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Segmental Myorhythmia with Palatal Tremor due to Bilateral Hypertrophic Olivary Degeneration in Wilson Disease
Yury Seliverstov1*, Aleksandr Suslin1, Elena Kremneva1, Marina Krotenkova1 1 – Research Center of Neurology, Moscow, Russia
*Corresponding author Yury Seliverstov, MD, PhD Research Center of Neurology, Volokolamskoe shosse 80, Moscow, Russia 125367 +7 916 799 22 28 [email protected]
Text word count: 796 Title word count: 14 Running Title: Bilateral Hypertrophic Olivary Degeneration in WD Number of figures: 1 Number of videos: 1 Number of references: 4
Keywords Wilson disease, bilateral hypertrophic olivary degeneration, myorhythmia, palatal tremor
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/mdc3.13017
This article is protected by copyright. All rights reserved.
Wilson disease (WD) is a rare treatable disorder of copper metabolism with an autosomal recessive inheritance due to mutations in the ATP7B gene. In this article, we present a patient with biochemically and genetically confirmed WD, who through the course of the disease developed symptomatic bilateral hypertrophic olivary degeneration (HOD).
Case report A 47-year-old man with a two-year history of WD presented with increased drooling. His diagnosis was based on clinical findings (including Kayser-Fleischer rings), laboratory tests (low serum ceruloplasmin, increased 24-hour urine copper excretion), and genetic test. Sanger sequencing of the ATP7B gene showed compound heterozygosity for two pathogenic point mutations: c.2827G>A (has been described before) and c.1630C>T (novel variant leading to the termination of the protein synthesis). The Global Assessment Scale for Wilson Disease score was the following: tier 1 — L1, C3, M3, O0*; tier 2 — 25. On examination, apart from marked parkinsonism with severe postural instability and mild limitation of the eye movements in upgaze that were present at the previous examination a year ago, continuous symmetric rhythmic involuntary movement of the lower facial muscles, soft palate, and larynx was found. By observing his irregular breathing movements of the abdominal wall, diaphragmal involvement in the hyperkinesis could be suspected as well (Video). According to patient, those involuntary movements developed 8 months earlier; however, they did not bother him. His caregiver reported that the movements were persistent during sleep. Patient’s medical treatment was stable for the last 8 months and included 500 mg penicillamine/daily, pyridoxine 25 mg, elementary zinc 80 mg/daily, levodopa 300 mg/daily, and biperiden 6 mg/daily. His liver function was compensated, urinary copper excretion test showed 230 mcg/day, which indicated a relatively adequate penicillamine dose. Previous attempts to slightly increase penicillamine dose led to the exacerbation of the neurological deficit (trientine is not available in Russia). In comparison with previous 2-yearold brain MRI, which showed bilateral T2 and FLAIR hyperintensities in the dorsal midbrain and pons, atrophy of the middle cerebellar peduncles, as well as mild T2 bilateral
This article is protected by copyright. All rights reserved.
hypointensities in the globus pallidus (Fig. 1, A-D), the repeated brain MRI showed marked increase of the midbrain and dorsal pons atrophy, bilateral symmetric HOD, and bilateral T2* hypointensities in substantia nigra, red and dentate nuclei (Fig. 1, E-H). Bilateral symmetric HOD corresponded with the new clinical findings. To exclude other possible genetic causes of bilateral HOD, we did a next generation sequencing‐based gene panel test with 723 genes included, which just confirmed ATP7B mutations but did not show any pathogenic variants in POLG, SURF1, or GFAP genes. Discussion HOD is a rare form of anterograde transsynaptic degeneration due to damage to the dentatorubro-olivary pathway (also known as Guillain-Mollaret triangle). Pathologically, HOD is characterized by the presence of hypertrophied neurons with vacuolar degeneration of the cytoplasm and prominent gemistocytic astrocytes [1]. Despite the previous consideration of a bilateral HOD as a rare phenomenon, later studies showed that it is a relatively common radiological finding. For instance, in a clinico-radiologic study of 95 patients with radiologically proven HOD, Konno et al. found that bilateral HOD was observed in 56 cases [2]. Interestingly, in 52% of those cases, the etiology was unknown, whereas 48% of patients had acquired bilateral HOD [2]. According to the recent study by Wang et al., who reviewed 151 cases of HOD reported in the English language between 1964 and 2019, bilateral HOD was found in 45.7% of patients [3]. In their review, the most common etiologies included vascular lesions and tumors. Less frequent causes of HOD were traumatic brain injuries, inflammatory and infectious conditions [3]. While some cases of HOD remain idiopathic, others are associated with conditions due to mutations in POLG, SURF1, and GFAP nuclear genes and with spinocerebellar ataxia type 20. Bilateral HOD with clinical manifestation in WD is rare. Otto et al. have previously reported a case of bilateral HOD in WD; however, neither palatal nor ocular or any other hyperkinetic disorder was observed [4]. Moreover, based on our literature review, myorhythmia of the facial and laryngeal muscles along with palatal tremor have not been described in WD before. The vast involvement of various muscle groups in our patient may be attributed to substantial
This article is protected by copyright. All rights reserved.
white matter damage in the brainstem. Thus, deafferentation of the inferior olives could occur due to damage to both dentato-rubral and rubro-olivary (central tegmental tract) fibers which led to altered inhibitory output from the both cerebellar hemispheres. The latter resulted in disinhibition of the brainstem oscillators, including rhythmic activity of the trigeminal and facial motor nuclei as well as nucleus ambiguus. Disruption of these pathways could also be aggravated by abnormal iron accumulation in the dentate and red nuclei seen in T2 and T2* sequences. In conclusion, our case expands the clinical and radiological phenotype of WD demonstrating symptomatic bilateral HOD in this condition.
This article is protected by copyright. All rights reserved.
Acknowledgment: none. Author Roles: 1. Research project: A. Conception, B. Organization, C. Execution 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing of the first draft, B. Review and Critique;
YuS: 1A, 1B, 1C, 3A AS: 1C, 3A EK: 1C, 3B MK: 1B, 3B
Disclosures Funding Sources and Conflict of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.
Financial Disclosures for the previous 12 months: Yury Seliverstov has received compensations from Allergan for talks on dystonia. Aleksandr Suslin, Elena Kremneva, and Marina Krotenkova declare that there are no additional disclosures to report.
Ethical Compliance Statement We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that the
This article is protected by copyright. All rights reserved.
patient provided verbal and written consent for this work, but because this article is a case report no IRB approval was necessary.
References 1
Goto N, Kaneko M. Olivary enlargement: chronological and morphometric analyses. Acta Neuropathol 1981;54:275–82. doi:10.1007/BF00697000
2
Konno T, Broderick DF, Tacik P, et al. Hypertrophic olivary degeneration: a clinicoradiologic study. Parkinsonism Relat Disord 2016;28:36–40. doi:10.1016/j.parkreldis.2016.04.008
3
Wang H, Wang Y, Wang R, et al. Hypertrophic olivary degeneration: a comprehensive review focusing on etiology. Brain Res 2019;1718:53–63. doi:10.1016/J.BRAINRES.2019.04.024
4
Otto J, Guenther P, Hoffmann K-T. Bilateral hypertrophic olivary degeneration in Wilson disease. Korean J Radiol 2013;14:316–20. doi:10.3348/kjr.2013.14.2.316
Legends for Supplemental files Legend to the figure: On the 2017 brain MRI, no olivary hypertrophy is seen (A). Bilateral FLAIR hyperintensities in the dorsal midbrain and pons (B), atrophy of the middle cerebellar peduncles (C), as well as mild bilateral T2 hypointensities in the globus pallidus (D) can be observed. After two years, brain MRI showed bilateral symmetric hypertrophic olivary degeneration (E), marked increase of the midbrain and dorsal pons atrophy (F), and bilateral T2* hypointensities in substantia nigra, red (G) and dentate nuclei (H).
This article is protected by copyright. All rights reserved.
Legend to the video: Continuous symmetric myorhythmia of the lower facial muscles, larynx, and possibly diaphragm. Palatal tremor with a clicking sound is also observed.
This article is protected by copyright. All rights reserved.
Accepted Article
Segmental Myorhythmia with Palatal Tremor due to Bilateral Hypertrophic Olivary Degeneration in Wilson Disease
Yury Seliverstov1*, Aleksandr Suslin1, Elena Kremneva1, Marina Krotenkova1 1 – Research Center of Neurology, Moscow, Russia
*Corresponding author Yury Seliverstov, MD, PhD Research Center of Neurology, Volokolamskoe shosse 80, Moscow, Russia 125367 +7 916 799 22 28 [email protected]
Text word count: 796 Title word count: 14 Running Title: Bilateral Hypertrophic Olivary Degeneration in WD Number of figures: 1 Number of videos: 1 Number of references: 4
Keywords Wilson disease, bilateral hypertrophic olivary degeneration, myorhythmia, palatal tremor
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/mdc3.13017
This article is protected by copyright. All rights reserved.
Wilson disease (WD) is a rare treatable disorder of copper metabolism with an autosomal recessive inheritance due to mutations in the ATP7B gene. In this article, we present a patient with biochemically and genetically confirmed WD, who through the course of the disease developed symptomatic bilateral hypertrophic olivary degeneration (HOD).
Case report A 47-year-old man with a two-year history of WD presented with increased drooling. His diagnosis was based on clinical findings (including Kayser-Fleischer rings), laboratory tests (low serum ceruloplasmin, increased 24-hour urine copper excretion), and genetic test. Sanger sequencing of the ATP7B gene showed compound heterozygosity for two pathogenic point mutations: c.2827G>A (has been described before) and c.1630C>T (novel variant leading to the termination of the protein synthesis). The Global Assessment Scale for Wilson Disease score was the following: tier 1 — L1, C3, M3, O0*; tier 2 — 25. On examination, apart from marked parkinsonism with severe postural instability and mild limitation of the eye movements in upgaze that were present at the previous examination a year ago, continuous symmetric rhythmic involuntary movement of the lower facial muscles, soft palate, and larynx was found. By observing his irregular breathing movements of the abdominal wall, diaphragmal involvement in the hyperkinesis could be suspected as well (Video). According to patient, those involuntary movements developed 8 months earlier; however, they did not bother him. His caregiver reported that the movements were persistent during sleep. Patient’s medical treatment was stable for the last 8 months and included 500 mg penicillamine/daily, pyridoxine 25 mg, elementary zinc 80 mg/daily, levodopa 300 mg/daily, and biperiden 6 mg/daily. His liver function was compensated, urinary copper excretion test showed 230 mcg/day, which indicated a relatively adequate penicillamine dose. Previous attempts to slightly increase penicillamine dose led to the exacerbation of the neurological deficit (trientine is not available in Russia). In comparison with previous 2-yearold brain MRI, which showed bilateral T2 and FLAIR hyperintensities in the dorsal midbrain and pons, atrophy of the middle cerebellar peduncles, as well as mild T2 bilateral
This article is protected by copyright. All rights reserved.
hypointensities in the globus pallidus (Fig. 1, A-D), the repeated brain MRI showed marked increase of the midbrain and dorsal pons atrophy, bilateral symmetric HOD, and bilateral T2* hypointensities in substantia nigra, red and dentate nuclei (Fig. 1, E-H). Bilateral symmetric HOD corresponded with the new clinical findings. To exclude other possible genetic causes of bilateral HOD, we did a next generation sequencing‐based gene panel test with 723 genes included, which just confirmed ATP7B mutations but did not show any pathogenic variants in POLG, SURF1, or GFAP genes. Discussion HOD is a rare form of anterograde transsynaptic degeneration due to damage to the dentatorubro-olivary pathway (also known as Guillain-Mollaret triangle). Pathologically, HOD is characterized by the presence of hypertrophied neurons with vacuolar degeneration of the cytoplasm and prominent gemistocytic astrocytes [1]. Despite the previous consideration of a bilateral HOD as a rare phenomenon, later studies showed that it is a relatively common radiological finding. For instance, in a clinico-radiologic study of 95 patients with radiologically proven HOD, Konno et al. found that bilateral HOD was observed in 56 cases [2]. Interestingly, in 52% of those cases, the etiology was unknown, whereas 48% of patients had acquired bilateral HOD [2]. According to the recent study by Wang et al., who reviewed 151 cases of HOD reported in the English language between 1964 and 2019, bilateral HOD was found in 45.7% of patients [3]. In their review, the most common etiologies included vascular lesions and tumors. Less frequent causes of HOD were traumatic brain injuries, inflammatory and infectious conditions [3]. While some cases of HOD remain idiopathic, others are associated with conditions due to mutations in POLG, SURF1, and GFAP nuclear genes and with spinocerebellar ataxia type 20. Bilateral HOD with clinical manifestation in WD is rare. Otto et al. have previously reported a case of bilateral HOD in WD; however, neither palatal nor ocular or any other hyperkinetic disorder was observed [4]. Moreover, based on our literature review, myorhythmia of the facial and laryngeal muscles along with palatal tremor have not been described in WD before. The vast involvement of various muscle groups in our patient may be attributed to substantial
This article is protected by copyright. All rights reserved.
white matter damage in the brainstem. Thus, deafferentation of the inferior olives could occur due to damage to both dentato-rubral and rubro-olivary (central tegmental tract) fibers which led to altered inhibitory output from the both cerebellar hemispheres. The latter resulted in disinhibition of the brainstem oscillators, including rhythmic activity of the trigeminal and facial motor nuclei as well as nucleus ambiguus. Disruption of these pathways could also be aggravated by abnormal iron accumulation in the dentate and red nuclei seen in T2 and T2* sequences. In conclusion, our case expands the clinical and radiological phenotype of WD demonstrating symptomatic bilateral HOD in this condition.
This article is protected by copyright. All rights reserved.
Acknowledgment: none. Author Roles: 1. Research project: A. Conception, B. Organization, C. Execution 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing of the first draft, B. Review and Critique;
YuS: 1A, 1B, 1C, 3A AS: 1C, 3A EK: 1C, 3B MK: 1B, 3B
Disclosures Funding Sources and Conflict of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.
Financial Disclosures for the previous 12 months: Yury Seliverstov has received compensations from Allergan for talks on dystonia. Aleksandr Suslin, Elena Kremneva, and Marina Krotenkova declare that there are no additional disclosures to report.
Ethical Compliance Statement We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that the
This article is protected by copyright. All rights reserved.
patient provided verbal and written consent for this work, but because this article is a case report no IRB approval was necessary.
References 1
Goto N, Kaneko M. Olivary enlargement: chronological and morphometric analyses. Acta Neuropathol 1981;54:275–82. doi:10.1007/BF00697000
2
Konno T, Broderick DF, Tacik P, et al. Hypertrophic olivary degeneration: a clinicoradiologic study. Parkinsonism Relat Disord 2016;28:36–40. doi:10.1016/j.parkreldis.2016.04.008
3
Wang H, Wang Y, Wang R, et al. Hypertrophic olivary degeneration: a comprehensive review focusing on etiology. Brain Res 2019;1718:53–63. doi:10.1016/J.BRAINRES.2019.04.024
4
Otto J, Guenther P, Hoffmann K-T. Bilateral hypertrophic olivary degeneration in Wilson disease. Korean J Radiol 2013;14:316–20. doi:10.3348/kjr.2013.14.2.316
Legends for Supplemental files Legend to the figure: On the 2017 brain MRI, no olivary hypertrophy is seen (A). Bilateral FLAIR hyperintensities in the dorsal midbrain and pons (B), atrophy of the middle cerebellar peduncles (C), as well as mild bilateral T2 hypointensities in the globus pallidus (D) can be observed. After two years, brain MRI showed bilateral symmetric hypertrophic olivary degeneration (E), marked increase of the midbrain and dorsal pons atrophy (F), and bilateral T2* hypointensities in substantia nigra, red (G) and dentate nuclei (H).
This article is protected by copyright. All rights reserved.
Legend to the video: Continuous symmetric myorhythmia of the lower facial muscles, larynx, and possibly diaphragm. Palatal tremor with a clicking sound is also observed.
This article is protected by copyright. All rights reserved.
Accepted Article
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