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Official Journal of the European Paediatric Neurology Society
Original article
Paroxysmal tonic upward gaze as a presentation of de-novo mutations in CACNA1A Lubov Blumkin a,b,*,e, Esther Leshinsky-Silver b,c,d,e, Marina Michelson b,c, Ayelet Zerem a,b, Sara Kivity a,b, Dorit Lev b,c, Tally Lerman-Sagie a,b a
Pediatric Neurology Unit, Wolfson Medical Center, Sackler School of Medicine, Tel-Aviv University, Holon, Israel Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Sackler School of Medicine, Tel-Aviv University, Holon, Israel c Institute of Medical Genetics, Wolfson Medical Center, Sackler School of Medicine, Tel-Aviv University, Holon, Israel d Molecular Laboratory, Wolfson Medical Center, Sackler School of Medicine, Tel-Aviv University, Holon, Israel b
article info
abstract
Article history:
Objective: Paroxysmal tonic upward gaze was initially described as a benign phenomenon
Received 18 September 2014
with negative investigations and eventual complete resolution of symptoms. Later publi-
Received in revised form
cations demonstrated that a similar clinical picture may arise from structural brain lesions,
24 December 2014
channelopathies, neurotransmitter disorders, and epileptic seizures. CACNA1A related
Accepted 25 December 2014
disorders manifest as a wide spectrum of paroxysmal neurological disorders: episodic ataxia 2, hemiplegic migraine, benign paroxysmal torticollis of infancy, and paroxysmal
Keywords:
vertigo. Paroxysmal tonic upward gaze as a phenomenon in patients with mutations in the
Paroxysmal tonic upward gaze
CACNA1A gene has only been reported once.
CACNA1A
Methods: We describe three patients with multiple episodes of paroxysmal tonic up-
Ataxia
ward gaze that appeared during the first months of life. In addition the patients demonstrated motor and language delay and cerebellar ataxia. A sequence analysis of the CACNA1A gene in one patient and whole exome sequencing in the other patients were performed. Results: Sequence analysis of the CACNA1A gene in one patient and whole exome sequencing in the two other patients revealed 3 different de-novo mutations in the CACNA1A gene. Conclusion: CACNA1A mutations should be evaluated in infants and young children with paroxysmal tonic upgaze especially if associated with developmental delay, cerebellar signs, and other types of paroxysmal event. © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Pediatric Neurology Unit, Metabolic-Neurogenetic Clinic, Wolfson Medical Center, POB 5, Holon 58100, Israel. Tel.: þ972 3 5028458; fax: þ972 3 5028141. E-mail address: [email protected] (L. Blumkin). e These authors contributed equally. http://dx.doi.org/10.1016/j.ejpn.2014.12.018 1090-3798/© 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
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 9 2 e2 9 7
1.
Introduction
Ouvrier and Billson1 were the first to describe the entity of paroxysmal tonic upward gaze (PTU).1 The clinical features of PTU comprise recurrent episodes of sustained conjugate upward deviation of the eyes with neck flexion (chin down), down-beating saccades on attempted down-gaze, preserved horizontal eye movements, unaffected consciousness and sometimes, impaired coordination. The episodes of tonic upgaze may last for a few minutes, hours and days with diurnal fluctuation of symptoms, frequently relieved by sleep, and accompanied by varying degrees of ataxia.1,2 The entity was defined as an apparently benign phenomenon with negative investigations and eventual complete resolution of the symptoms.1 A later review of 45 additional cases and other publications have demonstrated that a similar clinical picture may arise from structural brain lesions and that PTU may be associated with later development of epilepsy, chronic ataxia, borderline cognitive abilities and residual minor oculomotor disorders.2e13 Ataxia may occur either intermittently at the time of the attacks of tonic upgaze or as a chronic disability and independent from the ocular movement disorder.2,4,5,7,8,11 The association of this syndrome with epileptic disorders8,12,13 and intellectual disability6 has been reported in a few cases. The epileptic seizures can appear before or after the onset of PTU, and are classified as absence seizure. The etiology of PTU remains obscure. Autosomal dominant or recessive inheritance has been described but the involved genes have not been found.5,7 We describe three patients who presented with multiple episodes of paroxysmal upward eye deviation that appeared during the first months of life. They all demonstrated motor and speech delay and later developed cerebellar ataxia. Sequence analysis of the CACNA1A gene in one patient and whole exome sequencing in the other two patients revealed 3 different de-novo mutations in the CACNA1A gene.
deviation, commonly accompanied by the chin down phenomenon and downbeat nystagmus in attempt to look downward. During these episodes she was comfortable, and demonstrated normal eye contact in the superior visual field. These episodes occurred several times a day, lasting a few seconds to a few minutes and exacerbated by fatigue. When she was placed in the supine position, these episodes would be accompanied by slow side-to-side head movements and would cease by distraction. On neurologic examination at the age of six months the patient demonstrated normal horizontal eye movements, but difficulties with downward gaze. Attempts to look downwards triggered downbeat and eyelid nystagmus and initiated attacks of tonic upward gaze. She had head titubation and horizontal saccadic intrusions on pursuit. The PTU episodes disappeared spontaneously by the age of three years. On examination at the age of three years the patient was alert and communicative. She had normal physical development and head circumference. Ocular motor examination showed bilateral alternate convergent strabismus, gaze evoked horizontal nystagmus with no ophthalmoplegia, slow horizontal smooth pursuit with saccadic intrusions, difficulties with saccade initiation. She had very mild dysmetria of the hands, and a wide based ataxic gait. She ambulated with support of a walker. Her speech was mildly dysarthric but with a good vocabulary and age appropriate expressive abilities. Her behavior was inattentive and hyperactive and she demanded immediate satisfaction of her wishes. The rest of the neurologic examination was normal. She no longer manifested paroxysmal eye deviations, but had a few episodes of head tilt accompanied by eye blinking. An extensive evaluation was normal and included: video EEG monitoring during the episodes, ophthalmologic evaluations, metabolic tests, CSF for neurotransmitters and CGH microarray. Brain Magnetic Resonance Imaging (MRI) was performed at the age of eight months and demonstrated an enlargement of the subarachnoid spaces.
2.2.
2. 2.1.
293
Patient 2
Patients and methods Patient1
The patient is a three-year old girl who presented to the neurology clinic at the age of six months for evaluation of recurrent episodes of paroxysmal conjugate upward eye deviation. The patient is the only child of non-consanguineous parents. There is a strong family history of migraine without aura in both parents but no neurologic diseases, or paroxysmal neurologic phenomena have been reported. Early medical history and physical development were normal. She sustained one febrile convulsion. Motor development was slow: she rolled over at 8 months, sat at 20 months and started crawling and standing with support at the age of 24 months. First words appeared at the age of 24 months, and by the age of three years she achieved age appropriate expressive and receptive speech. The paroxysmal episodes started during the neonatal period and manifested with conjugate tonic upward eye
We have previously described this patient.14 He was referred to our clinic at the age of three years for evaluation of global psychomotor delay and dyskinesia. His perinatal history was uneventful. Motor development was significantly delayed. At the age of four months when the child was held upright, episodes of upward gaze deviation appeared. At the age of three and a half years he only manifested rare brief episodes of upward gaze deviation that increased during stress. Other abnormal movements appeared later and presented with transient horizontal rhythmic head movements, simple motor stereotypies, non-specific involuntary movements, and head and hand tremor, usually provoked by motor activity and stress. Cerebellar abnormalities, pyramidal signs, and episodic coma associated with seizures and autonomic symptoms became apparent after the age of two years. The first brain MRI at the age of 8 months was normal. The second study, done during the last episode of coma at the age of 6 years, revealed severe cerebellar atrophy and mild right hemisphere edema.
294
2.3.
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Patient 3
A 5-year-old girl presented to our metabolic-neurogenetic clinic due to global developmental delay and abnormal eye movements. She is the only child of non-consanguineous healthy Moroccan-Jews. The perinatal history was uneventful. The patient's psychomotor development had been delayed, especially her gross motor skills. She started rolling over at 14 months, sat unsupported at 24 months, walked at the age of 35 months. Her gait was unsteady and she frequently fell. She manifested expressive speech delay. Recurrent attacks of abnormal eye movements started at the age of three days. These attacks manifested as conjugate upward eye deviation, lasting for 5e6 s, and appearing multiple times daily. Later on, the episodes appeared two to three times weekly and were accompanied by the chin down phenomenon and lack of response to command and touch. The frequency of the episodes decreased significantly by the age of five years. Since one year of age she demonstrated other paroxysmal attacks: recurrent staring, episodes of torticollis accompanied by nystagmus, lasting a few minutes, and periods of imbalance, lasting for a few hours that caused a deterioration of her baseline unsteady gait. Recurrent interictal EEG studies were normal. Treatment with acetazolamide significantly decreased the frequency of episodic ataxia but did not improve her unsteadiness. On examination at the age of five years she was cooperative but easily distracted, inattentive, hyperactive, and childish. Physical development and head circumference were age appropriate. She exhibited upbeat nystagmus on vertical gaze, convergent strabismus, dysarthria, limb dysmetria and tremor, and an ataxic gait. There were no signs of oculomotor apraxia. She had repetitive involuntary mouth opening, significantly increased by stress and motor activity, reminding jaw-opening oromandibular dystonia. The patient's investigations were normal and included thyroid function tests, carnitine, acylcarnitine, blood amino acids, urine organic acids, lactic acid, creatine phosphokinase, ammonia, cerebrospinal fluid lactic acid and glucose. Visual evoked potentials were normal. Brain MRIs performed at the age of 14 and 24 months demonstrated a large cisterna magna. MR spectroscopy was normal. Genetic studies including: karyotype, CGH microarray, SepSecS mutations, MECP2 gene sequencing and multiplex ligation-dependent probe amplification (MLPA), and methylation for Angelman syndrome were normal.
3.
Molecular analysis
CACNA1A sequencing was performed according to Blumkin et al.14 Whole exome sequencing was performed on the patient's DNA. The sample was enriched with Sureselect Human All Exome v.2 kit which was targeted 50 Mb (Agilent, Santa Clara, CA, USA). Sequencing was carried out on HiSeq2000 (Illumina,
San diego, CA, USA) as 100-bp paired-end runs. Image analysis and base calling were performed with the Genome Analyzer Pipeline version 1.5 with default parameters. Reads were mapped to the human reference genome sequence (assembly GRCh37/hg19) using the Burrows-Wheeler Alignment Tool (BWA) version 0.5.8c, and allelic variants were detected using the Genome Analysis Toolkit (GATK). Dataset files including the annotated information were analyzed using ANNOVAR according to the dbSNP database (build 135) and the NHLBI exome variant database with the following filtering steps: variant type including missense, nonsense, and splice-site; not within segmental duplications; minor allele frequency (MAF) less than 0.01; SIFT score 0.85 when available.
4.
Results
Sequence analysis of the CACNA1A gene in patient 2 revealed a de novo heterozygous mutation p.R1349Q; isoforms1,2,3,5; p.1348Q in isoform4 (formally reported mistakenly as R1350Q). Whole exome sequencing revealed the de novo heterozygous mutation p.V1350L; isoform1,2,3,5; V1349L in isoform4 in patient 1 and the de novo heterozygous p.C272Y mutation in patient 3(all isoforms). All these mutations are predicted to be damaging according to polyphen2, mutation taster and SIFT. These mutations are located in the ion transport domains (139e358,179e1510) and in the voltage dependent channel (1235e1356).
5.
Discussion
We describe three patients, harboring different de-novo mutations in the CACNA1A gene, who demonstrated the unique phenomenon of paroxysmal conjugate upward eye deviation, known as paroxysmal tonic upward gaze. In addition they all manifest developmental delay and cerebellar ataxia. There is only one previous report of PTU in two siblings with a CACNA1A mutation.15 The patients belonged to a two-generation family with several individuals affected by periodic paroxysmal neurological manifestations whose clinical description was consistent with PTU, benign paroxysmal torticollis of infancy or episodic ataxia. One patient displayed both paroxysmal tonic upgaze during infancy and episodic ataxia from his teens.15 This patient also had language delay but both siblings are not described as having persistent ataxia like our patients have. The clinical features of CACNA1A related PTU attacks in general are similar to the events, described in the literature (Table 1). Salmina et al. reviewed the clinical characteristics of benign PTU attacks in their own series and in the children reported in the literature.16 The duration of the attacks was between 3 s to two hours, but longer events were also described. The frequency of the episodes ranged from 2 to 3/ day to 10/day. In some patients, febrile illnesses, fatigue, stressful events, and supine position exacerbated the attacks. More than one third of the patients manifested coordination difficulties during the period of recurrent PTU attacks. Results of imaging studies were normal in all children, but one who
Abnormal coordination during febrile illnesses 2/17 (12%)
Coordination difficulties developmental delay in 5/17 (30%)
Recovery usually by 22 months Coordination difficulties in 17/46 (40%)
Cryptogenic PTU CACNA1A related PTU
5 patients: 3 from our series and 2 from Roubertie et al., 2008 3 days-10 months (60% before 4 months) Clusters of 2e8 s lasting a few minutes to one hour (sec-to min in 80%) Multiple daily episodes to several times per week Febrile illnesses, fatigue, supine position Brain MRI normal in 3/3 head CT normal in 1/1 PTU evolution Recovery by 13 months-5 years Associated ictal symptoms Ataxia, torticollis, pallor, chin down, downbeat nystagmus, side-to-side head movements, stereotypic hand movements (100%) Associated interictal disorder Ataxia, dystonia, dyskinesia, nystagmus, episodic coma, paroxysmal torticollis, developmental delay during period of PTU (80%) Symptoms after PTU recovery Cerebellar dysfunction: gait and limb ataxia, nystagmus, abnormal smooth pursuit, dysarthria 3/5 (60%) Paroxysmal attacks: 5/5 (100%) episodic ataxia type 2 paroxysmal torticollis Other abnormal movements: 3/5 (60%) dystonia, dyskinesia, stereotypies Other features: attention and behavioral difficulties, ID (1patient), language delay, pyramidal signs Number of patients Age at onset Duration of attacks Frequency Triggers Imaging at the time of PTU
Table 1 e Comparison of the clinical features of patients with CACNA1A related PTU and patients with cryptogenic PTU.
46 patients, Salmina et al., 2012 2 weeks-90 months, median 9 months (80% before 24 months) 3 seconds-2 hours (3e10 s in 50%) (>24 h in 2 children) 2-/day to 10/day Fever, fatigue, stress, immunization, supine position Normal neuroimaging (MRI, CT, US) in 34/34
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had an acute demyelinating brain diisorder. All patients demonstrated eventual improvement and recovery. In a minority of children the coordination problems persisted or were noted during febrile illnesses after the PTU attacks had disappeared. The patients with CACNA1A related PTU demonstrate a tendency to short lasting (seconds to minutes) multiple daily episodes that start during the first months (a few days to 10 months), and exacerbate during febrile illnesses, fatigue and the supine position. Prominent features demonstrated by our patients with CACNA1A mutations were developmental delay, ictal and/or interictal imbalance, additional types of paroxysmal attacks, and gradual emergence of clear cerebellar signs in contrast to lack of cerebellar abnormalities on brain MRI. Two out of three of our patients demonstrated an additional movement disorder which could be defined as dystonia. The anatomical substrate and the underlying pathophysiological mechanism of paroxysmal tonic upward eye deviation in CACNA1A related disorders are not clear. Tonic gaze deviation refers to sustained eye movement in a particular direction, either horizontal or vertical and is considered a supranuclear disorder of eye movements.17 It is a poor localizing sign and has been described in association with different lesions in the cortico-mesencephalic-pontine pathway for conjugate eye movement control. The concomitant ictal and interictal cerebellar ataxia, seen in some patients with cryptogenic and all patients with CACNA1A-related PTU, as well as the abundant expression of CACNA1A in Purkinje cells suggest a dysfunction of the cerebellum in the pathogenesis of this phenomenon. The cerebellum is involved in other CACNA1A-related paroxysmal disorders such as episodic ataxia type 2 and paroxysmal vertigo.15,18 Interestingly, in patients with CACNA1A-related paroxysmal vertigo, systematic bedside vestibular testing showed findings indicative of central abnormalities of the vestibular system, suggesting an impaired cerebellar control of vestibular mechanisms.19 PTU is a paroxysmal movement disorder but the underlying phenomenology of CACNA1A-related PTU is not obvious. Both ictal and interictal dyskinesias have been associated with CACNA1A mutations. The abnormal movements can be chronic or paroxysmal and may manifest in early childhood to late adulthood.14,20e25 We suggest that the CACNA1A related PTU episodes are dystonic in nature. Dystonia is traditionally believed to result from aberrant activity within the basal ganglia and their efferent connections to the thalamus and brainstem.26,27 Recent clinical and animal studies demonstrate a connection between dystonia and a defective interaction among different nodes in the motor network, rather than a functional defect in one motor pathway.28 Therefore, dystonia has been proposed as a circuit disorder involving cortico-ponto-cerebello-thalamo-cortical and cortico-basal ganglia-thalamo-cortical pathways.28 Recent findings advance even direct basal ganglia and cerebellum interconnection.28 Many forms of dystonia share a common phenomenon: enhanced intracortical excitability29 or impaired cortical inhibition.30 Cerebellar connectivity reduction leads to a loss of inhibition in the sensorimotor and supplementary motor cortices.31
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Dystonia is a recognized component of the phenotype in the tottering mutant mouse (CACNA1Atg), a mouse model that results from homozygous mutations in the mouse CACNA1A gene.32 Dystonia has been described in progressive cerebellar ataxias associated with known causative genes such as SCA3, SCA7, and SCA12,33e35 ataxia telangiectasia36 and some spinocerebellar ataxias (SCA) of unknown genetic origin.37 Rare cases with isolated cerebellar lesions producing dystonia have been described.38,39 LeDoux and Brady reviewed 25 patients with secondary dystonia and found that the most common causes were cerebellar lesions.40 The dystonic nature of benign paroxysmal torticollis in patients with CACNA1A mutations has been suggested by some authors.15,41,42 Although the phenomenology of paroxysmal torticollis in patients, harboring CACNA1A mutations has not been investigated, Kimura and Nezu have demonstrated that surface EMG features during attacks of paroxysmal torticollis of unknown origin are compatible with dystonia.43 Interestingly, one of the patients from Giffin's series manifested “rolled up eyes” during the attacks of paroxysmal torticollis.41 Although patients with PTU associated with CACNA1A mutations have not been treated with levodopa, the improvement under this treatment, noted in some patients with cryptogenic PTU may indicate some similarity of these attacks to DOPA-responsive dystonia.3,5,16 Deonna suggested classifying PTU within the group of inherited dystonias.3 We propose that the dystonic nature of PTU in patients with CACNA1A mutations may be due to an underlying cerebellar dysfunction. Moreover, the CACNA1A gene encodes the transmembrane pore-forming subunit of the P/Q-type or CaV2.1 voltage-gated calcium channel (VGCC).44 P/Q type calcium channels may predominantly mediate inhibitory GABA release onto Purkinje cells in the mouse model.45 A loss of function P/Q mutation may episodically remove the GABAergic inhibition and produce sustained over activity of motor pathways.41 Alternatively, it has been suggested that idiopathic PTU may result from a transient immature function of neurotransmission.7,10
6.
Conclusion
Paroxysmal tonic upward eye deviation associated with persistent cerebellar ataxia and other types of paroxysmal attacks can be caused by CACNA1A mutations. The role of CACNA1A mutations in benign PTU should be assessed in further studies.
Conflict of interest None.
references
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25. Molloy A, Kimmich O, Martindale J, Moore H, Hutchinson M, O'Riordan S. A novel CACNA1A mutation associated with adult-onset, paroxysmal head tremor. Mov Disord 2013;28:842e3. 26. Vitek JL. Pathophysiology of dystonia: a neuronal model. Mov Disord 2002;17:S49e62. 27. DeLong MR, Wichmann T. Circuits and circuit disorders of the basal ganglia. Arch Neurol 2007;64:20e4. 28. Filip P, Lungu OV, Bares M. Dystonia and the cerebellum: a new field of interest in movement disorders? Clin Neurophysiol 2013;124:1269e76. 29. Murase N, Rothwell JC, Kaji R, Urushihara R, Nakamura K, Murayama N, et al. Subthreshold low-frequency repetitive transcranial magnetic stimulation over the premotor cortex modulates writer's cramp. Brain 2005;128:104e15. 30. Hallett M. Pathophysiology of dystonia. J Neural Transm Suppl 2006:485e8. 31. Abbruzzese G, Berardelli A. Further progress in understanding the pathophysiology of primary dystonia. Mov Disord 2011;26:1185e6. 32. Fletcher CF, Tottene A, Lennon VA, et al. Dystonia and cerebellar atrophy in Cacna1a null mice lacking P/Q calcium channel activity. FASEB J 2001;15:1288e90. 33. Lang AE, Rogaeva EA, Tsuda T, Hutterer J, St George-Hyslop P. Homozygous inheritance of the Machado-Joseph disease gene. Ann Neurol 1994;36:443e7. 34. Modi G, Modi M, Martinus I, Rodda J, Saffer D. The clinical and genetic characteristics of spinocerebellar ataxia type 7 (SCA7) in three Black South African families. Acta Neurol Scand 2000;101:177e82. 35. O'Hearn E, Holmes SE, Calvert PC, Ross CA, Margolis RL. SCA12: tremor with cerebellar and cortical atrophy is associated with a CAG repeat expansion. Neurology 2001;56:299e303.
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36. Le Ber I, Clot F, Vercueil L, Camuzat A, Viemont M, Benamar N, et al. Predominant dystonia with marked cerebellar atrophy: a rare phenotype in familial dystonia. Neurology 2006;67:1769e73. € ki M, Giunti P, Quinn N, Wood NW, Bhatia KP. 37. Kuoppama Slowly progressive cerebellar ataxia and cervical dystonia: clinical presentation of a new form of spinocerebellar ataxia? Mov Disord 2003;18:200e6. 38. Alarcon F, Tolosa E, Munoz E. Focal limb dystonia in a patient with a cerebellar mass. Arch Neurol 2001;58:1125e7. 39. O'Rourke K, O'Riordan S, Gallagher J, Hutchinson M. Paroxysmal torticollis and blepharospasm following bilateral cerebellar infarction. J Neurol 2006;253:1644e5. 40. LeDoux MS, Brady KA. Secondary cervical dystonia associated with structural lesions of the central nervous system. Mov Disord 2003;18:60e9. 41. 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. 42. Cuenca-Leon E, Corominas R, Fernandez-Castillo N, et al. Genetic analysis of 27 Spanish patients with hemiplegic migraine, basilar-type migraine and childhood periodic syndromes. Cephalalgia 2008;28:1039e47. 43. Kimura S, Nezu A. Electromyographic study in an infant with benign paroxysmal torticollis. Pediatr Neurol 1998;19:236e8. 44. Kordasiewicz HB, Thompson RM, Clark HB, Gomez CM. Ctermini of P/Q-type Ca(2þ) channel alpha1A subunits translocate to nuclei and promote polyglutamine-mediated toxicity. Hum Mol Genet 2006;15:1587e99. 45. Stephens GJ, Morris NP, Fyffe REW, Robertson B. The Ca(v)2.1/ alpha 1A (P/Q-type) voltage-dependent calcium channel mediates inhibitory neurotransmission onto mouse cerebellar Purkinje cells. Eur J Neurosci 2001;13:1902e12.
Official Journal of the European Paediatric Neurology Society
Original article
Paroxysmal tonic upward gaze as a presentation of de-novo mutations in CACNA1A Lubov Blumkin a,b,*,e, Esther Leshinsky-Silver b,c,d,e, Marina Michelson b,c, Ayelet Zerem a,b, Sara Kivity a,b, Dorit Lev b,c, Tally Lerman-Sagie a,b a
Pediatric Neurology Unit, Wolfson Medical Center, Sackler School of Medicine, Tel-Aviv University, Holon, Israel Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Sackler School of Medicine, Tel-Aviv University, Holon, Israel c Institute of Medical Genetics, Wolfson Medical Center, Sackler School of Medicine, Tel-Aviv University, Holon, Israel d Molecular Laboratory, Wolfson Medical Center, Sackler School of Medicine, Tel-Aviv University, Holon, Israel b
article info
abstract
Article history:
Objective: Paroxysmal tonic upward gaze was initially described as a benign phenomenon
Received 18 September 2014
with negative investigations and eventual complete resolution of symptoms. Later publi-
Received in revised form
cations demonstrated that a similar clinical picture may arise from structural brain lesions,
24 December 2014
channelopathies, neurotransmitter disorders, and epileptic seizures. CACNA1A related
Accepted 25 December 2014
disorders manifest as a wide spectrum of paroxysmal neurological disorders: episodic ataxia 2, hemiplegic migraine, benign paroxysmal torticollis of infancy, and paroxysmal
Keywords:
vertigo. Paroxysmal tonic upward gaze as a phenomenon in patients with mutations in the
Paroxysmal tonic upward gaze
CACNA1A gene has only been reported once.
CACNA1A
Methods: We describe three patients with multiple episodes of paroxysmal tonic up-
Ataxia
ward gaze that appeared during the first months of life. In addition the patients demonstrated motor and language delay and cerebellar ataxia. A sequence analysis of the CACNA1A gene in one patient and whole exome sequencing in the other patients were performed. Results: Sequence analysis of the CACNA1A gene in one patient and whole exome sequencing in the two other patients revealed 3 different de-novo mutations in the CACNA1A gene. Conclusion: CACNA1A mutations should be evaluated in infants and young children with paroxysmal tonic upgaze especially if associated with developmental delay, cerebellar signs, and other types of paroxysmal event. © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Pediatric Neurology Unit, Metabolic-Neurogenetic Clinic, Wolfson Medical Center, POB 5, Holon 58100, Israel. Tel.: þ972 3 5028458; fax: þ972 3 5028141. E-mail address: [email protected] (L. Blumkin). e These authors contributed equally. http://dx.doi.org/10.1016/j.ejpn.2014.12.018 1090-3798/© 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
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1.
Introduction
Ouvrier and Billson1 were the first to describe the entity of paroxysmal tonic upward gaze (PTU).1 The clinical features of PTU comprise recurrent episodes of sustained conjugate upward deviation of the eyes with neck flexion (chin down), down-beating saccades on attempted down-gaze, preserved horizontal eye movements, unaffected consciousness and sometimes, impaired coordination. The episodes of tonic upgaze may last for a few minutes, hours and days with diurnal fluctuation of symptoms, frequently relieved by sleep, and accompanied by varying degrees of ataxia.1,2 The entity was defined as an apparently benign phenomenon with negative investigations and eventual complete resolution of the symptoms.1 A later review of 45 additional cases and other publications have demonstrated that a similar clinical picture may arise from structural brain lesions and that PTU may be associated with later development of epilepsy, chronic ataxia, borderline cognitive abilities and residual minor oculomotor disorders.2e13 Ataxia may occur either intermittently at the time of the attacks of tonic upgaze or as a chronic disability and independent from the ocular movement disorder.2,4,5,7,8,11 The association of this syndrome with epileptic disorders8,12,13 and intellectual disability6 has been reported in a few cases. The epileptic seizures can appear before or after the onset of PTU, and are classified as absence seizure. The etiology of PTU remains obscure. Autosomal dominant or recessive inheritance has been described but the involved genes have not been found.5,7 We describe three patients who presented with multiple episodes of paroxysmal upward eye deviation that appeared during the first months of life. They all demonstrated motor and speech delay and later developed cerebellar ataxia. Sequence analysis of the CACNA1A gene in one patient and whole exome sequencing in the other two patients revealed 3 different de-novo mutations in the CACNA1A gene.
deviation, commonly accompanied by the chin down phenomenon and downbeat nystagmus in attempt to look downward. During these episodes she was comfortable, and demonstrated normal eye contact in the superior visual field. These episodes occurred several times a day, lasting a few seconds to a few minutes and exacerbated by fatigue. When she was placed in the supine position, these episodes would be accompanied by slow side-to-side head movements and would cease by distraction. On neurologic examination at the age of six months the patient demonstrated normal horizontal eye movements, but difficulties with downward gaze. Attempts to look downwards triggered downbeat and eyelid nystagmus and initiated attacks of tonic upward gaze. She had head titubation and horizontal saccadic intrusions on pursuit. The PTU episodes disappeared spontaneously by the age of three years. On examination at the age of three years the patient was alert and communicative. She had normal physical development and head circumference. Ocular motor examination showed bilateral alternate convergent strabismus, gaze evoked horizontal nystagmus with no ophthalmoplegia, slow horizontal smooth pursuit with saccadic intrusions, difficulties with saccade initiation. She had very mild dysmetria of the hands, and a wide based ataxic gait. She ambulated with support of a walker. Her speech was mildly dysarthric but with a good vocabulary and age appropriate expressive abilities. Her behavior was inattentive and hyperactive and she demanded immediate satisfaction of her wishes. The rest of the neurologic examination was normal. She no longer manifested paroxysmal eye deviations, but had a few episodes of head tilt accompanied by eye blinking. An extensive evaluation was normal and included: video EEG monitoring during the episodes, ophthalmologic evaluations, metabolic tests, CSF for neurotransmitters and CGH microarray. Brain Magnetic Resonance Imaging (MRI) was performed at the age of eight months and demonstrated an enlargement of the subarachnoid spaces.
2.2.
2. 2.1.
293
Patient 2
Patients and methods Patient1
The patient is a three-year old girl who presented to the neurology clinic at the age of six months for evaluation of recurrent episodes of paroxysmal conjugate upward eye deviation. The patient is the only child of non-consanguineous parents. There is a strong family history of migraine without aura in both parents but no neurologic diseases, or paroxysmal neurologic phenomena have been reported. Early medical history and physical development were normal. She sustained one febrile convulsion. Motor development was slow: she rolled over at 8 months, sat at 20 months and started crawling and standing with support at the age of 24 months. First words appeared at the age of 24 months, and by the age of three years she achieved age appropriate expressive and receptive speech. The paroxysmal episodes started during the neonatal period and manifested with conjugate tonic upward eye
We have previously described this patient.14 He was referred to our clinic at the age of three years for evaluation of global psychomotor delay and dyskinesia. His perinatal history was uneventful. Motor development was significantly delayed. At the age of four months when the child was held upright, episodes of upward gaze deviation appeared. At the age of three and a half years he only manifested rare brief episodes of upward gaze deviation that increased during stress. Other abnormal movements appeared later and presented with transient horizontal rhythmic head movements, simple motor stereotypies, non-specific involuntary movements, and head and hand tremor, usually provoked by motor activity and stress. Cerebellar abnormalities, pyramidal signs, and episodic coma associated with seizures and autonomic symptoms became apparent after the age of two years. The first brain MRI at the age of 8 months was normal. The second study, done during the last episode of coma at the age of 6 years, revealed severe cerebellar atrophy and mild right hemisphere edema.
294
2.3.
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Patient 3
A 5-year-old girl presented to our metabolic-neurogenetic clinic due to global developmental delay and abnormal eye movements. She is the only child of non-consanguineous healthy Moroccan-Jews. The perinatal history was uneventful. The patient's psychomotor development had been delayed, especially her gross motor skills. She started rolling over at 14 months, sat unsupported at 24 months, walked at the age of 35 months. Her gait was unsteady and she frequently fell. She manifested expressive speech delay. Recurrent attacks of abnormal eye movements started at the age of three days. These attacks manifested as conjugate upward eye deviation, lasting for 5e6 s, and appearing multiple times daily. Later on, the episodes appeared two to three times weekly and were accompanied by the chin down phenomenon and lack of response to command and touch. The frequency of the episodes decreased significantly by the age of five years. Since one year of age she demonstrated other paroxysmal attacks: recurrent staring, episodes of torticollis accompanied by nystagmus, lasting a few minutes, and periods of imbalance, lasting for a few hours that caused a deterioration of her baseline unsteady gait. Recurrent interictal EEG studies were normal. Treatment with acetazolamide significantly decreased the frequency of episodic ataxia but did not improve her unsteadiness. On examination at the age of five years she was cooperative but easily distracted, inattentive, hyperactive, and childish. Physical development and head circumference were age appropriate. She exhibited upbeat nystagmus on vertical gaze, convergent strabismus, dysarthria, limb dysmetria and tremor, and an ataxic gait. There were no signs of oculomotor apraxia. She had repetitive involuntary mouth opening, significantly increased by stress and motor activity, reminding jaw-opening oromandibular dystonia. The patient's investigations were normal and included thyroid function tests, carnitine, acylcarnitine, blood amino acids, urine organic acids, lactic acid, creatine phosphokinase, ammonia, cerebrospinal fluid lactic acid and glucose. Visual evoked potentials were normal. Brain MRIs performed at the age of 14 and 24 months demonstrated a large cisterna magna. MR spectroscopy was normal. Genetic studies including: karyotype, CGH microarray, SepSecS mutations, MECP2 gene sequencing and multiplex ligation-dependent probe amplification (MLPA), and methylation for Angelman syndrome were normal.
3.
Molecular analysis
CACNA1A sequencing was performed according to Blumkin et al.14 Whole exome sequencing was performed on the patient's DNA. The sample was enriched with Sureselect Human All Exome v.2 kit which was targeted 50 Mb (Agilent, Santa Clara, CA, USA). Sequencing was carried out on HiSeq2000 (Illumina,
San diego, CA, USA) as 100-bp paired-end runs. Image analysis and base calling were performed with the Genome Analyzer Pipeline version 1.5 with default parameters. Reads were mapped to the human reference genome sequence (assembly GRCh37/hg19) using the Burrows-Wheeler Alignment Tool (BWA) version 0.5.8c, and allelic variants were detected using the Genome Analysis Toolkit (GATK). Dataset files including the annotated information were analyzed using ANNOVAR according to the dbSNP database (build 135) and the NHLBI exome variant database with the following filtering steps: variant type including missense, nonsense, and splice-site; not within segmental duplications; minor allele frequency (MAF) less than 0.01; SIFT score 0.85 when available.
4.
Results
Sequence analysis of the CACNA1A gene in patient 2 revealed a de novo heterozygous mutation p.R1349Q; isoforms1,2,3,5; p.1348Q in isoform4 (formally reported mistakenly as R1350Q). Whole exome sequencing revealed the de novo heterozygous mutation p.V1350L; isoform1,2,3,5; V1349L in isoform4 in patient 1 and the de novo heterozygous p.C272Y mutation in patient 3(all isoforms). All these mutations are predicted to be damaging according to polyphen2, mutation taster and SIFT. These mutations are located in the ion transport domains (139e358,179e1510) and in the voltage dependent channel (1235e1356).
5.
Discussion
We describe three patients, harboring different de-novo mutations in the CACNA1A gene, who demonstrated the unique phenomenon of paroxysmal conjugate upward eye deviation, known as paroxysmal tonic upward gaze. In addition they all manifest developmental delay and cerebellar ataxia. There is only one previous report of PTU in two siblings with a CACNA1A mutation.15 The patients belonged to a two-generation family with several individuals affected by periodic paroxysmal neurological manifestations whose clinical description was consistent with PTU, benign paroxysmal torticollis of infancy or episodic ataxia. One patient displayed both paroxysmal tonic upgaze during infancy and episodic ataxia from his teens.15 This patient also had language delay but both siblings are not described as having persistent ataxia like our patients have. The clinical features of CACNA1A related PTU attacks in general are similar to the events, described in the literature (Table 1). Salmina et al. reviewed the clinical characteristics of benign PTU attacks in their own series and in the children reported in the literature.16 The duration of the attacks was between 3 s to two hours, but longer events were also described. The frequency of the episodes ranged from 2 to 3/ day to 10/day. In some patients, febrile illnesses, fatigue, stressful events, and supine position exacerbated the attacks. More than one third of the patients manifested coordination difficulties during the period of recurrent PTU attacks. Results of imaging studies were normal in all children, but one who
Abnormal coordination during febrile illnesses 2/17 (12%)
Coordination difficulties developmental delay in 5/17 (30%)
Recovery usually by 22 months Coordination difficulties in 17/46 (40%)
Cryptogenic PTU CACNA1A related PTU
5 patients: 3 from our series and 2 from Roubertie et al., 2008 3 days-10 months (60% before 4 months) Clusters of 2e8 s lasting a few minutes to one hour (sec-to min in 80%) Multiple daily episodes to several times per week Febrile illnesses, fatigue, supine position Brain MRI normal in 3/3 head CT normal in 1/1 PTU evolution Recovery by 13 months-5 years Associated ictal symptoms Ataxia, torticollis, pallor, chin down, downbeat nystagmus, side-to-side head movements, stereotypic hand movements (100%) Associated interictal disorder Ataxia, dystonia, dyskinesia, nystagmus, episodic coma, paroxysmal torticollis, developmental delay during period of PTU (80%) Symptoms after PTU recovery Cerebellar dysfunction: gait and limb ataxia, nystagmus, abnormal smooth pursuit, dysarthria 3/5 (60%) Paroxysmal attacks: 5/5 (100%) episodic ataxia type 2 paroxysmal torticollis Other abnormal movements: 3/5 (60%) dystonia, dyskinesia, stereotypies Other features: attention and behavioral difficulties, ID (1patient), language delay, pyramidal signs Number of patients Age at onset Duration of attacks Frequency Triggers Imaging at the time of PTU
Table 1 e Comparison of the clinical features of patients with CACNA1A related PTU and patients with cryptogenic PTU.
46 patients, Salmina et al., 2012 2 weeks-90 months, median 9 months (80% before 24 months) 3 seconds-2 hours (3e10 s in 50%) (>24 h in 2 children) 2-/day to 10/day Fever, fatigue, stress, immunization, supine position Normal neuroimaging (MRI, CT, US) in 34/34
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295
had an acute demyelinating brain diisorder. All patients demonstrated eventual improvement and recovery. In a minority of children the coordination problems persisted or were noted during febrile illnesses after the PTU attacks had disappeared. The patients with CACNA1A related PTU demonstrate a tendency to short lasting (seconds to minutes) multiple daily episodes that start during the first months (a few days to 10 months), and exacerbate during febrile illnesses, fatigue and the supine position. Prominent features demonstrated by our patients with CACNA1A mutations were developmental delay, ictal and/or interictal imbalance, additional types of paroxysmal attacks, and gradual emergence of clear cerebellar signs in contrast to lack of cerebellar abnormalities on brain MRI. Two out of three of our patients demonstrated an additional movement disorder which could be defined as dystonia. The anatomical substrate and the underlying pathophysiological mechanism of paroxysmal tonic upward eye deviation in CACNA1A related disorders are not clear. Tonic gaze deviation refers to sustained eye movement in a particular direction, either horizontal or vertical and is considered a supranuclear disorder of eye movements.17 It is a poor localizing sign and has been described in association with different lesions in the cortico-mesencephalic-pontine pathway for conjugate eye movement control. The concomitant ictal and interictal cerebellar ataxia, seen in some patients with cryptogenic and all patients with CACNA1A-related PTU, as well as the abundant expression of CACNA1A in Purkinje cells suggest a dysfunction of the cerebellum in the pathogenesis of this phenomenon. The cerebellum is involved in other CACNA1A-related paroxysmal disorders such as episodic ataxia type 2 and paroxysmal vertigo.15,18 Interestingly, in patients with CACNA1A-related paroxysmal vertigo, systematic bedside vestibular testing showed findings indicative of central abnormalities of the vestibular system, suggesting an impaired cerebellar control of vestibular mechanisms.19 PTU is a paroxysmal movement disorder but the underlying phenomenology of CACNA1A-related PTU is not obvious. Both ictal and interictal dyskinesias have been associated with CACNA1A mutations. The abnormal movements can be chronic or paroxysmal and may manifest in early childhood to late adulthood.14,20e25 We suggest that the CACNA1A related PTU episodes are dystonic in nature. Dystonia is traditionally believed to result from aberrant activity within the basal ganglia and their efferent connections to the thalamus and brainstem.26,27 Recent clinical and animal studies demonstrate a connection between dystonia and a defective interaction among different nodes in the motor network, rather than a functional defect in one motor pathway.28 Therefore, dystonia has been proposed as a circuit disorder involving cortico-ponto-cerebello-thalamo-cortical and cortico-basal ganglia-thalamo-cortical pathways.28 Recent findings advance even direct basal ganglia and cerebellum interconnection.28 Many forms of dystonia share a common phenomenon: enhanced intracortical excitability29 or impaired cortical inhibition.30 Cerebellar connectivity reduction leads to a loss of inhibition in the sensorimotor and supplementary motor cortices.31
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Dystonia is a recognized component of the phenotype in the tottering mutant mouse (CACNA1Atg), a mouse model that results from homozygous mutations in the mouse CACNA1A gene.32 Dystonia has been described in progressive cerebellar ataxias associated with known causative genes such as SCA3, SCA7, and SCA12,33e35 ataxia telangiectasia36 and some spinocerebellar ataxias (SCA) of unknown genetic origin.37 Rare cases with isolated cerebellar lesions producing dystonia have been described.38,39 LeDoux and Brady reviewed 25 patients with secondary dystonia and found that the most common causes were cerebellar lesions.40 The dystonic nature of benign paroxysmal torticollis in patients with CACNA1A mutations has been suggested by some authors.15,41,42 Although the phenomenology of paroxysmal torticollis in patients, harboring CACNA1A mutations has not been investigated, Kimura and Nezu have demonstrated that surface EMG features during attacks of paroxysmal torticollis of unknown origin are compatible with dystonia.43 Interestingly, one of the patients from Giffin's series manifested “rolled up eyes” during the attacks of paroxysmal torticollis.41 Although patients with PTU associated with CACNA1A mutations have not been treated with levodopa, the improvement under this treatment, noted in some patients with cryptogenic PTU may indicate some similarity of these attacks to DOPA-responsive dystonia.3,5,16 Deonna suggested classifying PTU within the group of inherited dystonias.3 We propose that the dystonic nature of PTU in patients with CACNA1A mutations may be due to an underlying cerebellar dysfunction. Moreover, the CACNA1A gene encodes the transmembrane pore-forming subunit of the P/Q-type or CaV2.1 voltage-gated calcium channel (VGCC).44 P/Q type calcium channels may predominantly mediate inhibitory GABA release onto Purkinje cells in the mouse model.45 A loss of function P/Q mutation may episodically remove the GABAergic inhibition and produce sustained over activity of motor pathways.41 Alternatively, it has been suggested that idiopathic PTU may result from a transient immature function of neurotransmission.7,10
6.
Conclusion
Paroxysmal tonic upward eye deviation associated with persistent cerebellar ataxia and other types of paroxysmal attacks can be caused by CACNA1A mutations. The role of CACNA1A mutations in benign PTU should be assessed in further studies.
Conflict of interest None.
references
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