into another pattern. T. S. Eliot Four Quartets
