Bhatia, KP

Latorre, A

Martinez‐Castrillo, JC

Pareés, I

Ros‐Castelló, V

Álvarez‐Linera, J

English

UCL Discovery

Ros-Castelló Victoria (Orcid ID: 0000-0002-9523-3012) Latorre Anna (Orcid ID: 0000-0001-7103-5209) Bhatia Kailash (Orcid ID: 0000-0001-8185-286X)  Video is part of ms Dystonia in a female fragile X premutation carrier: a case report   Victoria Ros-Castelló MD1, Anna Latorre MD, PhD2, Juan Álvarez-Linera MD3, Juan C Martinez-Castrillo MD, PhD1, Kailash P Bhatia FRCP, MD2, Isabel Pareés MD, PhD1  1Neurology Department, Hospital Ramón y Cajal, IRYCIS, Madrid, Spain. 2Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, United Kingdom. 3Radiology Department, Hospital Ruber Internacional, Madrid, Spain.   Corresponding author: Victoria Ros Castelló  Address: Ctra. De Colmenar Viejo, km. 9,100, 28034 Madrid, Spain Telephone: 0034687481404 Email address: victoriaroscastello@gmail.com    Short running title:  Dystonia in a female FMR1 premutation carrier  Key words: dystonia, fragile X syndrome, FMR1 premutation, FXTAS                         This article has been accepted for publication and undergone full peer review but has notbeen through the copyediting, typesetting, pagination and proofreading process whichmay lead to differences between this version and the Version of Record. Please cite thisarticle as doi: 10.1002/mdc3.13234This article is protected by copyright. All rights reserved.Video is part of ms   Fragile X-associated tremor ataxia syndrome (FXTAS) is the most common neurological manifestation described in carriers of a premutation expansion (55–200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene1. FXTAS affects mainly men, partially because of a protective effect of the second X chromosome in females1. Female carriers often develop FMR1-related primary ovarian insufficiency but movement disorder phenotypes other than FXTAS have rarely been described1.  Here, we report a female carrying the FMR1 premutation who presented in our clinic with cervical dystonia as the main symptom.   CASE REPORT  This 59-year-old woman was referred to our movement disorders clinic because of progressive head tremor since age 58. She had a son aged 29 years old with fragile-X syndrome and she had been found to be a carrier of the premutation expansion of the FMR1 gene in the family screening. She was not on any medication. The neurological examination showed mild saccadic intrusions in slow pursuit movements and a “no-no” head tremor with right torticollis. Gait was normal and there were no other cerebellar signs including intention tremor (Video 1). She did not report any sensory trick for her dystonia. Laboratory tests, including ceruloplasmin, copper, ferritin and thyroid function, were normal. Genetic testing revealed 90 CGG repeats in the FMR1 gene. Brain MRI showed no abnormalities in cerebellum, middle cerebellar peduncles (MCP) or corpus callosum in FLAIR, diffusion tensor imaging or fractional anisotropy (Figure 1). No specific treatment was started, as she did not report a significant impact of her symptoms in her daily life.  DISCUSSION   We herein report a female FMR1 premutation carrier who presented with cervical dystonia as the main clinical phenotype in whom other secondary causes of dystonia were excluded.   Video is part of ms  Since the initial description, an increasing number of women with FXTAS have been identified, but there are very few reports of female FMR1 premutation carriers presenting with dystonia. A small case series has suggested that dystonia and bruxism present more commonly in female FMR1 premutation carriers than in the general population and a prevalence of 35% (8 out of 23 female carriers) for dystonia compared to 0.73% (p < 0.01) has also been reported2. Of those with dystonia, only four presented with cervical involvement2. A case of oromandibular dystonia in a patient carrying the FMR1 premutation has also been reported3 and only one female patient with FXTAS diagnosis who presented with cervical and laryngeal dystonia has been published to date4.  Our patient did not meet criteria for FXTAS1.  Therefore, our report contributes to the previous literature emphasizing that dystonia should be included in the spectrum of clinical manifestations in FMR1 premutation carriers. That is of interest as dystonia is not included in the diagnostic criteria of FXTAS and could potentially be another etiology of the tremor seen in FXTAS5.  Premutation carriers have slightly reduced FMR1 protein levels with significant elevation of FMR1 messenger RNA (mRNA) and a potential toxic effect in brain white matter and motor fiber tracts has been proposed6,7. Pathophysiologic findings in patients with FXTAS include marked dropout of Purkinje cells and white matter disease throughout the cerebellum, including the MCP8. Typical neuroimaging findings in patients with FXTAS include brain and cerebellar atrophy and white matter tracts changes with involvement of the MCP known as the MCP sign6. Radiological abnormalities in thalamus, basal ganglia and the splenium of the corpus callosum have also been reported9. However, radiologic findings are milder in female premutation carriers as compared with males and white matter hyperintensities in the splenium and genu of corpus callosum are more frequent than the MCP sign5.  Recent studies have suggested that alterations in activity, connectivity and structure of the cerebellum may play a role in the development of dystonia. There is evidence supporting that cerebellar atrophy, cerebellar degenerative disease, cerebellar lesions and histopathological alterations such as Purkinje cell loss or dentate nucleus cell loss may be associated with dystonia10. One could argue that abnormalities in the cerebellum and its connections with the basal ganglia and motor cortex may be involved in the development Video is part of ms  of dystonia in patients with the FMR1 premutation. Our patient did not display abnormalities in the neuroimaging studies, which is in concordance with the previous mentioned low rate of brain MRI abnormalities in females. However, it could be suggested that dystonia is a manifestation secondary to a cerebellar dysfunction occurring without neuroimaging evidence of the disease or even before neuroimaging abnormalities occur. Further follow-up is warranted to assess clinical and neuroimaging disease progression in those patients.  In conclusion, our case supports the previous suggestion that dystonia can be part of the clinical spectrum of females carrying a premutation expansion in the FMR1 gene and that FMR1 premutation-sized repeat expansions should be added to the differential diagnosis of craniocervical dystonia in females. However, larger studies are needed to confirm this clinical observation.   Author Roles:   (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution,C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.  1. VRC: 1A, 1B, 1C, 3A 2. AL: 1C, 3A, 3B  3. JAL: 1C, 3B  4. JCMC: 3B 5. KB: 1A, 3B 6. IP: 1A, 1B, 3A, 3B  Disclosures  Funding Sources and Conflict of Interest: The authors declare that there are no funding sources or conflicts of interest relevant to this work.  Financial Disclosures for the previous 12 months:   Video is part of ms  VRC has received honoraria as an speaker from Zambon.  JCMC has received honoraria as an speaker from AbbVie, Allergan, Bial, Krka, Merz, Ipsen, Italfarmaco, Medtronic, TEVA, and Zambon; travel grants from AbbVie, Allergan, Bial, Italfarmaco, TEVA, Merz, Krka and Zambón; research grants from AbbVie, Allergan, Merz, Italfarmaco, and Zambon; and participated in advisory boards of AbbVie, Allergan, Bial, Merz,  Italfarmaco, Lundbeck, Orion, UCB, and Zambon.  KPB has received grant support from Horizon 2020 EU grant 634821 and honoraria/financial support to speak/attend meetings from GSK, Boehringer-Ingelheim, Ipsen, Merz, Sun Pharma, Allergan, Teva, Lundbeck and Orion pharmaceutical companies. KPB receives royalties from Oxford University press and a stipend for MDCP editorship. This research study was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre and the Edmond J. Safra Philanthropic Foundation.  IP has received travel expenses to attend scientific meetings from Neuroaxpharm and International Parkinsonism and Movement Disorder Society and honoraria for speaking at meetings from Allergan, and International Parkinsonism and Movement Disorders Society.  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 approval of an institutional review board was not required for this work. Oral informed consent was obtained from the patient.  References  1. Hagerman RJ, Hagerman P. Fragile X-associated tremor/ataxia syndrome - features, mechanisms and management. Nat Rev Neurol. 2016 Jul;12:403-12.  Video is part of ms  2. Hall DA, M.A. Leehey, E. Berry-Kravis. Dystonia and bruxism are increased in female fragile X premutation carriers [abstract]. Movement Disorders 2013;28 Suppl 1:667.  3. Zhang L, Sukharev D, Schneider et al. Case report: Dystonia in a Fragile X Carrier Mov Disord. 2014 June ; 29: E4–E5.  4. Horvath J, Burkhard PR, Morris M et al. Expanding the phenotype of fragile X-associated tremor/ataxia syndrome: a new female case. Mov Disord. 2007 Aug 15;22:1677-8.   5. Schneider A, Summers S, Tassone F et al. Women with Fragile X-associated Tremor/Ataxia Syndrome. Mov Disord Clin Pract. 2020 Sep 23;7:910-919.   6. Adams JS, Adams PE, Nguyen D et al. Volumetric brain changes in females with fragile X-associated tremor/ataxia syndrome (FXTAS). Neurology. 2007 Aug 28;69:851-9.  7. Wang JY, Hessl D, Schneider A et al. Fragile X–Associated Tremor/Ataxia Syndrome: Influence of the FMR1 Gene on Motor Fiber Tracts in Males With Normal and Premutation. JAMA Neurol. 2013 August; 70: 1022–1029.  8. Salcedo-Arellano MJ, Dufour B, McLennan Y et al. Fragile X syndrome and associated disorders: Clinical aspects and pathology. Neurobiol Dis. 2020;136:104740.  9. Wang JY, Hagerman RJ, Rivera S et al. A multimodal imaging analysis of subcortical gray matter in fragile X premutation carriers. Mov Disord. 2013 August ; 28: 1278–1284  10. Shakkottai VG, Batla A, Bhatia KP et al. Current Opinions and Areas of Consensus on the Role of the Cerebellum in Dystonia. Cerebellum. 2017 Apr;16:577-594.   Legend  Figure 1. Brain MRI showing no abnormalities in cerebellum and middle cerebellar peduncules in FLAIR (A), corpus callosum in sagittal FLAIR (B) Video is part of ms  and diffusion tensor imaging with tractography (C) or fractional anisotropy (D).   Video  Video 1. Segment 1: “No-no” head tremor with right torticollis. Segment 2. Finger to nose test with no cerebellar signs. Segment 3. Normal tandem walking test. Segment 4. Null point: tremor is alleviated when head is turned completely to the right.     This article is protected by copyright. All rights reserved.Accepted Article

Dystonia in a female fragile X premutation carrier: a case report

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Dystonia in a female fragile X premutation carrier: a case report

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