Pediatric Neurology 52 (2015) 125e127

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Clinical Observations

Paroxysmal Tonic Upward Gaze Complicating Angelman Syndrome Shinobu Fukumura MD a, b, *, Toshihide Watanabe MD, PhD a, b, Rumiko Takayama MD, PhD a, b, Hiroyuki Tsutsumi MD, PhD b a b

Department of Child Neurology, Hokkaido Medical Center for Child Health and Rehabilitation, Sapporo, Japan Department of Pediatrics, School of Medicine, Sapporo Medical University, Sapporo, Japan

abstract BACKGROUND: Paroxysmal tonic upward gaze is a childhood oculomotor syndrome characterized by episodes of conjugate upward deviation of the eyes. Its pathogenesis is unknown, and the etiology is heterogeneous. PATIENT DESCRIPTION: We describe a 2-year-old girl with Angelman syndrome who developed paroxysmal tonic upward gaze at 9 months of age. She presented with developmental delay, blond hair, jerky movements, ataxia, and epilepsy. Genetic testing revealed a maternal deletion of 15q11-13, confirming Angelman syndrome. CONCLUSIONS: This is the first report of Angelman syndrome complicated by paroxysmal tonic upward gaze. Both transient paroxysmal tonic upward gaze and Angelman syndrome have been associated with dopaminergic neurons. We speculate that the dopaminergic abnormalities present in Angelman syndrome may cause paroxysmal tonic upward gaze. Keywords: paroxysmal tonic upward gaze, movement disorder, Angelman syndrome, chromosome 15

Pediatr Neurol 2015; 52: 125-127 Ó 2015 Elsevier Inc. All rights reserved.

Introduction

Angelman syndrome (OMIM 105830), classified as a neurogenetic disorder, results from the absence of the ubiquitin-protein ligase E3A (UBE3A) gene expression, usually because of a deletion of the maternally inherited chromosome 15q11-q13.1,2 In addition to severe cognitive and motor delay, the following are listed as characteristic features: severely impaired speech, a wide-based ataxic gait, jerky movements, intractable epilepsy with characteristic electroencephalographic (EEG) abnormalities, subtle dysmorphic facial features, choroidal pigment hypoplasia, hyperexcitable personality, sleep disorders, and a happy disposition with a tendency to frequent paroxysms of laughter.2-4 Ophthalmic abnormalities associated with Angelman syndrome include strabismus, nystagmus, Article History: Received June 11, 2014; Accepted in final form August 26, 2014 * Communications should be addressed to: Dr. Fukumura; Department of Pediatrics; School of Medicine; Sapporo Medical University; S1 W16 Chuo-ku; 060-8556 Sapporo, Japan. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2014.08.022

refractive errors, amblyopia, iris and choroidal hypopigmentation, optic nerve atrophy or optic disk pallor, retinochoroidal atrophy, ptosis, and keratoconus.2,5 However, there have been no reports of paroxysmal tonic upward gaze (PTU) in an individual with Angelman syndrome. Patient Description This girl was born at 33 weeks’ gestation as the first child of healthy nonconsanguineous Japanese parents. Her Apgar scores were 9 and 9 after 1 and 5 minutes, respectively, with a birth weight of 1820 g. The neonatal period was significant for transient neonatal jaundice as well as milk intolerance and reflux. There was no family history of hereditary disorders. Moreover, her head growth slowly decelerated from the first months of age. She had delayed developmental milestones, i.e., head control at 5 months, sitting at 14 months, and aided walking at 24 months. At 9 months, she began to exhibit intermittent upward deviation of the eyes, with each episode lasting for a few seconds (Fig 1). These episodes occurred multiple times per day with a spontaneous resumption of normal ocular movements. The episodes occurred in small clusters and were not accompanied by any clouding of consciousness. Furthermore, she did not have downbeating saccades during attempted downgaze. These attacks increased while eating but disappeared during sleep. There was no history of infection or drug ingestion. Subsequent to

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FIGURE 1. Episode of sudden upward deviation of the eyes during a meal. her initial presentation, the episodes increased in number during the following weeks. We first saw the patient when she was 10-months-old. Neurological and ophthalmologic examinations were normal aside from her gross motor delay and microcephaly with a head circumference of 40.5 cm (2.5 S.D.). She had blond hair, a wide mouth, and showed jerky movements. Chest radiography, abdominal sonogram, cerebrospinal fluid examination, serum lactate, chemistry profile, and urinary catecholamines were normal. Brain magnetic resonance imaging revealed no abnormalities, including white matter. Interictal EEG revealed a high-amplitude background activity ranging from 5 to 6 Hz. Video EEG was performed during tonic upward gaze episodes and revealed no epileptic abnormalities (Fig 2). As a result, we diagnosed her eye movements as PTU. These episodes occurred at the same frequency during the following 2 months, after which they decreased but did not completely disappear. At 16 months of age, she presented with afebrile generalized tonicclonic and myoclonic seizures. EEG revealed generalized slow-wave activity with paroxysmal spike waves. Altogether, the epileptic seizures, EEG findings, in addition to both mental and motor delays, and characteristic hair and facial features led us to suspect Angelman syndrome. Fluorescence in situ hybridization studies demonstrated a deletion on the long arm of chromosome 15, a finding typical of Angelman syndrome.

Discussion

The causes of paroxysmal upward deviation of the eyes in children include epilepsy, oculogyric crisis, and PTU.6 In our patient, epilepsy can be excluded because of the absence of spike activity on the EEG performed at the time of tonic upward gaze. Oculogyric crisis is characterized by a maximal upward deviation of the eyes in a sustained fashion lasting from a few seconds to hours. This condition is most frequently described in antidopaminergic drugrelated crises and metabolic disorders. Other benign stereotypic movement, such as tic or periodic nonsustained upward gaze can be observed in many normal and developmentally delayed children, but they are not consistent with the character observed in our patient. PTU, which was originally reported by Ouvrier and Billson7 in 1988, is a childhood syndrome characterized by sudden ocular movements with a sustained upward deviation of the eyes. Its clinical features are as follows: onset in early to midinfancy with subsequent resolution, day-time fluctuation, frequent relief during sleep, and the absence of deterioration during long-term follow-up. Neurological examination and laboratory testing are typically normal.6 The pathophysiological basis of PTU is not completely understood. Further, although parental inheritance is not

FIGURE 2. Electroencephalography (EEG) performed during eating. Diffuse highamplitude theta rhythms from 5 to 6 Hz were evident in the background activity. Video EEG during tonic upward gaze (arrow) episodes showed no epileptic abnormalities. ECG ¼ electrocardiogram.

present in many PTU patients, a few cases have demonstrated autosomal dominant inheritance. The occurrence of PTU in families suggests a genetic contribution to the development of the disorder.8,9 In contrast, Angelman syndrome is a genetic disorder resulting from the deletion of the maternal origin 15q11q13. Therefore, in this child with Angelman syndrome, complicating PTU may be associated with an abnormality of the chromosome 15q. Joseph et al.10 reported a boy with PTU who expressed the 15q extra euchromatin. In addition to PTU, he also exhibited hypotonia and gross motor delay. They speculated that the 15q extra euchromatin was associated with his PTU. However, we did not examine the detailed range of our patient’s chromosome 15q deletion. Therefore, it was unclear whether the deletion in our case extended to the region that Joseph et al. demonstrated to contain the 15q extra euchromatin. Thus, further examination may provide clues that will aid in identifying a specific region in the chromosome 15q responsible for PTU. The structural lesions responsible for PTU have been postulated as delayed myelination, long-standing hydrocephalus, and white matter abnormalities, including periventricular leukomalacia.11,12 The anatomic site responsible for tonic upward gaze deviation has been suggested to be located in the midbrain.6,12,13 In contrast, the coexistence of PTU with many other cerebral problems (e.g., microcephaly, intellectual disability, speech delay, and epilepsy) would seem to favor a cerebral origin of PTU. Furthermore, it may be a transient neurological dysfunction affecting the immature corticomesencephalic control of vertical eye movement during development.6,12 Because PTU is paroxysmal and not typically associated with structural brain lesions, some authors have postulated that it may result from localized neurotransmitter dysfunction.6 This is particularly relevant for dopamine because of the improvement some PTU patients have shown after dopa treatment.8 Casseron et al.14 reported

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two sisters with DOPA-sensitive dystonia-plus syndrome who exhibited episodes of PTU. Some authors have also reported an association between Angelman syndrome and dopaminergic abnormalities. In animal studies, Angelman syndrome model mice lacking maternal Ube3a (Ube3a m/pþ mice) have reduced dopamine cell numbers in the substantia nigra pars compacta.15 In drosophila, Ube3A has been demonstrated to regulate GTP cyclohydrolase I, an essential enzyme in dopamine biosynthesis.16 A study of two adults with Angelman syndrome demonstrated that levodopa (L-dopa) administration dramatically improved resting tremor and rigidity, leading to a clinical trial of L-dopa in individuals with Angelman syndrome.17,18 The concurrence of transient PTU with Angelman syndrome in our patient suggests a common pathogenesis of dopaminergic abnormalities. We suspect that the neurochemical substrate underlying transient PTU involves dopaminergic abnormalities. However, we did not use L-dopa for our patient because her tonic upward deviation of the eyes gradually resolved. Further research in dopaminergic abnormalities in patients with transient PTU and Angelman syndrome should be conducted. The authors thank Dr. Peter Olley (Professor Emeritus, University of Alberta) for English language advice. There is no funding or financial support for this article.

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3. Williams CA. Neurological aspects of the Angelman syndrome. Brain Dev. 2005;27:88-89. 4. Thibert RL, Larson AM, Hsieh DT, Raby AR, Thiele EA. Neurologic manifestations of Angelman syndrome. Pediatr Neurol. 2013;48: 271-279. 5. Michieletto P, Bonanni P, Pensiero S. Ophthalmic findings in Angelman syndrome. J AAPOS. 2011;15:158-161. 6. Ouvrier RA, Billson F. Paroxysmal tonic upgaze of childhoodea review. Brain Dev. 2005;27:185-188. 7. Ouvrier RA, Billson F. Benign paroxysmal tonic upgaze of childhood. J Child Neurol. 1988;3:177-180. 8. Guerrini R, Belmonte A, Carrozzo R. Paroxysmal tonic upgaze of childhood with ataxia: a benign transient dystonia with autosomal dominant inheritance. Brain Dev. 1998;20:116-118. 9. Hayman M, Harvey AS, Hopkins IJ, et al. Paroxysmal tonic upgaze: a reappraisal of outcome. Ann Neurol. 1998;43:514-520. 10. Joseph K, Avallone J, Difazio M. Paroxysmal tonic upgaze and partial tetrasomy of chromosome 15: a novel genetic association. J Child Neurol. 2005;20:165-168. 11. Sugie H, Sugie Y, Ito M, et al. A case of paroxysmal tonic upward gaze associated with psychomotor retardation. Dev Med Child Neurol. 1995;37:362-365. 12. Spalice A, Parisi P, Iannetti P. Paroxysmal tonic upgaze: physiopathological considerations in three additional cases. J Child Neurol. 2000;15:15-18. 13. Jacobs K, Heffner RR, Newman RP. Selective paralysis of downward gaze caused by bilateral lesions of the periaqueductal gray matter. Neurology. 1985;35:516-521. 14. Casseron W, Genton P. DOPA-sensitive dystonia-plus syndrome. Dev Med Child Neurol. 2005;47:200-203. 15. Mulherkar SA, Jana NR. Loss of dopaminergic neurons and resulting behavioural deficits in mouse model of Angelman syndrome. Neurobiol Dis. 2010;40:586-592. 16. Ferdousy F, Bodeen W, Summers K, et al. Drosophila Ube3a regulates monoamine synthesis by increasing GTP cyclohydrolase I activity via a non-ubiquitin ligase mechanism. Neurobiol Dis. 2011; 41:669-677. 17. Harbord M. Levodopa responsive Parkinsonism in adults with Angelman Syndrome. J Clin Neurosci. 2001;8:421-422. 18. A Trial of Levodopa in Angelman Syndrome. NIH Web site. Available at: http://clinicaltrials.gov/ct2/show/NCT01281475. Accessed October 1, 2012.

Paroxysmal tonic upward gaze complicating Angelman syndrome.

Paroxysmal tonic upward gaze is a childhood oculomotor syndrome characterized by episodes of conjugate upward deviation of the eyes. Its pathogenesis ...
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