JNS-13911; No of Pages 3 Journal of the Neurological Sciences xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the editor Spinocerebellar ataxia 36 accompanied by cervical dystonia
Keywords: Spinocerebellar ataxia Cervical dystonia Dystonia SCA36
Dear Sir Spinocerebellar ataxia 36 (SCA36) was reported in Japan for the first time in 2011 as an autosomal dominant neurodegenerative disorder caused by a hexanucleotide GGCCTG repeat expansion within intron 1 of the nucleolar protein 56 (NOP56) gene [1,2]. Patients with SCA36 have over 650 GGCCTG repeat expansions, while the normal range is from 5 to 14 [2]. These expansions are considered to cause SCA36 by a toxic RNA gain-of-function mechanism [1]. The main clinical symptoms consist of slowly progressive ataxia of the trunk and limbs, dysarthria, and abnormal eye movements developed in middle age, followed by tongue and muscle atrophy as seen in motor neuron diseases [2]. Several reports have mentioned additional neurological findings, including sensorineural loss, cognitive dysfunction, ptosis, postural tremor, or reduced vibration sense [2], and one paper reported a Japanese SCA36 patient with oromandibular dystonia [3]. Here we describe two siblings with SCA36 presenting with cervical dystonia. The study protocol was approved by the Ethics Committee of the University of Miyazaki. Written informed consent was obtained from the patients.
1. Case reports
Case 1. A 66-year-old Japanese woman, the elder sister, was admitted to our hospital for slowly progressive cerebellar ataxia. Her mother was diagnosed with spinocerebellar ataxia in middle age. The patient first noticed gait ataxia at age 53, and three months she developed cervical dystonia. She began to experience dysarthria at age 55. Her gait disturbance gradually progressed, and at age 60, she no longer walked without support and also had difficulty swallowing liquids. Her neurological examination revealed marked cerebellar ataxia with dysmetria on bilateral finger-to-nose and heel-to-knee tests. She also had severe truncal titubation. She showed gaze-evoked nystagmus, hypermetria on eye movement, and scanning speech. Furthermore, she had bulbar palsy findings, specifically tongue atrophy and fasciculations and dysphagia. Muscle atrophy and weakness were observed predominantly in the distal limbs, with hyperreflexia and pathological reflexes
such as extensor plantar responses. The patient did not have any symptoms of parkinsonism, sensory disturbance, or autonomic dysfunction. Case 2. A 64-year-old woman, the younger sister, developed cervical dystonia as the first symptom of spinocerebellar ataxia at age 37. She experienced slowly progressive gait disturbance and dysarthria from her 50s to 60s. She began having difficulty swallowing liquids at age 62. On neurological examination, she had more severe cerebellar ataxia than Case 1. She also had bulbar palsy. She had distal dominant muscle atrophy and weakness with hyperreflexia, but no pathological reflexes. In comparison with Case 1, she had a milder form of motor neuron disease. She did not have any symptom of parkinsonism nor disturbances of sensory or autonomic systems. Needle electromyography in both cases demonstrated neurogenic changes with denervation findings, including fasciculation potentials at the tongue and upper and lower limbs. Nerve conduction studies showed normal findings in both patients. Brain magnetic resonance imaging (MRI) in both patients showed remarkable atrophy of the cerebellar vermis and hemispheres and mild atrophy of the brainstem (Fig. 1). Other areas were preserved. Brain scintigraphy, which was performed using the 99mTc-ethylcysteinate dimer (99mTc-ECD) as a tracer and analyzed with the easy Z-score imaging system (eZIS), revealed reduced regional cerebellar and brainstem blood flow. Frontal lobe blood flow was normal in both patients (Fig. 1). Genetic analysis performed by repeat-primed polymerase chain reaction analysis revealed a GGCCTG hexanucleotide repeat expansion, known as a sawtooth pattern in the NOP56 gene in both cases [1,3].
2. Discussion This is the first report describing SCA36 accompanied by cervical dystonia. We cannot deny a possibility that two siblings with SCA36 may coincidentally have cervical dystonia. Nevertheless, we speculated that cervical dystonia would be related to cerebellar dysfunction resulting from SCA36, since patients with SCA36 are rare and cervical dystonia is also a relatively rare condition. In fact, oromandibular dystonia was reported in a SCA36 patient [3]. This oromandibular dystonia was suggested to be caused by functional disconnectivity of the cerebello-thalamo-cortical pathway or interaction between the basal ganglia and cerebellothalamic circuit [3]. In a study of 25 patients with secondary cervical dystonia, 13 had lesions of the cerebellum or inferior olive [4]. The dysfunction of the cerebello-thalamo-cortical connectivity was indicated to be associated with generation of dystonia in some dystonic patients by the neuroimaging method [5]. Furthermore, the clinical symptom of cervical dystonia was improved by repetitive magnetic stimulation over the cerebellum [6]. On the other hand, several animal models of dystonia exhibit cerebellar abnormalities [7]. A recent study in mice indicated that some of dystonic symptoms were independent of the basal ganglia and that dysfunction of cerebellar outputs generated by olive nuclei led
http://dx.doi.org/10.1016/j.jns.2015.07.012 0022-510X/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Y. Nakazato, et al., J Neurol Sci (2015), http://dx.doi.org/10.1016/j.jns.2015.07.012
2
Letter to the editor
Case 1 A
B
C
R
D
E
Case 2 F
G
H
R
I
J 70 60 50 40 30 20 (ml/100g/min)
Fig. 1. MRI scans (A, B) with axial T2-weighted sequences and (C) with sagittal in Case 1 demonstrate remarkable atrophy of the cerebellar vermis and hemispheres and mild atrophy of the brainstem. Cerebral scintigraphy (D, E) in Case 1 shows reduced rCBF in the cerebellum and brainstem. MRI scans (G, H, I) and cerebral scintigraphy (G, H) in Case 2 show the same findings as Case 1.
to dystonia [7]. Taken together, some types of cerebellar dysfunction could be a candidate for generation of dystonia. A postmortem study of a Japanese SCA36 patient demonstrated that RNA foci of the abnormal hexanucleotide GGCCUG repeat expansion were detected frequently in the inferior olive [8]. The present study did not identify gene mutations in DYT1, 6, 11, or 25, each of which was previously found to be responsible for cervical dystonia in Japan. Although segregation between the NOP56 hexanucleotide repeat and other genes causing cervical dystonia cannot be completely denied,
cerebellar dysfunction in the present patients might be related to cervical dystonia. A recent study performed in France and Japan comparing 27 SCA36 patients who had typically long GGCCTG repeat expansions with three SCA36 patients who had small repeat expansions demonstrated that the clinical features of the two groups were indistinguishable [2]. Thus, the cervical dystonia seen in our patients is unlikely to be related to the number of repeat expansions. Further studies investigating the association between SCA36 pathology and cervical dystonia are needed.
Please cite this article as: Y. Nakazato, et al., J Neurol Sci (2015), http://dx.doi.org/10.1016/j.jns.2015.07.012
Letter to the editor
Competing interests None. Funding None. References [1] H. Kobayashi, K. Abe, T. Matsuura, et al., Expansion of intronic GGCCTG hexanucleotide repeat in NOP 56 cause SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement, Am. J. Hum. Genet. 89 (2011) 121–130, http://dx.doi.org/10.1016/j.ajhg.2011.05.015. [2] M. Obayashi, G. Stevanin, M. Synofzik, et al., Spinocerebellar ataxia type 36 exists in diverse populations and can be caused by a short hexanucleotide GGCCTG repeat expansion, JNNP (2014)http://dx.doi.org/10.1136/jnnp-2014-309153 (in press). [3] A. Miyashiro, K. Sugihara, T. Kawarai, et al., Oromandibular dystonia associated with SCA36, Mov. Disord. 28 (2013) 557–559, http://dx.doi.org/10.1002/mds.25304. [4] M.S. LeDoux, K.A. Brady, Secondary cervical dystonia associated with structural lesions of the central nervous system, Mov. Disord. 18 (2003) 60–69. [5] M. Argyelan, M. Carbon, et al., Cerebellothalamocortical connectivity regulates penetrance in dystonia, J. Neurosci. 29 (31) (2009) 9740–9747, http://dx.doi.org/ 10.1523/JNEUROSCI.2300-0.9.2009. [6] G. Koch, P. Porcacchia, et al., Effects of two weeks of cerebellar theta burst stimulation in cervical dystonia patients, Brain Stimul. 7 (2014) 564–572, http://dx.doi.org/10. 1016/j.brs.2014.05.002. [7] C. Hisatsune, H. Miyamoto, et al., IP3R1 deficiency in the cerebellum/brainstem causes basal ganglia-independent dystonia by triggering tonic Purkinje cell firings in mice, Front Neural Circ. 7 (2013) 1–13, http://dx.doi.org/10.3389/fncir.2013.00156. [8] W. Liu, Y. Ikeda, N. Hishikawa, et al., Characteristic RNA foci of the abnormal hexanucleotide GGCCUG repeat expansion in spinocerebellar ataxia type 36 (Asidan), Eur. J. Neurol. 21 (2014) 1377–1386, http://dx.doi.org/10.1111/ene.12491.
3
Yuki Nakazato Hitoshi Mochizuki⁎ Nobuyuki Ishii Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan ⁎Corresponding author at: Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 8891692, Japan. E-mail address: [email protected] (H. Mochizuki) Ryuichi Ohkubo Ryuki Hirano Hiroshi Takashima Department of Neurology and Geriatrics, Faculty of Medicine, Kagoshima University, Kagoshima, Japan Kazutaka Shiomi Masamitsu Nakazato Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
Please cite this article as: Y. Nakazato, et al., J Neurol Sci (2015), http://dx.doi.org/10.1016/j.jns.2015.07.012
12 May 2015 Available online xxxx
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the editor Spinocerebellar ataxia 36 accompanied by cervical dystonia
Keywords: Spinocerebellar ataxia Cervical dystonia Dystonia SCA36
Dear Sir Spinocerebellar ataxia 36 (SCA36) was reported in Japan for the first time in 2011 as an autosomal dominant neurodegenerative disorder caused by a hexanucleotide GGCCTG repeat expansion within intron 1 of the nucleolar protein 56 (NOP56) gene [1,2]. Patients with SCA36 have over 650 GGCCTG repeat expansions, while the normal range is from 5 to 14 [2]. These expansions are considered to cause SCA36 by a toxic RNA gain-of-function mechanism [1]. The main clinical symptoms consist of slowly progressive ataxia of the trunk and limbs, dysarthria, and abnormal eye movements developed in middle age, followed by tongue and muscle atrophy as seen in motor neuron diseases [2]. Several reports have mentioned additional neurological findings, including sensorineural loss, cognitive dysfunction, ptosis, postural tremor, or reduced vibration sense [2], and one paper reported a Japanese SCA36 patient with oromandibular dystonia [3]. Here we describe two siblings with SCA36 presenting with cervical dystonia. The study protocol was approved by the Ethics Committee of the University of Miyazaki. Written informed consent was obtained from the patients.
1. Case reports
Case 1. A 66-year-old Japanese woman, the elder sister, was admitted to our hospital for slowly progressive cerebellar ataxia. Her mother was diagnosed with spinocerebellar ataxia in middle age. The patient first noticed gait ataxia at age 53, and three months she developed cervical dystonia. She began to experience dysarthria at age 55. Her gait disturbance gradually progressed, and at age 60, she no longer walked without support and also had difficulty swallowing liquids. Her neurological examination revealed marked cerebellar ataxia with dysmetria on bilateral finger-to-nose and heel-to-knee tests. She also had severe truncal titubation. She showed gaze-evoked nystagmus, hypermetria on eye movement, and scanning speech. Furthermore, she had bulbar palsy findings, specifically tongue atrophy and fasciculations and dysphagia. Muscle atrophy and weakness were observed predominantly in the distal limbs, with hyperreflexia and pathological reflexes
such as extensor plantar responses. The patient did not have any symptoms of parkinsonism, sensory disturbance, or autonomic dysfunction. Case 2. A 64-year-old woman, the younger sister, developed cervical dystonia as the first symptom of spinocerebellar ataxia at age 37. She experienced slowly progressive gait disturbance and dysarthria from her 50s to 60s. She began having difficulty swallowing liquids at age 62. On neurological examination, she had more severe cerebellar ataxia than Case 1. She also had bulbar palsy. She had distal dominant muscle atrophy and weakness with hyperreflexia, but no pathological reflexes. In comparison with Case 1, she had a milder form of motor neuron disease. She did not have any symptom of parkinsonism nor disturbances of sensory or autonomic systems. Needle electromyography in both cases demonstrated neurogenic changes with denervation findings, including fasciculation potentials at the tongue and upper and lower limbs. Nerve conduction studies showed normal findings in both patients. Brain magnetic resonance imaging (MRI) in both patients showed remarkable atrophy of the cerebellar vermis and hemispheres and mild atrophy of the brainstem (Fig. 1). Other areas were preserved. Brain scintigraphy, which was performed using the 99mTc-ethylcysteinate dimer (99mTc-ECD) as a tracer and analyzed with the easy Z-score imaging system (eZIS), revealed reduced regional cerebellar and brainstem blood flow. Frontal lobe blood flow was normal in both patients (Fig. 1). Genetic analysis performed by repeat-primed polymerase chain reaction analysis revealed a GGCCTG hexanucleotide repeat expansion, known as a sawtooth pattern in the NOP56 gene in both cases [1,3].
2. Discussion This is the first report describing SCA36 accompanied by cervical dystonia. We cannot deny a possibility that two siblings with SCA36 may coincidentally have cervical dystonia. Nevertheless, we speculated that cervical dystonia would be related to cerebellar dysfunction resulting from SCA36, since patients with SCA36 are rare and cervical dystonia is also a relatively rare condition. In fact, oromandibular dystonia was reported in a SCA36 patient [3]. This oromandibular dystonia was suggested to be caused by functional disconnectivity of the cerebello-thalamo-cortical pathway or interaction between the basal ganglia and cerebellothalamic circuit [3]. In a study of 25 patients with secondary cervical dystonia, 13 had lesions of the cerebellum or inferior olive [4]. The dysfunction of the cerebello-thalamo-cortical connectivity was indicated to be associated with generation of dystonia in some dystonic patients by the neuroimaging method [5]. Furthermore, the clinical symptom of cervical dystonia was improved by repetitive magnetic stimulation over the cerebellum [6]. On the other hand, several animal models of dystonia exhibit cerebellar abnormalities [7]. A recent study in mice indicated that some of dystonic symptoms were independent of the basal ganglia and that dysfunction of cerebellar outputs generated by olive nuclei led
http://dx.doi.org/10.1016/j.jns.2015.07.012 0022-510X/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Y. Nakazato, et al., J Neurol Sci (2015), http://dx.doi.org/10.1016/j.jns.2015.07.012
2
Letter to the editor
Case 1 A
B
C
R
D
E
Case 2 F
G
H
R
I
J 70 60 50 40 30 20 (ml/100g/min)
Fig. 1. MRI scans (A, B) with axial T2-weighted sequences and (C) with sagittal in Case 1 demonstrate remarkable atrophy of the cerebellar vermis and hemispheres and mild atrophy of the brainstem. Cerebral scintigraphy (D, E) in Case 1 shows reduced rCBF in the cerebellum and brainstem. MRI scans (G, H, I) and cerebral scintigraphy (G, H) in Case 2 show the same findings as Case 1.
to dystonia [7]. Taken together, some types of cerebellar dysfunction could be a candidate for generation of dystonia. A postmortem study of a Japanese SCA36 patient demonstrated that RNA foci of the abnormal hexanucleotide GGCCUG repeat expansion were detected frequently in the inferior olive [8]. The present study did not identify gene mutations in DYT1, 6, 11, or 25, each of which was previously found to be responsible for cervical dystonia in Japan. Although segregation between the NOP56 hexanucleotide repeat and other genes causing cervical dystonia cannot be completely denied,
cerebellar dysfunction in the present patients might be related to cervical dystonia. A recent study performed in France and Japan comparing 27 SCA36 patients who had typically long GGCCTG repeat expansions with three SCA36 patients who had small repeat expansions demonstrated that the clinical features of the two groups were indistinguishable [2]. Thus, the cervical dystonia seen in our patients is unlikely to be related to the number of repeat expansions. Further studies investigating the association between SCA36 pathology and cervical dystonia are needed.
Please cite this article as: Y. Nakazato, et al., J Neurol Sci (2015), http://dx.doi.org/10.1016/j.jns.2015.07.012
Letter to the editor
Competing interests None. Funding None. References [1] H. Kobayashi, K. Abe, T. Matsuura, et al., Expansion of intronic GGCCTG hexanucleotide repeat in NOP 56 cause SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement, Am. J. Hum. Genet. 89 (2011) 121–130, http://dx.doi.org/10.1016/j.ajhg.2011.05.015. [2] M. Obayashi, G. Stevanin, M. Synofzik, et al., Spinocerebellar ataxia type 36 exists in diverse populations and can be caused by a short hexanucleotide GGCCTG repeat expansion, JNNP (2014)http://dx.doi.org/10.1136/jnnp-2014-309153 (in press). [3] A. Miyashiro, K. Sugihara, T. Kawarai, et al., Oromandibular dystonia associated with SCA36, Mov. Disord. 28 (2013) 557–559, http://dx.doi.org/10.1002/mds.25304. [4] M.S. LeDoux, K.A. Brady, Secondary cervical dystonia associated with structural lesions of the central nervous system, Mov. Disord. 18 (2003) 60–69. [5] M. Argyelan, M. Carbon, et al., Cerebellothalamocortical connectivity regulates penetrance in dystonia, J. Neurosci. 29 (31) (2009) 9740–9747, http://dx.doi.org/ 10.1523/JNEUROSCI.2300-0.9.2009. [6] G. Koch, P. Porcacchia, et al., Effects of two weeks of cerebellar theta burst stimulation in cervical dystonia patients, Brain Stimul. 7 (2014) 564–572, http://dx.doi.org/10. 1016/j.brs.2014.05.002. [7] C. Hisatsune, H. Miyamoto, et al., IP3R1 deficiency in the cerebellum/brainstem causes basal ganglia-independent dystonia by triggering tonic Purkinje cell firings in mice, Front Neural Circ. 7 (2013) 1–13, http://dx.doi.org/10.3389/fncir.2013.00156. [8] W. Liu, Y. Ikeda, N. Hishikawa, et al., Characteristic RNA foci of the abnormal hexanucleotide GGCCUG repeat expansion in spinocerebellar ataxia type 36 (Asidan), Eur. J. Neurol. 21 (2014) 1377–1386, http://dx.doi.org/10.1111/ene.12491.
3
Yuki Nakazato Hitoshi Mochizuki⁎ Nobuyuki Ishii Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan ⁎Corresponding author at: Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 8891692, Japan. E-mail address: [email protected] (H. Mochizuki) Ryuichi Ohkubo Ryuki Hirano Hiroshi Takashima Department of Neurology and Geriatrics, Faculty of Medicine, Kagoshima University, Kagoshima, Japan Kazutaka Shiomi Masamitsu Nakazato Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
Please cite this article as: Y. Nakazato, et al., J Neurol Sci (2015), http://dx.doi.org/10.1016/j.jns.2015.07.012
12 May 2015 Available online xxxx
