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Two cases of early-onset myoclonic seizures with continuous parietal delta activity caused by EEF1A2 mutations
Brain & Development 38 (2016) 520–524 www.elsevier.com/locate/braindev
Case Report
Two cases of early-onset myoclonic seizures with continuous parietal delta activity caused by EEF1A2 mutations Takehiko Inui a,⇑,1, Satoru Kobayashi b,1, Yuka Ashikari b, Ryo Sato c, Wakaba Endo a, Mitsugu Uematsu c, Hiroshi Oba d, Hirotomo Saitsu e, Naomichi Matsumoto e, Shigeo Kure c, Kazuhiro Haginoya a a
Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, Sendai, Miyagi, Japan b Department of Pediatrics, Nagoya City West Medical Center, Nagoya, Japan c Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan d Department of Radiology, Teikyo University Hospital, Tokyo, Japan e Department of Human Genetics, Yokohama City University, Graduate School of Medicine, Yokohama, Japan Received 3 June 2015; received in revised form 7 November 2015; accepted 9 November 2015
Abstract Background: Mutations in the elongation factor 1 alpha 2 (EEF1A2) gene have recently been shown to cause severe intellectual disability with early-onset epilepsy. The specific manifestations of mutations in this gene remain unknown. Case report: We report two cases of severe intellectual disability accompanied by early-onset epilepsy with continuous delta activity evident on electroencephalography. Both cases presented with developmental delay and repetitive myoclonic seizures in early infancy. Both cases showed continuous high-voltage delta activity over both parietal areas when awake, as revealed by interictal electroencephalograms. After the emergence of continuous delta activity, development stagnated. One case showed some development after relief of the seizures and epileptic activity, but drug resistant seizures recurred, and the development again became stagnant. In both cases, a de novo recurrent heterozygous mutation in EEF1A2 [c.364G > A (p.E122K)] was identified by wholeexome sequencing. Conclusion: This report provides clinical data on epileptic encephalopathy in patients with EEF1A2 mutation. Continuous highvoltage delta activity seen over both parietal areas may be a unique manifestation of EEF1A2 mutation. Epileptic activity may aggravate the effect of the mutation on brain development. Ó 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Pediatrics; Epilepsy; Genetics; EEF1A2; High voltage delta activity; Intellectual disability; Myoclonic seizure
Abbreviations: EEF1A2, elongation factor 1 alpha 2; EEG, electroencephalogram; MRI, magnetic resonance imaging; ESID, Enjoji Scale of Infant Analytical Development; CNS, central nervous system ⇑ Corresponding author at: Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, 20 Shishioto, Akiu Yumoto, Taihaku, Sendai, Miyagi 982-0241, Japan. Tel.: +81 22 398 2221; fax: +81 22 397 2697. E-mail address: [email protected] (T. Inui). 1 These authors contributed equally to this report.
1. Introduction Whole-exome sequencing has led to the identification of genes responsible for many epilepsy syndromes. This technique has also identified other phenotypes caused by mutation in known epilepsy-causing genes, and has thus expanded the phenotypic spectrum of known epileptic genes [1].
http://dx.doi.org/10.1016/j.braindev.2015.11.003 0387-7604/Ó 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
T. Inui et al. / Brain & Development 38 (2016) 520–524
Mutations in the elongation factor 1 alpha 2 (EEF1A2) gene have been shown to cause severe intellectual disability with early-onset epilepsy, infantile spasms, and autistic spectrum disorder [2–4]. Because the manifestations of reported cases were not specific, the condition cannot be diagnosed until global gene testing is performed. We report two cases with EEF1A2 mutations accompanied by characteristic findings on electroencephalograms (EEGs) and EEG changes during development. We believe that this report may assist in the early diagnosis of mutations in this gene and help us to understand the mechanism by which mutation causes severe intellectual disability. 2. Case studies 2.1. Case 1 A female aged 2 years, 2 months was referred to our clinic for treatment of anticonvulsant-resistant seizures. She had been born normally at 41 weeks of gestation with birth weight, body height and head circumference of 3150 g (+0.4 SD), 50 cm (+0.8 SD) and 33.5 cm (+0.4 SD), respectively. Her family history was unremarkable. She had syndactyly of the left fourth and fifth toes, and internal strabismus was apparent at 1 month. She showed facial features including a tented upper lip, everted lower lip, and downward corners of the mouth. At 10 months, she presented with repetitive myoclonic seizures. At that time, she had no head control, social smile or visual pursuit. Magnetic resonance imaging (MRI) was normal (Fig. 1A). Her waking EEG showed continuous synchronous high-amplitude delta activity over the both parietal areas, some of which was preceded by sharp waves (Fig. 1B). Frequent diffuse polyspikes and multifocal spikes were seen during sleep. Valproate and pyridoxine had no effect. At 1 year 3 months although diffuse spike and waves remained, both the seizures and the continuous delta activity were relieved upon treatment with clobazam (Fig. 1C), followed by development of head control, visual pursuit, social smile, vocalization, and reach to toys. At 1 year 6 months, the continuous delta activity recurred. She presented repetitive atypical absence seizures, which were resistant to acetazolamide and pulse steroid therapy (Fig. 1D), and her development stagnated. At 2 years 2 months, she could not roll over or speak meaningful words. Her developmental quotient was 21 as measured by the Enjoji Scale of Infant Analytical Development (ESID). 2.2. Case 2 A male aged 2 years 2 months was referred to our hospital for treatment of developmental delay. He had
521
been born normally at 41 weeks of gestation with a birth weight of 3280 g (+0.7 SD). His family history was unremarkable. He exhibited unusual facial features, including a depressed nasal bridge, tented upper lip, everted lower lip, and downward corners of the mouth. At 8 months, he presented with repetitive myoclonic seizures and myoclonic–atonic seizures. At 1 year and 3 months, he was able to sit unaided for only a few seconds. His MRI was normal (Fig. 1E). His EEG showed frequent diffuse spike and waves or multifocal spikes during sleep. Valproate, clonazepam, nitrazepam, levetiracetam, ethosuximide, topiramate, and lamotrgine had no effect. At 1 year 6 months, his waking EEG showed continuous synchronous high-amplitude delta activity over both parietal areas, some of which was preceded by sharp waves (Fig. 1F). His development stagnated after the continuous delta activity developed. MRI at 1 year 9 months revealed cerebral atrophy (Fig. 1E). At 2 years 2 months, he could not stand unaided or speak meaningful words. His developmental quotient was 18, as measured by the ESID. 3. Genetic analysis Whole-exome sequencing of the two patients identified a heterozygous EEF1A2 mutation [c.364G > A (p. E122K)], which was validated de novo by Sanger sequencing. In fact, the de novo c.364G > A mutation in EEF1A2 has been reported in a patient with nodding spasms [4]. The mutation was not found in the 6500 exomes sequenced by the National Heart, Lung, and Blood Institute exome project or among our 575 inhouse control exomes. 4. Discussion We report on two patients with the same EEF1A2 mutation, who exhibited repetitive seizures, continuous delta activity, and severe intellectual disability. In case 1, development stagnated during the period in which she suffered repetitive seizures and continuous delta activity, and resumed after the delta activity disappeared. In case 2, development stagnated after continuous delta activity developed. The clinical courses of these cases were more severe than that of a previously reported case with the same mutation [4]. This indicates that epileptic activity may aggravate the effect of the mutation on brain development, which can be considered as a form of epileptic encephalopathy. Synchronous delta activity is also noted in patients with epilepsy with myoclonic–atonic seizures, Angelman syndrome, Rett syndrome, and ring chromosome 20 syndrome [5–8]. The delta activity in our cases was characterized by (1) near-continuous presence while awake
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T. Inui et al. / Brain & Development 38 (2016) 520–524
Fig. 1. (A)–(D) Structural magnetic resonance imaging (MRI) and an electroencephalogram (EEG) of case 1. (A) MRI at 1 year. An asymmetrical sulcus was evident in the left fronto-parietal area (arrow). As the cortical thickness and clarity of the adjacent cortical–white matter junction appeared to be normal, we considered that the variant was in fact normal. (B) An awake EEG at 10 months. Delta activity (200–300 lV) was observed continuously over both parietal areas. Note that sharp waves precede some of the slow waves. (C) An awake EEG at 1 year 4 months. After treatment with clobazam, the continuous delta activity disappeared. (D) An ictal EEG at 1 year 6 months. An atypical absence seizure (arrow) was associated with a 2 Hz-burst of diffuse spikes and waves. (E) and (F) MRI and EEG data for case 2. (E) The upper and lower panels show MRIs at age 1 year 3 months and 1 years 9 months, respectively (left: T1-weighted image, right: T2-weighted image). Progressive atrophy is evident. (F) An awake EEG at 2 years 2 months. Delta activity (200–300 lV) was observed continuously over both parietal areas.
but absence during sleep; (2) some spike and wave components; (3) high voltage, and (4) developmental aggregation.
EEF1A2 is expressed in the central nervous system (CNS), myocardium, and skeletal muscles. EEF1A2 plays an essential role in protein synthesis, and
T. Inui et al. / Brain & Development 38 (2016) 520–524
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Table 1 Clinical summary of the patients with EEF1A2 mutations.
Sex Mutation Amino acid change Clinical diagnosis Head control Walk without support Facial dysmorphology Other dysmorphism MRI Epilepsy onset Seizure type
Electroencephalogram
Epilepsy prognosis
Case 1
Case 2
Nakajima case 24
Nakajima case 14
Ligt Trio912
Veeramah3
Female c.364G > A de novo p.E122K Severe ID
Male c.364G > A de novo p.E122K Severe ID
Female c.208G > A de novo p.G70S Severe ID, ASD n.d. 6–7y – n.d. n.d. 4m Myoclonus GTC, absence
2m Myoclonus infantile spasms GTC, atonic
Continious slow wave Diffuse spike
5m – + – Progressive cereberal atrophy 8m Myoclonus myoclonic-atonic seizure Continious slow wave Diffuse spike
Female c.754G > C de novo p.D252H Severe ID, ASD 5m – + – Cereberal atrophy 8y GTC
Male c.208G > A de novo p.G70S Severe ID
1y3 m – + Syndactyly Abnormal sulcus (normal variant) 10 m Myoclonus atypical absence
Female c.364G > A de novo p.E122K Severe ID, ASD 6m 6y + Clubfoot Cereberal atrophy 4m Nodding spasms Multiforcal spike Polyspikes
Multifocal sharp wave Multifocal spike and wave
n.d.
Multifocal sharp wave
Intractable
Intractable
Controlled
n.d.
n.d.
Generalized spike and wave To hypsarrhythmia To patten of LGS Intractable
+ + (instable) n.d. n.d. n.d.
Superscript number in the table means reference number. Abbreviations: ID = intellectual disability, ASD = autistic spectrum disorder, m = months, y = years, n.d. = not described, GTC = generalized tonic chronic seizure, IS = infantile spasms, LGS = Lennox Gastaut Syndrome.
knockout mice exhibit extensive neuronal vacuolar degeneration in the CNS [9,10]. Thus, EEF1A2 mutation may impair protein synthesis and trigger apoptosis of neuronal cells, in turn causing epilepsy, severe intellectual disability, and brain atrophy. To date, EEF1A2 mutations have been reported in only six patients, including our cases [2–4], many of whom have similar clinical features (Table 1). First, every case involved severe intellectual disability presented from early infancy. Second, four cases exhibited dysmorphic facial features. Third, four cases presented with seizures in infancy, most of which started with myoclonic seizures. It remains to be established whether continuous delta activity occurs in all patients with this mutation or only those who are severely affected, as no prior waking EEG data on patients with the mutation are available. In conclusion, this report deals with clinical aspects of epileptic encephalopathy in patients with EEF1A2 mutations. Continuous high-voltage delta activity evident over both parietal areas may be a unique manifestation of EEF1A2 mutation, although further cases are required before any conclusion can be safely drawn.
Acknowledgments We thank the patients’ families for the participation in this study. This study was supported by: the Japanese
Ministry of Health, Labour, and Welfare; a Grant-inAid for Scientific Research (A) (13313587); the Takeda Science Foundation; the fund for Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program in the Project for Developing Innovation Systems; the Strategic Research Program for Brain Sciences (11105137); and a Grant-in-Aid for Scientific Research on Innovative Areas (Transcription Cycle) from the Japanese Ministry of Education, Culture, Sports, Science, and Technology (N.M.) and the Japan Society for the Promotion of Science (a Grant-in-Aid for Scientific Research (B) (25293085); the Takeda Science Foundation (H.S.) We thank Dr. Shinji Saitoh, who cooperate with us in perform evoked potentials for case 2. References [1] Lillis KP, Dulla C, Maheshwari A, Coulter D, Mody I, Heinemann U, et al. WONOEP appraisal: molecular and cellular imaging in epilepsy. Epilepsia 2015;56:505–13. [2] de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med 2012;367:1921–9. [3] Veeramah KR, Johnstone L, Karafet TM, Wolf D, Sprissler R, Salogiannis J, et al. Exome sequencing reveals new causal mutations in children with epileptic encephalopathies. Epilepsia 2013;54:1270–81. [4] Nakajima J, Okamoto N, Tohyama J, Kato M, Arai H, Funahashi O, et al. De novo EEF1A2 mutations in patients with
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characteristic facial features, intellectual disability, autistic behaviors and epilepsy. Clin Genet 2015;87:356–61. [5] Trivisano M, Specchio N, Cappelletti S, Di Ciommo V, Claps D, Specchio LM, et al. Myoclonic astatic epilepsy: an age-dependent epileptic syndrome with favorable seizure outcome but variable cognitive evolution. Epilepsy Res 2011;97:133–41. [6] Thibert RL, Larson AM, Hsieh DT, Raby AR, Thiele EA. Neurologic manifestations of angelman syndrome. Pediatr Neurol 2013;48:271–9. [7] Dolce A, Ben-Zeev B, Naidu S, Kossoff EH. Rett syndrome and epilepsy: an update for child neurologists. Pediatr Neurol 2013;48:337–45.
[8] Ville D, Kaminska A, Bahi-Buisson N, Biraben A, Plouin P, Telvi L, et al. Early pattern of epilepsy in the ring chromosome 20 syndrome. Epilepsia 2006;47:543–9. [9] Chambers DM, Peters J, Abbott CM. The lethal mutation of the mouse wasted (wst) is a deletion that abolishes expression of a tissue-specific isoform of translation elongation factor 1a, encoded by the Eef1a2 gene. Proc Natl Acad Sci USA 1998;95:4463–8. [10] Thornton S, Anand N, Purcell D, Lee J. Not just for housekeeping: protein initiation and elongation factors in cell growth and tumorigenesis. J Mol Med 2003;81:536–48.
Case Report
Two cases of early-onset myoclonic seizures with continuous parietal delta activity caused by EEF1A2 mutations Takehiko Inui a,⇑,1, Satoru Kobayashi b,1, Yuka Ashikari b, Ryo Sato c, Wakaba Endo a, Mitsugu Uematsu c, Hiroshi Oba d, Hirotomo Saitsu e, Naomichi Matsumoto e, Shigeo Kure c, Kazuhiro Haginoya a a
Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, Sendai, Miyagi, Japan b Department of Pediatrics, Nagoya City West Medical Center, Nagoya, Japan c Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan d Department of Radiology, Teikyo University Hospital, Tokyo, Japan e Department of Human Genetics, Yokohama City University, Graduate School of Medicine, Yokohama, Japan Received 3 June 2015; received in revised form 7 November 2015; accepted 9 November 2015
Abstract Background: Mutations in the elongation factor 1 alpha 2 (EEF1A2) gene have recently been shown to cause severe intellectual disability with early-onset epilepsy. The specific manifestations of mutations in this gene remain unknown. Case report: We report two cases of severe intellectual disability accompanied by early-onset epilepsy with continuous delta activity evident on electroencephalography. Both cases presented with developmental delay and repetitive myoclonic seizures in early infancy. Both cases showed continuous high-voltage delta activity over both parietal areas when awake, as revealed by interictal electroencephalograms. After the emergence of continuous delta activity, development stagnated. One case showed some development after relief of the seizures and epileptic activity, but drug resistant seizures recurred, and the development again became stagnant. In both cases, a de novo recurrent heterozygous mutation in EEF1A2 [c.364G > A (p.E122K)] was identified by wholeexome sequencing. Conclusion: This report provides clinical data on epileptic encephalopathy in patients with EEF1A2 mutation. Continuous highvoltage delta activity seen over both parietal areas may be a unique manifestation of EEF1A2 mutation. Epileptic activity may aggravate the effect of the mutation on brain development. Ó 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Pediatrics; Epilepsy; Genetics; EEF1A2; High voltage delta activity; Intellectual disability; Myoclonic seizure
Abbreviations: EEF1A2, elongation factor 1 alpha 2; EEG, electroencephalogram; MRI, magnetic resonance imaging; ESID, Enjoji Scale of Infant Analytical Development; CNS, central nervous system ⇑ Corresponding author at: Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, 20 Shishioto, Akiu Yumoto, Taihaku, Sendai, Miyagi 982-0241, Japan. Tel.: +81 22 398 2221; fax: +81 22 397 2697. E-mail address: [email protected] (T. Inui). 1 These authors contributed equally to this report.
1. Introduction Whole-exome sequencing has led to the identification of genes responsible for many epilepsy syndromes. This technique has also identified other phenotypes caused by mutation in known epilepsy-causing genes, and has thus expanded the phenotypic spectrum of known epileptic genes [1].
http://dx.doi.org/10.1016/j.braindev.2015.11.003 0387-7604/Ó 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
T. Inui et al. / Brain & Development 38 (2016) 520–524
Mutations in the elongation factor 1 alpha 2 (EEF1A2) gene have been shown to cause severe intellectual disability with early-onset epilepsy, infantile spasms, and autistic spectrum disorder [2–4]. Because the manifestations of reported cases were not specific, the condition cannot be diagnosed until global gene testing is performed. We report two cases with EEF1A2 mutations accompanied by characteristic findings on electroencephalograms (EEGs) and EEG changes during development. We believe that this report may assist in the early diagnosis of mutations in this gene and help us to understand the mechanism by which mutation causes severe intellectual disability. 2. Case studies 2.1. Case 1 A female aged 2 years, 2 months was referred to our clinic for treatment of anticonvulsant-resistant seizures. She had been born normally at 41 weeks of gestation with birth weight, body height and head circumference of 3150 g (+0.4 SD), 50 cm (+0.8 SD) and 33.5 cm (+0.4 SD), respectively. Her family history was unremarkable. She had syndactyly of the left fourth and fifth toes, and internal strabismus was apparent at 1 month. She showed facial features including a tented upper lip, everted lower lip, and downward corners of the mouth. At 10 months, she presented with repetitive myoclonic seizures. At that time, she had no head control, social smile or visual pursuit. Magnetic resonance imaging (MRI) was normal (Fig. 1A). Her waking EEG showed continuous synchronous high-amplitude delta activity over the both parietal areas, some of which was preceded by sharp waves (Fig. 1B). Frequent diffuse polyspikes and multifocal spikes were seen during sleep. Valproate and pyridoxine had no effect. At 1 year 3 months although diffuse spike and waves remained, both the seizures and the continuous delta activity were relieved upon treatment with clobazam (Fig. 1C), followed by development of head control, visual pursuit, social smile, vocalization, and reach to toys. At 1 year 6 months, the continuous delta activity recurred. She presented repetitive atypical absence seizures, which were resistant to acetazolamide and pulse steroid therapy (Fig. 1D), and her development stagnated. At 2 years 2 months, she could not roll over or speak meaningful words. Her developmental quotient was 21 as measured by the Enjoji Scale of Infant Analytical Development (ESID). 2.2. Case 2 A male aged 2 years 2 months was referred to our hospital for treatment of developmental delay. He had
521
been born normally at 41 weeks of gestation with a birth weight of 3280 g (+0.7 SD). His family history was unremarkable. He exhibited unusual facial features, including a depressed nasal bridge, tented upper lip, everted lower lip, and downward corners of the mouth. At 8 months, he presented with repetitive myoclonic seizures and myoclonic–atonic seizures. At 1 year and 3 months, he was able to sit unaided for only a few seconds. His MRI was normal (Fig. 1E). His EEG showed frequent diffuse spike and waves or multifocal spikes during sleep. Valproate, clonazepam, nitrazepam, levetiracetam, ethosuximide, topiramate, and lamotrgine had no effect. At 1 year 6 months, his waking EEG showed continuous synchronous high-amplitude delta activity over both parietal areas, some of which was preceded by sharp waves (Fig. 1F). His development stagnated after the continuous delta activity developed. MRI at 1 year 9 months revealed cerebral atrophy (Fig. 1E). At 2 years 2 months, he could not stand unaided or speak meaningful words. His developmental quotient was 18, as measured by the ESID. 3. Genetic analysis Whole-exome sequencing of the two patients identified a heterozygous EEF1A2 mutation [c.364G > A (p. E122K)], which was validated de novo by Sanger sequencing. In fact, the de novo c.364G > A mutation in EEF1A2 has been reported in a patient with nodding spasms [4]. The mutation was not found in the 6500 exomes sequenced by the National Heart, Lung, and Blood Institute exome project or among our 575 inhouse control exomes. 4. Discussion We report on two patients with the same EEF1A2 mutation, who exhibited repetitive seizures, continuous delta activity, and severe intellectual disability. In case 1, development stagnated during the period in which she suffered repetitive seizures and continuous delta activity, and resumed after the delta activity disappeared. In case 2, development stagnated after continuous delta activity developed. The clinical courses of these cases were more severe than that of a previously reported case with the same mutation [4]. This indicates that epileptic activity may aggravate the effect of the mutation on brain development, which can be considered as a form of epileptic encephalopathy. Synchronous delta activity is also noted in patients with epilepsy with myoclonic–atonic seizures, Angelman syndrome, Rett syndrome, and ring chromosome 20 syndrome [5–8]. The delta activity in our cases was characterized by (1) near-continuous presence while awake
522
T. Inui et al. / Brain & Development 38 (2016) 520–524
Fig. 1. (A)–(D) Structural magnetic resonance imaging (MRI) and an electroencephalogram (EEG) of case 1. (A) MRI at 1 year. An asymmetrical sulcus was evident in the left fronto-parietal area (arrow). As the cortical thickness and clarity of the adjacent cortical–white matter junction appeared to be normal, we considered that the variant was in fact normal. (B) An awake EEG at 10 months. Delta activity (200–300 lV) was observed continuously over both parietal areas. Note that sharp waves precede some of the slow waves. (C) An awake EEG at 1 year 4 months. After treatment with clobazam, the continuous delta activity disappeared. (D) An ictal EEG at 1 year 6 months. An atypical absence seizure (arrow) was associated with a 2 Hz-burst of diffuse spikes and waves. (E) and (F) MRI and EEG data for case 2. (E) The upper and lower panels show MRIs at age 1 year 3 months and 1 years 9 months, respectively (left: T1-weighted image, right: T2-weighted image). Progressive atrophy is evident. (F) An awake EEG at 2 years 2 months. Delta activity (200–300 lV) was observed continuously over both parietal areas.
but absence during sleep; (2) some spike and wave components; (3) high voltage, and (4) developmental aggregation.
EEF1A2 is expressed in the central nervous system (CNS), myocardium, and skeletal muscles. EEF1A2 plays an essential role in protein synthesis, and
T. Inui et al. / Brain & Development 38 (2016) 520–524
523
Table 1 Clinical summary of the patients with EEF1A2 mutations.
Sex Mutation Amino acid change Clinical diagnosis Head control Walk without support Facial dysmorphology Other dysmorphism MRI Epilepsy onset Seizure type
Electroencephalogram
Epilepsy prognosis
Case 1
Case 2
Nakajima case 24
Nakajima case 14
Ligt Trio912
Veeramah3
Female c.364G > A de novo p.E122K Severe ID
Male c.364G > A de novo p.E122K Severe ID
Female c.208G > A de novo p.G70S Severe ID, ASD n.d. 6–7y – n.d. n.d. 4m Myoclonus GTC, absence
2m Myoclonus infantile spasms GTC, atonic
Continious slow wave Diffuse spike
5m – + – Progressive cereberal atrophy 8m Myoclonus myoclonic-atonic seizure Continious slow wave Diffuse spike
Female c.754G > C de novo p.D252H Severe ID, ASD 5m – + – Cereberal atrophy 8y GTC
Male c.208G > A de novo p.G70S Severe ID
1y3 m – + Syndactyly Abnormal sulcus (normal variant) 10 m Myoclonus atypical absence
Female c.364G > A de novo p.E122K Severe ID, ASD 6m 6y + Clubfoot Cereberal atrophy 4m Nodding spasms Multiforcal spike Polyspikes
Multifocal sharp wave Multifocal spike and wave
n.d.
Multifocal sharp wave
Intractable
Intractable
Controlled
n.d.
n.d.
Generalized spike and wave To hypsarrhythmia To patten of LGS Intractable
+ + (instable) n.d. n.d. n.d.
Superscript number in the table means reference number. Abbreviations: ID = intellectual disability, ASD = autistic spectrum disorder, m = months, y = years, n.d. = not described, GTC = generalized tonic chronic seizure, IS = infantile spasms, LGS = Lennox Gastaut Syndrome.
knockout mice exhibit extensive neuronal vacuolar degeneration in the CNS [9,10]. Thus, EEF1A2 mutation may impair protein synthesis and trigger apoptosis of neuronal cells, in turn causing epilepsy, severe intellectual disability, and brain atrophy. To date, EEF1A2 mutations have been reported in only six patients, including our cases [2–4], many of whom have similar clinical features (Table 1). First, every case involved severe intellectual disability presented from early infancy. Second, four cases exhibited dysmorphic facial features. Third, four cases presented with seizures in infancy, most of which started with myoclonic seizures. It remains to be established whether continuous delta activity occurs in all patients with this mutation or only those who are severely affected, as no prior waking EEG data on patients with the mutation are available. In conclusion, this report deals with clinical aspects of epileptic encephalopathy in patients with EEF1A2 mutations. Continuous high-voltage delta activity evident over both parietal areas may be a unique manifestation of EEF1A2 mutation, although further cases are required before any conclusion can be safely drawn.
Acknowledgments We thank the patients’ families for the participation in this study. This study was supported by: the Japanese
Ministry of Health, Labour, and Welfare; a Grant-inAid for Scientific Research (A) (13313587); the Takeda Science Foundation; the fund for Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program in the Project for Developing Innovation Systems; the Strategic Research Program for Brain Sciences (11105137); and a Grant-in-Aid for Scientific Research on Innovative Areas (Transcription Cycle) from the Japanese Ministry of Education, Culture, Sports, Science, and Technology (N.M.) and the Japan Society for the Promotion of Science (a Grant-in-Aid for Scientific Research (B) (25293085); the Takeda Science Foundation (H.S.) We thank Dr. Shinji Saitoh, who cooperate with us in perform evoked potentials for case 2. References [1] Lillis KP, Dulla C, Maheshwari A, Coulter D, Mody I, Heinemann U, et al. WONOEP appraisal: molecular and cellular imaging in epilepsy. Epilepsia 2015;56:505–13. [2] de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med 2012;367:1921–9. [3] Veeramah KR, Johnstone L, Karafet TM, Wolf D, Sprissler R, Salogiannis J, et al. Exome sequencing reveals new causal mutations in children with epileptic encephalopathies. Epilepsia 2013;54:1270–81. [4] Nakajima J, Okamoto N, Tohyama J, Kato M, Arai H, Funahashi O, et al. De novo EEF1A2 mutations in patients with
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T. Inui et al. / Brain & Development 38 (2016) 520–524
characteristic facial features, intellectual disability, autistic behaviors and epilepsy. Clin Genet 2015;87:356–61. [5] Trivisano M, Specchio N, Cappelletti S, Di Ciommo V, Claps D, Specchio LM, et al. Myoclonic astatic epilepsy: an age-dependent epileptic syndrome with favorable seizure outcome but variable cognitive evolution. Epilepsy Res 2011;97:133–41. [6] Thibert RL, Larson AM, Hsieh DT, Raby AR, Thiele EA. Neurologic manifestations of angelman syndrome. Pediatr Neurol 2013;48:271–9. [7] Dolce A, Ben-Zeev B, Naidu S, Kossoff EH. Rett syndrome and epilepsy: an update for child neurologists. Pediatr Neurol 2013;48:337–45.
[8] Ville D, Kaminska A, Bahi-Buisson N, Biraben A, Plouin P, Telvi L, et al. Early pattern of epilepsy in the ring chromosome 20 syndrome. Epilepsia 2006;47:543–9. [9] Chambers DM, Peters J, Abbott CM. The lethal mutation of the mouse wasted (wst) is a deletion that abolishes expression of a tissue-specific isoform of translation elongation factor 1a, encoded by the Eef1a2 gene. Proc Natl Acad Sci USA 1998;95:4463–8. [10] Thornton S, Anand N, Purcell D, Lee J. Not just for housekeeping: protein initiation and elongation factors in cell growth and tumorigenesis. J Mol Med 2003;81:536–48.