Challenges in diagnosis of fragile X-associated tremor/ataxia syndrome

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disease recently described in the literature with a low percentage of detectability in patients due to insufficient awareness of doctors. The clinical picture is characterized by high phenotypic variability and coincidence of symptoms with other, more well-known motor disorders, in connection with which patients are observed for a long time with erroneous diagnoses. The issue of the differential diagnosis fragile X-associated tremor/ataxia syndrome with essential tremor, Parkinson’s disease, multiple system atrophy, spinocerebellar ataxia and progressive supranuclear paralysis is highlighted separately. In order to demonstrate the complexity of the diagnosis of this disease, a description of a case of genetically confirmed case of genetically confirmed fragile X-associated tremor/ataxia syndrome is presented. The described clinical case is represented by a combination of asymmetric disabling postural kinetic tremor of the hands, minor resting tremor, moderate cerebellar ataxia, asymmetric moderate dopa-responsive parkinsonism syndrome, mild cognitive impairment and psychotic symptoms. Not only the clinical picture of the disease is described in detail, but also the hereditary history of the patient: the results of a genetic study of a daughter premutation carriers of the FMR1 gene and a grandson suffering from Martin–Bell syndrome. A special feature of the clinical case is the long-term erroneous observation of a patient diagnosed with Parkinson’s disease, as well as high-dose therapy with levodopa/carbidopa 250 mg + 25 mg (up to 6 tablets per day). When studying the available domestic literature, the previously described cases of fragile X-associated tremor/ataxia syndrome were not found.

Keywords

ataxia syndrome / FMR1 gene / fragile multiple system atrophy / FXTAS / Parkinson`s disease / tremor syndrome / X-associated

References

[1] Hagerman RJ, Leehey M, Heinrichs W, et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology. 2001;57(1):127–130. doi: 10.1212/wnl.57.1.127

[2] Hagerman R.J., Leehey M., Heinrichs W., et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X // Neurology. 2001. Vol. 57, N 1. P. 127–130. doi: 10.1212/wnl.57.1.127

[3] Hagerman RJ, Leehey M, Heinrichs W, et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology. 2001;57(1):127–130. doi: 10.1212/wnl.57.1.127

[4] Hall DA, Berry-Kravis E, Jacquemont S, et al. Initial diagnoses given to persons with the fragile X associated tremor/ataxia syndrome (FXTAS). Neurology. 2005;65(2):299–301. doi: 10.1212/01.wnl.0000168900.86323.9c

[5] Hall D.A., Berry-Kravis E., Jacquemont S., et al. Initial diagnoses given to persons with the fragile X associated tremor/ataxia syndrome (FXTAS) // Neurology. 2005. Vol. 65, N 2. P. 299–301. doi: 10.1212/01.wnl.0000168900.86323.9c

[6] Hall DA, Berry-Kravis E, Jacquemont S, et al. Initial diagnoses given to persons with the fragile X associated tremor/ataxia syndrome (FXTAS). Neurology. 2005;65(2):299–301. doi: 10.1212/01.wnl.0000168900.86323.9c

[7] Gamisoniya AM. Sindrom lomkoj X-hromosomy. GENOKARTA Geneticheskaya enciklopediya 2019. Available from: https://www.genokarta.ru/disease/Sindrom_lomkoj_X_hromosomy (In Russ.)

[8] Гамисония А.М. Синдром ломкой X-хромосомы [Internet]. ГЕНОКАРТА Генетическая энциклопедия, 2019. Дата обращения: 21.09.2024. Режим доступа: https://www.genokarta.ru/disease/Sindrom_lomkoj_X_hromosomy

[9] Gamisoniya AM. Sindrom lomkoj X-hromosomy. GENOKARTA Geneticheskaya enciklopediya 2019. Available from: https://www.genokarta.ru/disease/Sindrom_lomkoj_X_hromosomy (In Russ.)

[10] Hagerman PJ, Hagerman RJ. Fragile X-associated tremor/ataxia syndrome — an older face of the fragile X gene. Nat Clin Pract Neurol. 2007;3(2):107–112. doi: 10.1038/ncpneuro0373

[11] Hagerman P.J., Hagerman R.J. Fragile X-associated tremor/ataxia syndrome — an older face of the fragile X gene // Nat. Clin. Pract. Neurol. 2007. Vol. 3, N 2. P. 107–112. doi: 10.1038/ncpneuro0373

[12] Hagerman PJ, Hagerman RJ. Fragile X-associated tremor/ataxia syndrome — an older face of the fragile X gene. Nat Clin Pract Neurol. 2007;3(2):107–112. doi: 10.1038/ncpneuro0373

[13] Johnson K, Herring J, Richstein J. Fragile X Premutation Associated Conditions (FXPAC). Front Pediatr. 2020;8:266. doi: 10.3389/fped.2020.00266

[14] Johnson K., Herring J., Richstein J. Fragile X Premutation Associated Conditions (FXPAC) // Front Pediatr. 2020. Vol. 8. P. 266. doi: 10.3389/fped.2020.00266

[15] Johnson K, Herring J, Richstein J. Fragile X Premutation Associated Conditions (FXPAC). Front Pediatr. 2020;8:266. doi: 10.3389/fped.2020.00266

[16] Pereverzeva DS, Tyushkevich SA, Gorbachevskaia NL, et al. Heterogeneity of clinical characteristics of FMR1-related disorders. S.S. Korsakov Journal of Neurology and Psychiatry. 2019;119(7): 103–111. EDN: CHAHKE doi: 10.17116/jnevro2019119071103

[17] Pereverzeva D.S., Tyushkevich S.A., Gorbachevskaia N.L., et al. Heterogeneity of clinical characteristics of FMR1-related disorders // S.S. Korsakov Journal of Neurology and Psychiatry. 2019. Vol. 119, N 7. P. 103–111. EDN: CHAHKE doi: 10.17116/jnevro2019119071103

[18] Pereverzeva DS, Tyushkevich SA, Gorbachevskaia NL, et al. Heterogeneity of clinical characteristics of FMR1-related disorders. S.S. Korsakov Journal of Neurology and Psychiatry. 2019;119(7): 103–111. EDN: CHAHKE doi: 10.17116/jnevro2019119071103

[19] Cabal-Herrera AM, Tassanakijpanich N, Salcedo-Arellano MJ, Hagerman RJ. Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Pathophysiology and Clinical Implications. Int J Mol Sci. 2020;21(12):4391. doi: 10.3390/ijms21124391

[20] Cabal-Herrera A.M., Tassanakijpanich N., Salcedo-Arellano M.J., Hagerman R.J. Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Pathophysiology and Clinical Implications // Int. J. Mol. Sci. 2020. Vol. 21, N 12. P. 4391. doi: 10.3390/ijms21124391

[21] Cabal-Herrera AM, Tassanakijpanich N, Salcedo-Arellano MJ, Hagerman RJ. Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Pathophysiology and Clinical Implications. Int J Mol Sci. 2020;21(12):4391. doi: 10.3390/ijms21124391

[22] Orsucci D, Lorenzetti L, Baldinotti F, et al. Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): A Gender Perspective. J Clin Med. 2022 Feb 15;11(4):1002. doi: 10.3390/jcm11041002

[23] Orsucci D., Lorenzetti L., Baldinotti F., et al. Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): A Gender Perspective // J. Clin. Med. 2022. Vol. 11, N 4. P. 1002. doi: 10.3390/jcm11041002

[24] Orsucci D, Lorenzetti L, Baldinotti F, et al. Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): A Gender Perspective. J Clin Med. 2022 Feb 15;11(4):1002. doi: 10.3390/jcm11041002

[25] Salcedo-Arellano MJ, Cabal-Herrera AM, Tassanakijpanich N, et al. Ataxia as the Major Manifestation of Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Case Series. Biomedicines. 2020;8(5):136. doi: 10.3390/biomedicines8050136

[26] Salcedo-Arellano M.J., Cabal-Herrera A.M., Tassanakijpanich N., et al. Ataxia as the Major Manifestation of Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Case Series // Biomedicines. 2020. Vol. 8, N 5. P. 136. doi: 10.3390/biomedicines8050136

[27] Salcedo-Arellano MJ, Cabal-Herrera AM, Tassanakijpanich N, et al. Ataxia as the Major Manifestation of Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Case Series. Biomedicines. 2020;8(5):136. doi: 10.3390/biomedicines8050136

[28] Islam F, Lee W. A Case of Generalized Chorea Presenting as an Early Feature of Fragile-X Associated Tremor/Ataxia Syndrome. Mov Disord Clin Pract. 2020;7(4):464–466. doi: 10.1002/mdc3.12944

[29] Islam F., Lee W. A Case of Generalized Chorea Presenting as an Early Feature of Fragile-X Associated Tremor/Ataxia Syndrome // Mov. Disord. Clin. Pract. 2020. Vol. 7, N 4. P. 464–466. doi: 10.1002/mdc3.12944

[30] Islam F, Lee W. A Case of Generalized Chorea Presenting as an Early Feature of Fragile-X Associated Tremor/Ataxia Syndrome. Mov Disord Clin Pract. 2020;7(4):464–466. doi: 10.1002/mdc3.12944

[31] Gaillard F, Campos A, Hacking C, et al. Fragile X-associated tremor/ataxia syndrome. Reference article. Radiopaedia.org (Accessed on 21 Sep 2024). doi: 10.53347/rID-1359

[32] Gaillard F., Campos A., Hacking C., et al. Fragile X-associated tremor/ataxia syndrome. Reference article. Radiopaedia.org. doi: 10.53347/rID-1359

[33] Gaillard F, Campos A, Hacking C, et al. Fragile X-associated tremor/ataxia syndrome. Reference article. Radiopaedia.org (Accessed on 21 Sep 2024). doi: 10.53347/rID-1359

[34] Robertson EE, Hall DA, McAsey AR, O’Keefe JA. Fragile X-associated tremor/ataxia syndrome: phenotypic comparisons with other movement disorders. Clin Neuropsychol. 2016;30(6):849–900. doi: 10.1080/13854046.2016.1202239

[35] Robertson E.E., Hall D.A., McAsey A.R., O’Keefe J.A. Fragile X-associated tremor/ataxia syndrome: phenotypic comparisons with other movement disorders // Clin. Neuropsychol. 2016. Vol. 30, N 6. P. 849–900. doi: 10.1080/13854046.2016.1202239

[36] Robertson EE, Hall DA, McAsey AR, O’Keefe JA. Fragile X-associated tremor/ataxia syndrome: phenotypic comparisons with other movement disorders. Clin Neuropsychol. 2016;30(6):849–900. doi: 10.1080/13854046.2016.1202239

RIGHTS & PERMISSIONS

Eco-Vector