- Email: [email protected]
ATP1A3-related epileptic encephalopathy responding to ketogenic diet
Brain & Development xxx (2018) xxx–xxx www.elsevier.com/locate/braindev
Case Report
ATP1A3-related epileptic encephalopathy responding to ketogenic diet Tommaso Schirinzi a,b, Federica Graziola a,c, Raffaella Cusmai a, Lucia Fusco a, Francesco Nicita a, Mirella Elia d, Lorena Travaglini a, Enrico Bertini a, Paolo Curatolo c, Federico Vigevano a, Alessandro Capuano a,⇑ a
Dept. of Neuroscience, Bambino Gesu` Children’s Hospital, IRCCS, Rome, Italy b Dept. of Systems Medicine, University of Roma Tor Vergata, Rome, Italy c Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata University of Rome, Italy d Nutrition Clinic, Hepathology and Gastroenterology Unit, ‘‘Bambino Gesu`” Children’s Hospital, IRCCS, Rome, Italy Received 3 August 2017; received in revised form 19 December 2017; accepted 7 January 2018
Abstract Background: Alternating Hemiplegia of Childhood (AHC) is a rare neurological disease caused by mutations in ATP1A3 gene codifying for alpha3 subunit of Na+-K+ ATPase pump. Repeated and transient attacks of hemiplegia, usually affecting one side of the body or the other, or both sides of the body at once, are the core features of AHC. Monocular nystagmus, other abnormalities in ocular movements, dystonic posturing and epilepsy are commonly associated to AHC. However, the spectrum of ATP1A3 related diseases is still expanding and new phenotypes have been reported. Case report: Here, we described a patient who developed a severe early onset drug-resistant epileptic encephalopathy and months later, he presented episodes of hemiplegic attacks and monocular nystagmus. Thus, AHC was hypothesized and a novel mutation in ATP1A3 gene was found. Interestingly, ketogenic diet (KD) was started and both epileptic seizures and classical AHC paroxysmal episodes stopped. Long-term follow-up shows a global improvement of neurological development. Conclusions: Our case reinforces the role of KD as a novel therapeutic option for ATP1A3-related conditions. However, proper dedicated confirmatory trials on KD are necessary. Ó 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: ATP1A3; Ketogenic diet; Drug resistant epilepsy; Alternating hemiplegia of childhood
1. Introduction ATP1A3 gene encodes for a subunit of the Na+/K+ ATPase pump. Mutations in ATP1A3 are responsible for a wild spectrum of highly disabling syndromes, with ⇑ Corresponding author at: Dept. of Neuroscience, Bambino Gesu ` Children’s Hospital, IRCCS, Piazza Sant’Onofrio 4, 00165 Rome, Italy. E-mail address: [email protected] (A. Capuano).
early childhood onset. ATP1A3-related conditions indeed include either definite pictures as Alternating Hemiplegia of Childhood (AHC), Rapid-onset Dystonia-Parkinsonism (RDP) and CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss), or a number of intermediate phenotypes, also presenting with epilepsy, neurodevelopmental delay, ataxia, oculomotor abnormalities and movement disorders [1,2]. Since curative and targetspecific treatments are still lacking, therapeutic efforts
https://doi.org/10.1016/j.braindev.2018.01.002 0387-7604/Ó 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Schirinzi T et al. ATP1A3-related epileptic encephalopathy responding to ketogenic diet. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.01.002
2
T. Schirinzi et al. / Brain & Development xxx (2018) xxx–xxx
usually point at symptomatic relief or at preventing the reoccurrence of paroxysmal phenomena [1]. At this purpose flunarizine showed significant effectiveness in numerous patients with AHC [3] and in one case of RDP [4]. Overall, beside antiepileptics (AEDs) for seizures control [1,3] very few alternative treatments have been approached in patients with ATP1A3-related diseases. Aimed at expanding the knowledge on therapeutic opportunities for ATP1A3 diseases, here we describe a case of ATP1A3-related early onset drug-resistant epileptic encephalopathy responsive to ketogenic diet (KD).
2. Case report The patient was a boy, born at the 36th week of Caesarean birth for oligohydramnios. First months of life were regular. Since the third month, he presented arrest of motor development and clonic seizures on the right side associated with sporadic episodes of hyperpnoea. The child also exhibited scarce spontaneous motility with marked axial hypotonia, poor visual contact and occasional horizontal nystagmus. After brain images and metabolic tests, resulted both normal, and EEG, showing spikes and slow waves in left fronto-temporal region, patient started an antiepileptic treatment. Seizures were
Fig. 1. A: Exemplary screenshots of EEGs before ketogenic diet showed bilateral delta slow waves in temporal region and poor organization and differentiation of the background rhythm. B: exemplary screenshots of EEGs after several months from the beginning of the ketogenic diet. A background rhythm activity was more differentiated and organized, no abnormal activity was recorded.
Please cite this article in press as: Schirinzi T et al. ATP1A3-related epileptic encephalopathy responding to ketogenic diet. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.01.002
Improvement in the cognitive, motor and adaptive behaviour subtests, moderate language delay both in expressive and receptive communication LEV, VPA Seizures free for 16 months then sporadic (every 2-3 months) during concomitant febrile illness After KD
Attacks-free for 20 months, then sporadic once bimonthly triggered by fever, stressful events, not prolonged (lasting less than 30 minutes)
Daily, more than daily, status epilepticus at onset and in two other episodes Before KD
Legend: AEDs antiepileptic drugs; PB phenobarbital; VPA valproic acid; CBZ carbamazepine; LEV levetiracetam; CLZ clonazepam; MDZ midazolam; TPM topiramate.
Severe psychomotor development at 20 months PB, VPA, CBZ, LEV, CLZ, MDZ, TPM
Eye deviations, dystonic spells weekly, less than weekly Attacks-free 12 months onset weekly, less than weekly, prolonged (hours)
Development (Bayley Scales III edition) AEDs Dystonic spells/ frequency Hemi-quadriplegic attacks/frequency Seizures frequency
Table 1 Clinical outcome of patient after 32 months follow-up on ketogenic diet.
T. Schirinzi et al. / Brain & Development xxx (2018) xxx–xxx
3
initially responsive to phenobarbital and carbamazepine, but in two months, they became absolutely uncontrolled and following challenges with clonazepam, valproic acid, levetiracetam, and topiramate, resulted ineffective. At the age of 12 months, patient began to present frequent, brief, sleep episodes of apnea with sudden oxygen desaturation, cyanosis and hypotonia in the absence of significant EEG correlates. Moreover, he developed episodes of gaze deviation accompanied by unilateral nystagmus and alternating hemiplegia in laterality arose, occurring in wakening, lasting about 30 min and repeating in clusters for 3–4 days (Video). At this point, a form of ATP1A3-related condition was suspected and sequencing analysis of ATP1A3 gene was performed, showing a trinucleotide deletion c.2266_2268delGAC p.(D756del) (NM_001256214). At age 20 months the patient presented a sever global delay in various developmental areas assessed through Bayley Scales (Bayley Scales of Infant and Toddler DevelopmentÒ, Third Edition -Bayley-IIIÒ).
Video shows patient’s seizure. First, a generalized tonic seizure with vibratory/clonic components occurred lasting several minutes, then a monocular nystagmus of the right eye started during the post-critical phase. Monocular nystagmus is a specific hallmark of AHC.
Video.
A proper diagnosis of severe psychomotor developmental delay was given, and neurodevelopmental therapy started. A classical KD (ratio 3:1) was imposed with progressive clinical improvement. At 2 years and 7 months of follow-up, KD was well tolerated, the frequency of both epileptic and non-epileptic paroxysmal manifestations significantly decreased as well as the total amount of drugs intake. Fig. 1 shows also EEGs before and after KD; after KD, EEG did not show any epileptic discharges. By analysing in detail, the different evolution of the various developmental areas assessed before and after the KD diet it was evident an improvement in the cognitive, motor and adaptive behaviour subtests, however it persisted a mildmoderate language delay both in expressive and recep-
Please cite this article in press as: Schirinzi T et al. ATP1A3-related epileptic encephalopathy responding to ketogenic diet. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.01.002
4
CASE
Country
Gender
Genetics
Clinical features age of onset/symptoms
Developmental Delay
Epilepsy
KD ratio
Followup on KD
Effect of KD
1. Roubergue et al. JIMD Rep. 2015
France
F
ATP1A3 D923N familiar (mother, uncle and grandmother with exercise-induced dystonia)
N
N
MAD 0.9:1
15 months
Dystonic and plegic attacks free
2. Ulate-Campos A. et al. Pediatr Neurol. 2014
Spain
F
ATP1A3 T804I de novo Non-coding variation in SLC2A1 of unknown significance
Y
N
4:1
4 years
Sporadic attacks Motor development improvement
3. Vila-Pueyo M. et al. J Neurol Sci. 2014 4. Vila-Pueyo M. et al. J Neurol Sci. 2014 5. Vila-Pueyo M. et al. J Neurol Sci. 2014 6. Pisciotta L. et al. Brain Dev 2017 7. (our case)
Greece
F
ATP1A3 D801N de novo
8 months / focal/generalized dystonic attacks 20 months/ orolaryngeal dystonia 2 y 6 months /mono/ hemi/quadriplegic episodes 5 months global hypotonia 10 months episodes of strabismus 12 months right side hemiplegic attack 6 months paresis, dystonia
Y
N
–
1 year
Spain
M
ATP1A3 G947R de novo
Y
N
–
–
Spain
F
ATP1A3 G947R de novo
Y
N
–
2 years
Attacks-free
Italy
–
ATP1A3 A955D de novo
3 months ataxia, flaccid paresis, dystonia 0 months Nystagmus, Chorea, Dystonia, Flaccid paresis –
Reduced dystonic attacks behavioral and social improvement Attacks-free
–
–
–
–
Reported improved
Italy
M
ATP1A3 D756del de novo
3 months seizures
Y
Y
3:1
2 years and 7 months
Improved (see also Table 1 for details)
Legend: AHC, alternating hemiplegia of Childhood; F, female, M, male; KD, ketogenic diet.
T. Schirinzi et al. / Brain & Development xxx (2018) xxx–xxx
Please cite this article in press as: Schirinzi T et al. ATP1A3-related epileptic encephalopathy responding to ketogenic diet. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.01.002
Table 2 Summary of genetic, clinical data, efficacy of treatment of AHC patients treated with ketogenic diet previously reported, including our single case report.
T. Schirinzi et al. / Brain & Development xxx (2018) xxx–xxx
tive communication. Table 1 summarizes clinical data before and after KD. 3. Discussion AHC is a rare neurological disease with an onset before 18 months of age characterized by hemiplegic/ quadriplegic attacks, tonic/dystonic spells and ocular paroxysmal movements such as tonic gaze deviation and monocular nystagmus. Affected children usually have developmental delay, variable intellectual disability, seizures (50–80%), ataxia, and dysarthria [5]. Since ATP1A3 mutations were identified in AHC patients [6], the phenotypical spectrum of ATP1A3-related disease is expanding and still growing [5]. Intractable neonatal seizures, early life epilepsy, and status epilepticus have been reported in children with clinically defined AHC and an association has been made with the Glu815Lys mutations and neonatal-onset seizures [7]. Recently, a severe phenotype associated with catastrophic early life epilepsy, episodic prolonged apnea, and postnatal microcephaly has been described [8]. Our patient, harboring a novel ATP1A3 trinucleotide deletion c.2266_2268delGAC p.(D756del), showed a peculiar phenotype consisting in a complex picture of early onset drug-resistant epileptic encephalopathy, non-epileptic paroxysmal episodes (hypotonia, hemiplegia, apnea, monocular nystagmus) and developmental delay. Interestingly, other authors, including our group [4,9], described patients carrying missense mutation at same residue 756 displaying a phenotype mainly resembling RDP, and fever-induced encephalopathy with dystonia and ataxia. Recently, Yano et al. [10] hypothesized a new distinct phenotype associated to residue 756 comparing clinical features of new patients with those already described in the literature. Thus, our case certainly enlarges the spectrum of ATP1A3 genotypephenotype correlations. Moreover, the clinical course of our patient along with the efficacy of KD suggests the opportunity to alternatively treat an ATP1A3-related disease. There are few reports (case reports or short case series) of patients with AHC treated with KD during the course of disease. Table 2 summarizes all cases reported, to our knowledge in the literature, with their respective available clinical and genetic data. Among few others, our case has a long follow-up, KD is still well tolerated and the improvement is constant. Due to unique clinical presentation, as early-onset epileptic encephalopathy, our case is the only case reported with an improvement of both epileptic and not epileptic episodes after KD. In fact, our patient showed an excellent response to KD provided the first evidence of successful application of KD in a severe ATP1A3-related drug-resistant epileptic encephalopathy. In last decades, the practice of KD has
5
spread out, being frequently used for drug-resistant epilepsy and many other neurological disorders. KD antiepileptic activity is due to a complex intertwine of mechanisms which encompasses a direct anti-seizure action, the recovery of a new neurotransmitters balance, the rearrangement of both cellular and mitochondrial metabolism and an antioxidant effect [11]. However, the efficacy of KD in our case could be related to the specific action of ketones on ATP-sensitive potassium channels (KATP channels). In fact, since the blocking of Na+/K+ ATPase pump leads to the inhibition of KATP channels causing neuronal hyperexcitability [12], it is reasonable that, here, the diet-induced ketosis has improved epilepsy by the modulation of KATP channels, whose activity was affected by the dysfunction of Na+/K+ ATPase pump. Our case, together with other reports on AHC [3,13– 15] and compelling experimental findings, in turn, supporting the role of ketones in restoring cellular effects of Na+/K+ ATPase pump dysfunction, indicate KD as a novel therapeutic opportunity in some patients with ATP1A3-related conditions. However, proper dedicated confirmatory trials are necessary.
Acknowledgement We wish to thank patient’s parents for their kind support. Ethical approval This work did not need any ethical committee approval. Both patient’s parents signed written informed consensus to use relevant material for this paper. Financial disclosure The authors have no financial relationships relevant to this article to disclose. Conflict of interest None. References [1] Sweney MT, Newcomb TM, Swoboda KJ. The expanding spectrum of neurological phenotypes in children with ATP1A3 mutations, alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism CAPOS and beyond. Pediatr Neurol 2015;52:56–64. [2] Heinzen EL, Arzimanoglou A, Brashear A, Clapcote SJ, Gurrieri F, Goldstein DB, et al. Distinct neurological disorders with ATP1A3 mutations. Lancet Neurol 2014;13:503–14.
Please cite this article in press as: Schirinzi T et al. ATP1A3-related epileptic encephalopathy responding to ketogenic diet. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.01.002
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T. Schirinzi et al. / Brain & Development xxx (2018) xxx–xxx [3] Pisciotta L, Gherzi M, Stagnaro M, Calevo MG, Giannotta M, Vavassori MR, et al. Alternating hemiplegia of childhood: pharmacological treatment of 30 italian patients. Brain Dev. 2017;39:521–8. [4] Fornarino S, Stagnaro M, Rinelli M, Tiziano D, Mancardi MM, Traverso M, et al. Paroxysmal features responding to flunarizine in a child with rapid-onset dystonia-parkinsonism. Neurology 2014;82:2037–8. [5] Mikati MA, Kramer U, Zupanc ML, Shanahan RJ. Alternating hemiplegia of childhood: clinical manifestations and long-term outcome. Pediatr Neurol 2000;23:134–41. [6] Heinzen EL, Swoboda KJ, Hitomi Y, et al. De novo mutations in ATP1A3 cause alternating hemiplegia of childhood. Nat Genet 2012;44:1030–4. [7] Sasaki M, Ishii A, Saito Y, et al. Genotype-phenotype correlations in alternating hemiplegia of childhood. Neurology 2014;82:482–90. [8] Paciorkowski AR, McDaniel SS, Jansen LA, Tully H, Tuttle E, Ghoneim DH, et al. Novel mutations in ATP1A3 associated with catastrophic early life epilepsy, episodic prolonged apnea, and postnatal microcephaly. Epilepsia 2015;56:422–30. [9] Nicita F, Travaglini L, Sabatini S, Garavaglia B, Panteghini C, Valeriani M, et al. Childhood-onset ATP1A3-related conditions:
[10]
[11] [12]
[13]
[14]
[15]
report of two new cases of phenotypic spectrum. Parkinsonism Relat Disord 2016;30:81–2. Yano ST, Silver K, Young R, DeBrosse SD, Ebel RS, Swoboda KJ, et al. Fever-induced paroxysmal weakness and encephalopathy, a new phenotype of ATP1A3 mutation. Pediatr Neurol 2017;29. Rho JM. How does the ketogenic diet induce anti-seizure effects? Neurosci Lett 2017;637:4–10. Tanner GR, Lutas A, Martı´nez-Franc¸ois JR, Yellen G, Single K. ATP channel opening in response to action potential firing in mouse dentate granule neurons. J Neurosci 2011;31:8689–96. Ulate-Campos A, Fons C, Artuch R, Castejo´n E, Martorell L, Ozelius L, et al. Alternating hemiplegia of childhood with a de novo mutation in ATP1A3 and changes in SLC2A1 responsive to a ketogenic diet. Pediatr Neurol 2014;50:377–9. Roubergue A, Philibert B, Gautier A, Kuster A, Markowicz K, Billette de Villemeur T, et al. Excellent response to a ketogenic diet in a patient with alternating hemiplegia of childhood. JIMD Rep 2015;15:7–12. Vila-Pueyo M, Pons R, Raspall-Chaure M, Marce´-Grau A, Carren˜o O, Sintas C, et al. Clinical and genetic analysis in alternating hemiplegia of childhood: ten new patients from Southern Europe. J Neurol Sci 2014;344:37–42.
Please cite this article in press as: Schirinzi T et al. ATP1A3-related epileptic encephalopathy responding to ketogenic diet. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.01.002
Case Report
ATP1A3-related epileptic encephalopathy responding to ketogenic diet Tommaso Schirinzi a,b, Federica Graziola a,c, Raffaella Cusmai a, Lucia Fusco a, Francesco Nicita a, Mirella Elia d, Lorena Travaglini a, Enrico Bertini a, Paolo Curatolo c, Federico Vigevano a, Alessandro Capuano a,⇑ a
Dept. of Neuroscience, Bambino Gesu` Children’s Hospital, IRCCS, Rome, Italy b Dept. of Systems Medicine, University of Roma Tor Vergata, Rome, Italy c Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata University of Rome, Italy d Nutrition Clinic, Hepathology and Gastroenterology Unit, ‘‘Bambino Gesu`” Children’s Hospital, IRCCS, Rome, Italy Received 3 August 2017; received in revised form 19 December 2017; accepted 7 January 2018
Abstract Background: Alternating Hemiplegia of Childhood (AHC) is a rare neurological disease caused by mutations in ATP1A3 gene codifying for alpha3 subunit of Na+-K+ ATPase pump. Repeated and transient attacks of hemiplegia, usually affecting one side of the body or the other, or both sides of the body at once, are the core features of AHC. Monocular nystagmus, other abnormalities in ocular movements, dystonic posturing and epilepsy are commonly associated to AHC. However, the spectrum of ATP1A3 related diseases is still expanding and new phenotypes have been reported. Case report: Here, we described a patient who developed a severe early onset drug-resistant epileptic encephalopathy and months later, he presented episodes of hemiplegic attacks and monocular nystagmus. Thus, AHC was hypothesized and a novel mutation in ATP1A3 gene was found. Interestingly, ketogenic diet (KD) was started and both epileptic seizures and classical AHC paroxysmal episodes stopped. Long-term follow-up shows a global improvement of neurological development. Conclusions: Our case reinforces the role of KD as a novel therapeutic option for ATP1A3-related conditions. However, proper dedicated confirmatory trials on KD are necessary. Ó 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: ATP1A3; Ketogenic diet; Drug resistant epilepsy; Alternating hemiplegia of childhood
1. Introduction ATP1A3 gene encodes for a subunit of the Na+/K+ ATPase pump. Mutations in ATP1A3 are responsible for a wild spectrum of highly disabling syndromes, with ⇑ Corresponding author at: Dept. of Neuroscience, Bambino Gesu ` Children’s Hospital, IRCCS, Piazza Sant’Onofrio 4, 00165 Rome, Italy. E-mail address: [email protected] (A. Capuano).
early childhood onset. ATP1A3-related conditions indeed include either definite pictures as Alternating Hemiplegia of Childhood (AHC), Rapid-onset Dystonia-Parkinsonism (RDP) and CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss), or a number of intermediate phenotypes, also presenting with epilepsy, neurodevelopmental delay, ataxia, oculomotor abnormalities and movement disorders [1,2]. Since curative and targetspecific treatments are still lacking, therapeutic efforts
https://doi.org/10.1016/j.braindev.2018.01.002 0387-7604/Ó 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Schirinzi T et al. ATP1A3-related epileptic encephalopathy responding to ketogenic diet. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.01.002
2
T. Schirinzi et al. / Brain & Development xxx (2018) xxx–xxx
usually point at symptomatic relief or at preventing the reoccurrence of paroxysmal phenomena [1]. At this purpose flunarizine showed significant effectiveness in numerous patients with AHC [3] and in one case of RDP [4]. Overall, beside antiepileptics (AEDs) for seizures control [1,3] very few alternative treatments have been approached in patients with ATP1A3-related diseases. Aimed at expanding the knowledge on therapeutic opportunities for ATP1A3 diseases, here we describe a case of ATP1A3-related early onset drug-resistant epileptic encephalopathy responsive to ketogenic diet (KD).
2. Case report The patient was a boy, born at the 36th week of Caesarean birth for oligohydramnios. First months of life were regular. Since the third month, he presented arrest of motor development and clonic seizures on the right side associated with sporadic episodes of hyperpnoea. The child also exhibited scarce spontaneous motility with marked axial hypotonia, poor visual contact and occasional horizontal nystagmus. After brain images and metabolic tests, resulted both normal, and EEG, showing spikes and slow waves in left fronto-temporal region, patient started an antiepileptic treatment. Seizures were
Fig. 1. A: Exemplary screenshots of EEGs before ketogenic diet showed bilateral delta slow waves in temporal region and poor organization and differentiation of the background rhythm. B: exemplary screenshots of EEGs after several months from the beginning of the ketogenic diet. A background rhythm activity was more differentiated and organized, no abnormal activity was recorded.
Please cite this article in press as: Schirinzi T et al. ATP1A3-related epileptic encephalopathy responding to ketogenic diet. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.01.002
Improvement in the cognitive, motor and adaptive behaviour subtests, moderate language delay both in expressive and receptive communication LEV, VPA Seizures free for 16 months then sporadic (every 2-3 months) during concomitant febrile illness After KD
Attacks-free for 20 months, then sporadic once bimonthly triggered by fever, stressful events, not prolonged (lasting less than 30 minutes)
Daily, more than daily, status epilepticus at onset and in two other episodes Before KD
Legend: AEDs antiepileptic drugs; PB phenobarbital; VPA valproic acid; CBZ carbamazepine; LEV levetiracetam; CLZ clonazepam; MDZ midazolam; TPM topiramate.
Severe psychomotor development at 20 months PB, VPA, CBZ, LEV, CLZ, MDZ, TPM
Eye deviations, dystonic spells weekly, less than weekly Attacks-free 12 months onset weekly, less than weekly, prolonged (hours)
Development (Bayley Scales III edition) AEDs Dystonic spells/ frequency Hemi-quadriplegic attacks/frequency Seizures frequency
Table 1 Clinical outcome of patient after 32 months follow-up on ketogenic diet.
T. Schirinzi et al. / Brain & Development xxx (2018) xxx–xxx
3
initially responsive to phenobarbital and carbamazepine, but in two months, they became absolutely uncontrolled and following challenges with clonazepam, valproic acid, levetiracetam, and topiramate, resulted ineffective. At the age of 12 months, patient began to present frequent, brief, sleep episodes of apnea with sudden oxygen desaturation, cyanosis and hypotonia in the absence of significant EEG correlates. Moreover, he developed episodes of gaze deviation accompanied by unilateral nystagmus and alternating hemiplegia in laterality arose, occurring in wakening, lasting about 30 min and repeating in clusters for 3–4 days (Video). At this point, a form of ATP1A3-related condition was suspected and sequencing analysis of ATP1A3 gene was performed, showing a trinucleotide deletion c.2266_2268delGAC p.(D756del) (NM_001256214). At age 20 months the patient presented a sever global delay in various developmental areas assessed through Bayley Scales (Bayley Scales of Infant and Toddler DevelopmentÒ, Third Edition -Bayley-IIIÒ).
Video shows patient’s seizure. First, a generalized tonic seizure with vibratory/clonic components occurred lasting several minutes, then a monocular nystagmus of the right eye started during the post-critical phase. Monocular nystagmus is a specific hallmark of AHC.
Video.
A proper diagnosis of severe psychomotor developmental delay was given, and neurodevelopmental therapy started. A classical KD (ratio 3:1) was imposed with progressive clinical improvement. At 2 years and 7 months of follow-up, KD was well tolerated, the frequency of both epileptic and non-epileptic paroxysmal manifestations significantly decreased as well as the total amount of drugs intake. Fig. 1 shows also EEGs before and after KD; after KD, EEG did not show any epileptic discharges. By analysing in detail, the different evolution of the various developmental areas assessed before and after the KD diet it was evident an improvement in the cognitive, motor and adaptive behaviour subtests, however it persisted a mildmoderate language delay both in expressive and recep-
Please cite this article in press as: Schirinzi T et al. ATP1A3-related epileptic encephalopathy responding to ketogenic diet. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.01.002
4
CASE
Country
Gender
Genetics
Clinical features age of onset/symptoms
Developmental Delay
Epilepsy
KD ratio
Followup on KD
Effect of KD
1. Roubergue et al. JIMD Rep. 2015
France
F
ATP1A3 D923N familiar (mother, uncle and grandmother with exercise-induced dystonia)
N
N
MAD 0.9:1
15 months
Dystonic and plegic attacks free
2. Ulate-Campos A. et al. Pediatr Neurol. 2014
Spain
F
ATP1A3 T804I de novo Non-coding variation in SLC2A1 of unknown significance
Y
N
4:1
4 years
Sporadic attacks Motor development improvement
3. Vila-Pueyo M. et al. J Neurol Sci. 2014 4. Vila-Pueyo M. et al. J Neurol Sci. 2014 5. Vila-Pueyo M. et al. J Neurol Sci. 2014 6. Pisciotta L. et al. Brain Dev 2017 7. (our case)
Greece
F
ATP1A3 D801N de novo
8 months / focal/generalized dystonic attacks 20 months/ orolaryngeal dystonia 2 y 6 months /mono/ hemi/quadriplegic episodes 5 months global hypotonia 10 months episodes of strabismus 12 months right side hemiplegic attack 6 months paresis, dystonia
Y
N
–
1 year
Spain
M
ATP1A3 G947R de novo
Y
N
–
–
Spain
F
ATP1A3 G947R de novo
Y
N
–
2 years
Attacks-free
Italy
–
ATP1A3 A955D de novo
3 months ataxia, flaccid paresis, dystonia 0 months Nystagmus, Chorea, Dystonia, Flaccid paresis –
Reduced dystonic attacks behavioral and social improvement Attacks-free
–
–
–
–
Reported improved
Italy
M
ATP1A3 D756del de novo
3 months seizures
Y
Y
3:1
2 years and 7 months
Improved (see also Table 1 for details)
Legend: AHC, alternating hemiplegia of Childhood; F, female, M, male; KD, ketogenic diet.
T. Schirinzi et al. / Brain & Development xxx (2018) xxx–xxx
Please cite this article in press as: Schirinzi T et al. ATP1A3-related epileptic encephalopathy responding to ketogenic diet. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.01.002
Table 2 Summary of genetic, clinical data, efficacy of treatment of AHC patients treated with ketogenic diet previously reported, including our single case report.
T. Schirinzi et al. / Brain & Development xxx (2018) xxx–xxx
tive communication. Table 1 summarizes clinical data before and after KD. 3. Discussion AHC is a rare neurological disease with an onset before 18 months of age characterized by hemiplegic/ quadriplegic attacks, tonic/dystonic spells and ocular paroxysmal movements such as tonic gaze deviation and monocular nystagmus. Affected children usually have developmental delay, variable intellectual disability, seizures (50–80%), ataxia, and dysarthria [5]. Since ATP1A3 mutations were identified in AHC patients [6], the phenotypical spectrum of ATP1A3-related disease is expanding and still growing [5]. Intractable neonatal seizures, early life epilepsy, and status epilepticus have been reported in children with clinically defined AHC and an association has been made with the Glu815Lys mutations and neonatal-onset seizures [7]. Recently, a severe phenotype associated with catastrophic early life epilepsy, episodic prolonged apnea, and postnatal microcephaly has been described [8]. Our patient, harboring a novel ATP1A3 trinucleotide deletion c.2266_2268delGAC p.(D756del), showed a peculiar phenotype consisting in a complex picture of early onset drug-resistant epileptic encephalopathy, non-epileptic paroxysmal episodes (hypotonia, hemiplegia, apnea, monocular nystagmus) and developmental delay. Interestingly, other authors, including our group [4,9], described patients carrying missense mutation at same residue 756 displaying a phenotype mainly resembling RDP, and fever-induced encephalopathy with dystonia and ataxia. Recently, Yano et al. [10] hypothesized a new distinct phenotype associated to residue 756 comparing clinical features of new patients with those already described in the literature. Thus, our case certainly enlarges the spectrum of ATP1A3 genotypephenotype correlations. Moreover, the clinical course of our patient along with the efficacy of KD suggests the opportunity to alternatively treat an ATP1A3-related disease. There are few reports (case reports or short case series) of patients with AHC treated with KD during the course of disease. Table 2 summarizes all cases reported, to our knowledge in the literature, with their respective available clinical and genetic data. Among few others, our case has a long follow-up, KD is still well tolerated and the improvement is constant. Due to unique clinical presentation, as early-onset epileptic encephalopathy, our case is the only case reported with an improvement of both epileptic and not epileptic episodes after KD. In fact, our patient showed an excellent response to KD provided the first evidence of successful application of KD in a severe ATP1A3-related drug-resistant epileptic encephalopathy. In last decades, the practice of KD has
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spread out, being frequently used for drug-resistant epilepsy and many other neurological disorders. KD antiepileptic activity is due to a complex intertwine of mechanisms which encompasses a direct anti-seizure action, the recovery of a new neurotransmitters balance, the rearrangement of both cellular and mitochondrial metabolism and an antioxidant effect [11]. However, the efficacy of KD in our case could be related to the specific action of ketones on ATP-sensitive potassium channels (KATP channels). In fact, since the blocking of Na+/K+ ATPase pump leads to the inhibition of KATP channels causing neuronal hyperexcitability [12], it is reasonable that, here, the diet-induced ketosis has improved epilepsy by the modulation of KATP channels, whose activity was affected by the dysfunction of Na+/K+ ATPase pump. Our case, together with other reports on AHC [3,13– 15] and compelling experimental findings, in turn, supporting the role of ketones in restoring cellular effects of Na+/K+ ATPase pump dysfunction, indicate KD as a novel therapeutic opportunity in some patients with ATP1A3-related conditions. However, proper dedicated confirmatory trials are necessary.
Acknowledgement We wish to thank patient’s parents for their kind support. Ethical approval This work did not need any ethical committee approval. Both patient’s parents signed written informed consensus to use relevant material for this paper. Financial disclosure The authors have no financial relationships relevant to this article to disclose. Conflict of interest None. References [1] Sweney MT, Newcomb TM, Swoboda KJ. The expanding spectrum of neurological phenotypes in children with ATP1A3 mutations, alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism CAPOS and beyond. Pediatr Neurol 2015;52:56–64. [2] Heinzen EL, Arzimanoglou A, Brashear A, Clapcote SJ, Gurrieri F, Goldstein DB, et al. Distinct neurological disorders with ATP1A3 mutations. Lancet Neurol 2014;13:503–14.
Please cite this article in press as: Schirinzi T et al. ATP1A3-related epileptic encephalopathy responding to ketogenic diet. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.01.002
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T. Schirinzi et al. / Brain & Development xxx (2018) xxx–xxx [3] Pisciotta L, Gherzi M, Stagnaro M, Calevo MG, Giannotta M, Vavassori MR, et al. Alternating hemiplegia of childhood: pharmacological treatment of 30 italian patients. Brain Dev. 2017;39:521–8. [4] Fornarino S, Stagnaro M, Rinelli M, Tiziano D, Mancardi MM, Traverso M, et al. Paroxysmal features responding to flunarizine in a child with rapid-onset dystonia-parkinsonism. Neurology 2014;82:2037–8. [5] Mikati MA, Kramer U, Zupanc ML, Shanahan RJ. Alternating hemiplegia of childhood: clinical manifestations and long-term outcome. Pediatr Neurol 2000;23:134–41. [6] Heinzen EL, Swoboda KJ, Hitomi Y, et al. De novo mutations in ATP1A3 cause alternating hemiplegia of childhood. Nat Genet 2012;44:1030–4. [7] Sasaki M, Ishii A, Saito Y, et al. Genotype-phenotype correlations in alternating hemiplegia of childhood. Neurology 2014;82:482–90. [8] Paciorkowski AR, McDaniel SS, Jansen LA, Tully H, Tuttle E, Ghoneim DH, et al. Novel mutations in ATP1A3 associated with catastrophic early life epilepsy, episodic prolonged apnea, and postnatal microcephaly. Epilepsia 2015;56:422–30. [9] Nicita F, Travaglini L, Sabatini S, Garavaglia B, Panteghini C, Valeriani M, et al. Childhood-onset ATP1A3-related conditions:
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Please cite this article in press as: Schirinzi T et al. ATP1A3-related epileptic encephalopathy responding to ketogenic diet. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.01.002