e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 9 ( 2 0 1 5 ) 2 7 8 e2 7 9
Official Journal of the European Paediatric Neurology Society
Editorial
Paroxysmal tonic upward gaze of childhood “plus”: An oculomotor channelopathy? In the current issue of EJPN, Blumkin and colleagues1 describe 3 further cases of a rare oculomotor disorder, namely paroxysmal tonic upward gaze (PTU), with additional motor and language delay, as well as cerebellar ataxia, and by whom mutations of the CACNA1A gene could be demonstrated. The pathophysiological mechanisms controlling eye movements are complex and poorly understood. Upward deviation of the eyes may appear due to focal seizure activity, but it has also been observed in postencephalitic parkinsonism, coma, brainstem disorders, oculogyric crises on the ground of neurotransmitter or other metabolic disorders and retinal disease with bilateral central visual loss.1,2 Structural lesions responsible for PTU include, among others, delayed myelination, hydrocephalus and white matter abnormalities such as periventricular leukomalacia, although the responsible anatomic site has been suggested to be located in the midbrain.2 PTU was first described as an apparently benign oculomor syndrome of infancy with onset before the first year of age by Ouvrier and Billson in 1988.2 After more than 25 years and further description of almost 45 cases,1 it has been more than clear that PTU may coexist with several brain disorders (mainly microcephaly, intellectual disability, speech delay, epilepsy and movement disorders in particular ataxia), with cognitive issues and ataxia being slowly progressive after years of follow-up in many cases (“PTU plus”).1e3 These facts favored a cerebral origin of PTU, thus eliminating the term benign from the original definition. Regarding the so-called “pure” cases with normal EEG, MRI, metabolic and genetic work-up, and occurrence of spontaneous remission after months or years without any neurodevelopmental sequelae, a transient neurological dysfunction affecting the immature corticomesencephalic control of vertical eye movements during development was postulated.4 Moreover, an association with prior immunological events, such as febrile illness or vaccination, before the onset of PTU has been suggested, without clear-cut evidence though. Thus, although the exact pathogenetic mechanism of the disorder is still unknown, the report of some familial cases suggested the possible contribution of unrecognized genetic factors.2 Supporting that context, Roubertie et al.5 first reported on two siblings with PTU harboring the same CACNA1A mutation, suggesting that PTU could be included in the large list of
channelopathies that may present with paroxysmal symptomatology, namely paroxysmal tonic upward gaze of childhood, benign paroxysmal torticollis, and episodic ataxia type 2. Up to date, numerous CACNA1A mutations have been identified alone or in combination in patients with a variety of symptoms and conditions (both paroxysmal as well as chronic): ataxia (episodic, chronic progressive and in certain instances spinocerebellar), hemiplegic migraine (familial and non familial), dyskinesia and dystonia, head tremor, paroxysmal torticollis of infancy, alternating hemiplegia, seizures, absence epilepsy, status epilepticus, cerebral oedema, prolonged coma, developmental regression and/or mental retardation, hemiplegia-hemiconvulsions-epilepsy (HHE) syndrome, ictal hyperhidrosis, hypothermia and chronic diarrhoea.5e9 Especially regarding eye motility abnormalities, CACNA1A mutations have been associated with infantile nystagmus, slow saccadic velocities10 and, last but not least, PTU in the two siblings reported by Roubertie et al..5 Blumkin et al.1 with their current report support further evidence to the association between CACNA1A gene mutations and “PTU plus”, favoring the hypothesis of PTU being a paroxysmal dystonia due to an underlying cerebellar dysfunction in the context of a channelopathy. The need for direct assessing the CACNA1A gene or performing next generation sequencing (such as exome sequencing) in these patients, as well as the need for further follow-up, even if PTU has apparently resolved, in order not to overlook long-term associated neurodevelopmental abnormalities, should be emphasized.
references
1. Blumkin L, Leshinsky-Silver E, Michelson M, Zerem A, Kivity S, Lev D, et al. Paroxysmal tonic upward gaze as a presentation of de-novo mutations in CACNA1A. Eur J Paediatr Neurol 2015. http://dx.doi.org/10.1016/j.ejpn.2014.12.018 [Epub ahead of print]. 2. Ouvrier RA, Billson F. Paroxysmal tonic upgaze of childhood e a review. Brain Dev 2005;27:185e8. 3. Verrotti A, Di Marco G, la Torre R, Chiarelli F. Paroxysmal tonic upgaze of childhood and childhood absence epilepsy. Eur J Paediatr Neurol 2010;14:93.
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 9 ( 2 0 1 5 ) 2 7 8 e2 7 9
4. Salmina C, Taddeo I, Falesi M, Weber P, Bianchetti MG, Ramelli GP. Paroxysmal tonic upgaze in normal children: a case series and a review of the literature. Eur J Paediatr Neurol 2012;16:683e7. 5. Roubertie A, Echenne B, Leydet J, et al. Benign paroxysmal tonic upgaze, benign paroxysmal torticollis, episodic ataxia and CACNA1A mutation in a family. J Neurol 2008;255:1600e2. 6. Nachbauer W, Nocker M, Karner E, Stankovic I, Unterberger I, Eigentler A, et al. Episodic ataxia type 2: phenotype characteristics of a novel CACNA1A mutation and review of the literature. J Neurol 2014;261:983e91. 7. Giffin NJ, Benton S, Goadsby PJ. Benign paroxysmal torticollis of infancy: four new cases and linkage to CACNA1A mutation. Dev Med Child Neurol 2002;44:490e3. 8. Geerlings RP, Koehler PJ, Haane DY, et al. Head tremor related to CACNA1A mutations. Cephalalgia 2011;31:1315e9. 9. Zafeiriou DI, Lehmann-Horn F, Vargiami E, Teflioudi E, Ververi A, Jurkat-Rott K. Episodic ataxia type 2 showing ictal hyperhidrosis with hypothermia and interictal chronic diarrhea due to a novel CACNA1A mutation. Eur J Paediatr Neurol 2009;13:191e3.
279
10. Kipfer S, Jung S, Lemke JR, Kipfer-Kauer A, Howell JP, KaelinLang A, Nyffeler T, Gutbrod K, Abicht A, Mu¨ri RM. Novel CACNA1A mutation(s) associated with slow saccade velocities. J Neurol 2013;260:3010e4.
Dimitrios I. Zafeiriou* 1st Department of Pediatrics, Aristotle University of Thessaloniki, “Hippokratio” General Hospital, Egnatia St. 106, 54622 Thessaloniki, Greece *Tel.: þ30 2310 241845, þ30 6944 330587 (mobile); fax: þ30 2310 241845. E-mail address: [email protected] http://dx.doi.org/10.1016/j.ejpn.2015.03.003 1090-3798/© 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Official Journal of the European Paediatric Neurology Society
Editorial
Paroxysmal tonic upward gaze of childhood “plus”: An oculomotor channelopathy? In the current issue of EJPN, Blumkin and colleagues1 describe 3 further cases of a rare oculomotor disorder, namely paroxysmal tonic upward gaze (PTU), with additional motor and language delay, as well as cerebellar ataxia, and by whom mutations of the CACNA1A gene could be demonstrated. The pathophysiological mechanisms controlling eye movements are complex and poorly understood. Upward deviation of the eyes may appear due to focal seizure activity, but it has also been observed in postencephalitic parkinsonism, coma, brainstem disorders, oculogyric crises on the ground of neurotransmitter or other metabolic disorders and retinal disease with bilateral central visual loss.1,2 Structural lesions responsible for PTU include, among others, delayed myelination, hydrocephalus and white matter abnormalities such as periventricular leukomalacia, although the responsible anatomic site has been suggested to be located in the midbrain.2 PTU was first described as an apparently benign oculomor syndrome of infancy with onset before the first year of age by Ouvrier and Billson in 1988.2 After more than 25 years and further description of almost 45 cases,1 it has been more than clear that PTU may coexist with several brain disorders (mainly microcephaly, intellectual disability, speech delay, epilepsy and movement disorders in particular ataxia), with cognitive issues and ataxia being slowly progressive after years of follow-up in many cases (“PTU plus”).1e3 These facts favored a cerebral origin of PTU, thus eliminating the term benign from the original definition. Regarding the so-called “pure” cases with normal EEG, MRI, metabolic and genetic work-up, and occurrence of spontaneous remission after months or years without any neurodevelopmental sequelae, a transient neurological dysfunction affecting the immature corticomesencephalic control of vertical eye movements during development was postulated.4 Moreover, an association with prior immunological events, such as febrile illness or vaccination, before the onset of PTU has been suggested, without clear-cut evidence though. Thus, although the exact pathogenetic mechanism of the disorder is still unknown, the report of some familial cases suggested the possible contribution of unrecognized genetic factors.2 Supporting that context, Roubertie et al.5 first reported on two siblings with PTU harboring the same CACNA1A mutation, suggesting that PTU could be included in the large list of
channelopathies that may present with paroxysmal symptomatology, namely paroxysmal tonic upward gaze of childhood, benign paroxysmal torticollis, and episodic ataxia type 2. Up to date, numerous CACNA1A mutations have been identified alone or in combination in patients with a variety of symptoms and conditions (both paroxysmal as well as chronic): ataxia (episodic, chronic progressive and in certain instances spinocerebellar), hemiplegic migraine (familial and non familial), dyskinesia and dystonia, head tremor, paroxysmal torticollis of infancy, alternating hemiplegia, seizures, absence epilepsy, status epilepticus, cerebral oedema, prolonged coma, developmental regression and/or mental retardation, hemiplegia-hemiconvulsions-epilepsy (HHE) syndrome, ictal hyperhidrosis, hypothermia and chronic diarrhoea.5e9 Especially regarding eye motility abnormalities, CACNA1A mutations have been associated with infantile nystagmus, slow saccadic velocities10 and, last but not least, PTU in the two siblings reported by Roubertie et al..5 Blumkin et al.1 with their current report support further evidence to the association between CACNA1A gene mutations and “PTU plus”, favoring the hypothesis of PTU being a paroxysmal dystonia due to an underlying cerebellar dysfunction in the context of a channelopathy. The need for direct assessing the CACNA1A gene or performing next generation sequencing (such as exome sequencing) in these patients, as well as the need for further follow-up, even if PTU has apparently resolved, in order not to overlook long-term associated neurodevelopmental abnormalities, should be emphasized.
references
1. Blumkin L, Leshinsky-Silver E, Michelson M, Zerem A, Kivity S, Lev D, et al. Paroxysmal tonic upward gaze as a presentation of de-novo mutations in CACNA1A. Eur J Paediatr Neurol 2015. http://dx.doi.org/10.1016/j.ejpn.2014.12.018 [Epub ahead of print]. 2. Ouvrier RA, Billson F. Paroxysmal tonic upgaze of childhood e a review. Brain Dev 2005;27:185e8. 3. Verrotti A, Di Marco G, la Torre R, Chiarelli F. Paroxysmal tonic upgaze of childhood and childhood absence epilepsy. Eur J Paediatr Neurol 2010;14:93.
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 9 ( 2 0 1 5 ) 2 7 8 e2 7 9
4. Salmina C, Taddeo I, Falesi M, Weber P, Bianchetti MG, Ramelli GP. Paroxysmal tonic upgaze in normal children: a case series and a review of the literature. Eur J Paediatr Neurol 2012;16:683e7. 5. Roubertie A, Echenne B, Leydet J, et al. Benign paroxysmal tonic upgaze, benign paroxysmal torticollis, episodic ataxia and CACNA1A mutation in a family. J Neurol 2008;255:1600e2. 6. Nachbauer W, Nocker M, Karner E, Stankovic I, Unterberger I, Eigentler A, et al. Episodic ataxia type 2: phenotype characteristics of a novel CACNA1A mutation and review of the literature. J Neurol 2014;261:983e91. 7. Giffin NJ, Benton S, Goadsby PJ. Benign paroxysmal torticollis of infancy: four new cases and linkage to CACNA1A mutation. Dev Med Child Neurol 2002;44:490e3. 8. Geerlings RP, Koehler PJ, Haane DY, et al. Head tremor related to CACNA1A mutations. Cephalalgia 2011;31:1315e9. 9. Zafeiriou DI, Lehmann-Horn F, Vargiami E, Teflioudi E, Ververi A, Jurkat-Rott K. Episodic ataxia type 2 showing ictal hyperhidrosis with hypothermia and interictal chronic diarrhea due to a novel CACNA1A mutation. Eur J Paediatr Neurol 2009;13:191e3.
279
10. Kipfer S, Jung S, Lemke JR, Kipfer-Kauer A, Howell JP, KaelinLang A, Nyffeler T, Gutbrod K, Abicht A, Mu¨ri RM. Novel CACNA1A mutation(s) associated with slow saccade velocities. J Neurol 2013;260:3010e4.
Dimitrios I. Zafeiriou* 1st Department of Pediatrics, Aristotle University of Thessaloniki, “Hippokratio” General Hospital, Egnatia St. 106, 54622 Thessaloniki, Greece *Tel.: þ30 2310 241845, þ30 6944 330587 (mobile); fax: þ30 2310 241845. E-mail address: [email protected] http://dx.doi.org/10.1016/j.ejpn.2015.03.003 1090-3798/© 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
