Dementia in Fragile X-associated Tremor/Ataxia Syndrome

Nitrini, Ricardo; Gonçalves, Márcia Rúbia R.; Capelli, Leonardo P.; Barbosa, Egberto Reis; Porto, Cláudia Sellitto; Amaro, Edson; Otto, Paulo Alberto; Vianna-Morgante, Angela M.

doi:10.1590/S1980-57642010DN40100014

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a cause of movement disorders and cognitive decline which has probably been underdiagnosed, especially if its prevalence proves similar to those of progressive supranuclear palsy and amyotrophic lateral sclerosis. We report a case of a 74-year-old man who presented with action tremor, gait ataxia and forgetfulness. There was a family history of tremor and dementia, and one of the patient's grandsons was mentally deficient. Neuropsychological evaluation disclosed a frontal network syndrome. MRI showed hyperintensity of both middle cerebellar peduncles, a major diagnostic hallmark of FXTAS. Genetic testing revealed premutation of the FMR1 gene with an expanded (CGG)₉₀ repeat. The diagnosis of FXTAS is important for genetic counseling because the daughters of the affected individuals are at high risk of having offspring with fragile X syndrome. Tremors and cognitive decline should raise the diagnostic hypothesis of FXTAS, which MRI may subsequently reinforce, while the detection of the FMR1 premutation can confirm the condition.

Key words:
fragile X; dementia; tremor; essencial tremor; ataxia; premutation

Resumo

A síndrome de tremor-ataxia associada ao X-frágil (FXTAS) é uma causa de distúrbios do movimento e de declínio cognitivo que provavelmente tem sido subdiagnosticada, especialmente se a sua prevalência for realmente similar às da paralisia supranuclear progressiva e esclerose lateral amiotrófica. Relatamos um caso de um homem de 74 anos que se apresentou com tremor de ação, ataxia de marcha e esquecimento. Havia história familiar de tremor e de demência e um de seus netos era mentalmente deficiente. A avaliação neuropsicológica demonstrou uma síndrome frontal. A ressonância magnética (RM) revelou hiperintensidade de ambos os pedúnculos cerebelares médios, um critério maior para o diagnóstico de FXTAS. Os testes genéticos confirmaram a presença da pré-mutação do gene FMR1, com uma repetição (CGG)₉₀. O diagnóstico de FXTAS é importante para o aconselhamento genético porque as filhas dos indivíduos afetados tem alto risco de ter uma criança com síndrome do X-frágil. A presença de tremores e declínio cognitivo deve levantar a hipótese diagnóstica de FXTAS, que poderá ser reforçada pela RM e confirmada pela presença da pré-mutação do gene FMR1.

Palavras-chave:
X-frágil; demência; tremor; tremor essencial; ataxia; pré-mutação

Texto completo disponível apenas em PDF.

Full text available only in PDF format.

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;57:127-130.
²
Amiri K, Hagerman RJ, Hagerman PJ. Fragile X-associated tremor/ataxia syndrome: an aging face of the fragile X gene. Arch Neurol 2008;65:19-25.
³
Leehey MA, Munhoz RP, Lang AE, et al. The fragile X premutation presenting as essential tremor. Arch Neurol 2003;60: 117-121.
⁴
Allingham-Hawkins DJ, Babul-Hirji R, Chitayat D, et al. Fragile X premutation is a significant risk factor for premature ovarian failure: the International Collaborative POF in Fragile X study-preliminary data. Am J Med Genet 1999;83:322-325.
⁵
Vianna-Morgante AM, Costa SS, Pavanello RCM, Otto PA, Regina C, Mingroni-Netto RC. Premature ovarian failure (POF) in Brazilian fragile X carriers. Genet Mol Biol 1999;22:471-474.
⁶
Horvath J, Burkhard PR, Morris M, Bottani A, Moix I, Delavelle J. Expanding the phenotype of fragile X-associated tremor/ataxia syndrome: a new female case. Mov Dis 2007;22: 1677-1678.
⁷
Hagerman RJ, Leavitt BR, Farzin F, et al. Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation. Am J Hum Genet 2004;74:1051-1056.
⁸
O'Dwyer JP, Clabby C, Crown J, Barton DE, Hutchinson M. Fragile X-associated tremor/ataxia syndrome presenting in a woman after chemotherapy. Neurology 2005;65:331.
⁹
Gonçalves MRR, Capelli LP, Nitrini R, et al. Atypical clinical course of FXTAS: rapidly progressive dementia as the major symptom. Neurology 2007;68:1864-1866.
¹⁰
Greco CM, Hagerman RJ, Tassone F, et al. Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers. Brain 2002;125:1760-1771.
¹¹
Brunberg JA, Jacquemont S, Hagerman RJ, et al. Fragile X premutation carriers: characteristic MR imaging findings of adult male patients with progressive cerebellar and cognitive dysfunction. Am J Neuroradiol 2002;23:1757-1766.
¹²
Okamoto K, Tokiguchi S, Furusawa T, et al. MR features of diseases involving bilateral middle cerebellar peduncles. Am J Neuroradiol 2003;24:1946-1954
¹³
Storey E, Billimoria P. Increased T2 signal in the middle cerebellar peduncles on MRI is not specific for fragile X premutation syndrome. J Clin Neurosci 2005;12: 42-43.
¹⁴
Folstein MF, Folstein SE, McHugh PR. "Mini-mental State": a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-198.
¹⁵
Brucki SMD, Nitrini R, Caramelli P, Bertolucci PHF, Okamoto IH. Sugestões para o uso do Mini-Exame do Estado Mental no Brasil. Arq Neuropsiquiatr 2003;61:777-781.
¹⁶
Mattis S. Dementia Rating Scale: professional manual. Florida: Psychol Assess Res; 1988.
¹⁷
Porto SC, Charchat-Fichman H, Caramelli P, Bahia VA, Nitrini R. Dementia Rating Scale - DRS - in the diagnosis of patients with Alzheimer's dementia. Arq Neuropsiquiatr 2003;61:339-345.
¹⁸
Nitrini R, Lefèvre BH, Mathias SC, et al. Neuropsychological tests of simple application for diagnosing dementia. Arq Neuropsiquiatr 1994;52:457-465.
¹⁹
Nitrini R, Caramelli P, Herrera E Jr, et al. Performance of illiterate and literate nondemented elderly subjects in two tests of long-term memory. J Int Neuropsychol Soc 2004;10:634-638.
²⁰
Weschler D. Weschler Memory Scale: revised manual. New York: Psychological Corporation; 1987.
²¹
Stroop JR. Studies of interference in serial verbal reactions. J Exp Psychol 1935;18:643-662.
²²
Duncan MT. Assessment of normative data of Stroop test performance in a group of elementary school students in Niterói. J Bras Psiquiatr 2006;55:42-48.
²³
Pfeffer RI, Kurosaki TT, Harrah CH Jr, Chance JM, Filos S. Measurement of functional activities in older adults in the community. J Gerontol 1982;37:323-329.
²⁴
Jacquemont S, Hagerman RJ, Leehey M, et al. Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet 2003;72:869-878.
²⁵
Mesulam MM. Principles of behavior and cognitive neurology. 2 ed. Oxford, New York, 2000.
²⁶
Grigsby J, Leehey MA, Jacquemont S, et al. Cognitive impairment in a 65-year-old male with the fragile X-associated tremor-ataxia syndrome (FXTAS). Cog Behav Neurol 2006; 19:165-171.
²⁷
Lou JS, Jankovic J. Essential tremor: clinical correlates in 350 patients. Neurology 1991;41:234-238.
²⁸
Loesch DZ, Litewka L, Churchyard A, Gould E, Tassone F, Cook M. Tremor/ataxia syndrome and fragile X premutation: diagnostic caveats. J Clin Neurosci 2007;14:245-248.
²⁹
Capelli LP, Goncalves MRR, Kok F, et al. Fragile X-associated tremor/ataxia syndrome: intrafamilial variability and the size of the FMR1 premutation CGG repeat. Mov Dis 2007;22: 866-870
³⁰
Berry-Kravis E, Abrams L, Coffey SM, et al. Fragile X-associated tremor/ataxia syndrome: clinical features, genetics, and testing guidelines. Mov Disord 2007;22:2018-2030.

Publication Dates

Publication in this collection
Jan-Mar 2010

History

Received
23 Oct 2009
Accepted
17 Dec 2009

This is an open-access article distributed under the terms of the Creative Commons Attribution License

[1] ¹
Hagerman RJ, Leehey M, Heinrichs W, et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 2001;57:127-130.

[2] ²
Amiri K, Hagerman RJ, Hagerman PJ. Fragile X-associated tremor/ataxia syndrome: an aging face of the fragile X gene. Arch Neurol 2008;65:19-25.

[3] ³
Leehey MA, Munhoz RP, Lang AE, et al. The fragile X premutation presenting as essential tremor. Arch Neurol 2003;60: 117-121.

[4] ⁴
Allingham-Hawkins DJ, Babul-Hirji R, Chitayat D, et al. Fragile X premutation is a significant risk factor for premature ovarian failure: the International Collaborative POF in Fragile X study-preliminary data. Am J Med Genet 1999;83:322-325.

[5] ⁵
Vianna-Morgante AM, Costa SS, Pavanello RCM, Otto PA, Regina C, Mingroni-Netto RC. Premature ovarian failure (POF) in Brazilian fragile X carriers. Genet Mol Biol 1999;22:471-474.

[6] ⁶
Horvath J, Burkhard PR, Morris M, Bottani A, Moix I, Delavelle J. Expanding the phenotype of fragile X-associated tremor/ataxia syndrome: a new female case. Mov Dis 2007;22: 1677-1678.

[7] ⁷
Hagerman RJ, Leavitt BR, Farzin F, et al. Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation. Am J Hum Genet 2004;74:1051-1056.

[8] ⁸
O'Dwyer JP, Clabby C, Crown J, Barton DE, Hutchinson M. Fragile X-associated tremor/ataxia syndrome presenting in a woman after chemotherapy. Neurology 2005;65:331.

[9] ⁹
Gonçalves MRR, Capelli LP, Nitrini R, et al. Atypical clinical course of FXTAS: rapidly progressive dementia as the major symptom. Neurology 2007;68:1864-1866.

[10] ¹⁰
Greco CM, Hagerman RJ, Tassone F, et al. Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers. Brain 2002;125:1760-1771.

[11] ¹¹
Brunberg JA, Jacquemont S, Hagerman RJ, et al. Fragile X premutation carriers: characteristic MR imaging findings of adult male patients with progressive cerebellar and cognitive dysfunction. Am J Neuroradiol 2002;23:1757-1766.

[12] ¹²
Okamoto K, Tokiguchi S, Furusawa T, et al. MR features of diseases involving bilateral middle cerebellar peduncles. Am J Neuroradiol 2003;24:1946-1954

[13] ¹³
Storey E, Billimoria P. Increased T2 signal in the middle cerebellar peduncles on MRI is not specific for fragile X premutation syndrome. J Clin Neurosci 2005;12: 42-43.

[14] ¹⁴
Folstein MF, Folstein SE, McHugh PR. "Mini-mental State": a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-198.

[15] ¹⁵
Brucki SMD, Nitrini R, Caramelli P, Bertolucci PHF, Okamoto IH. Sugestões para o uso do Mini-Exame do Estado Mental no Brasil. Arq Neuropsiquiatr 2003;61:777-781.

[16] ¹⁶
Mattis S. Dementia Rating Scale: professional manual. Florida: Psychol Assess Res; 1988.

[17] ¹⁷
Porto SC, Charchat-Fichman H, Caramelli P, Bahia VA, Nitrini R. Dementia Rating Scale - DRS - in the diagnosis of patients with Alzheimer's dementia. Arq Neuropsiquiatr 2003;61:339-345.

[18] ¹⁸
Nitrini R, Lefèvre BH, Mathias SC, et al. Neuropsychological tests of simple application for diagnosing dementia. Arq Neuropsiquiatr 1994;52:457-465.

[19] ¹⁹
Nitrini R, Caramelli P, Herrera E Jr, et al. Performance of illiterate and literate nondemented elderly subjects in two tests of long-term memory. J Int Neuropsychol Soc 2004;10:634-638.

[20] ²⁰
Weschler D. Weschler Memory Scale: revised manual. New York: Psychological Corporation; 1987.

[21] ²¹
Stroop JR. Studies of interference in serial verbal reactions. J Exp Psychol 1935;18:643-662.

[22] ²²
Duncan MT. Assessment of normative data of Stroop test performance in a group of elementary school students in Niterói. J Bras Psiquiatr 2006;55:42-48.

[23] ²³
Pfeffer RI, Kurosaki TT, Harrah CH Jr, Chance JM, Filos S. Measurement of functional activities in older adults in the community. J Gerontol 1982;37:323-329.

[24] ²⁴
Jacquemont S, Hagerman RJ, Leehey M, et al. Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet 2003;72:869-878.

[25] ²⁵
Mesulam MM. Principles of behavior and cognitive neurology. 2 ed. Oxford, New York, 2000.

[26] ²⁶
Grigsby J, Leehey MA, Jacquemont S, et al. Cognitive impairment in a 65-year-old male with the fragile X-associated tremor-ataxia syndrome (FXTAS). Cog Behav Neurol 2006; 19:165-171.

[27] ²⁷
Lou JS, Jankovic J. Essential tremor: clinical correlates in 350 patients. Neurology 1991;41:234-238.

[28] ²⁸
Loesch DZ, Litewka L, Churchyard A, Gould E, Tassone F, Cook M. Tremor/ataxia syndrome and fragile X premutation: diagnostic caveats. J Clin Neurosci 2007;14:245-248.

[29] ²⁹
Capelli LP, Goncalves MRR, Kok F, et al. Fragile X-associated tremor/ataxia syndrome: intrafamilial variability and the size of the FMR1 premutation CGG repeat. Mov Dis 2007;22: 866-870

[30] ³⁰
Berry-Kravis E, Abrams L, Coffey SM, et al. Fragile X-associated tremor/ataxia syndrome: clinical features, genetics, and testing guidelines. Mov Disord 2007;22:2018-2030.

Brasil