Fragile X Associated Tremor Ataxia Syndrome

1. A D E W I J A Y A , M D – M A R C H 2 0 2 2
Fragile X-Associated
Tremor/Ataxia Syndrome
(FXTAS)

2. Outline:
 Fragile X syndrome
 Fragile X-associated tremor/ataxia syndrome
 Clinical Manifestation
 Pathophysiology
 Diagnosis
 Differential Diagnosis
 Management
 Summary

3. Fragile X Syndrome
 Fragile X syndrome (FXS) is the most common cause
of inherited intellectual disability and autism
spectrum disorder (ASD)
 Expansion of the CGG trinucleotide repeats (>200)
in the promoter region of the fragile X mental
retardation 1 (FMR1) gene, located at Xq27.3
Hagerman, R.J.; Berry-Kravis, E.; Hazlett, H.C.; Bailey, D.B.; Moine, H.; Kooy, R.F.; Tassone, F.; Gantois, I.; Sonenberg, N.;
Mandel, J.L.; et al. Fragile X syndrome. Nat. Rev. Dis. Primers 2017, 3, 17065

4. Fragile X Syndrome Clinical Spectrum
 Fragile X-associated primary ovarian insufficiency
(FXPOI)
 Fragile X-associated neuropsychiatric disorders
(FXAND)
 Fragile X-associated tremor/ataxia syndrome
(FXTAS)
Sherman, S.; Allen, E.G.; Jesica, S. Clinical manifestation and management of FXPOI. In FXTAS, FXPOI, and Other Premutation Disorders; Tassone, F., Hall, D.A., Eds.; Springer Nature: Basel,
Switzerland, 2016; pp. 199–224, ISBN 978-3-319-33896-5.
Hagerman, R.J.; Protic, D.; Rajaratnam, A.; Salcedo-Arellano, M.J.; Aydin, E.Y.; Schneider, A. Fragile X-Associated Neuropsychiatric Disorders (FXAND). Front. Psychiatry 2018, 9, 1–9.
Salcedo-Arellano, M.J.; Hagerman, R.J.; Martinez-Cerdeno, V. Fragile X associated tremor/ataxia syndrome: Its clinical presentation, pathology, and treatment TT—Sindrome de temblor y ataxia
asociado al X fragil: Presentacion clinica, patologia y tratamiento. Rev. Neurol. 2019, 68, 199–206.

5. Fragile X-associated tremor/ataxia syndrome
 First described in 2001 by Hagerman and colleagues
 Age-dependent neurodegenerative disorder with
prevalence increasing with age and affecting most
commonly males
 Early onset of FXTAS realated to neurotoxins, pollution,
illicit drugs, pesticides, and alcohol consumption
 The progression of FXTAS varies greatly among
individuals and the life expectancy after symptoms onset
has been established to be between 5 to 25 years with a
median of 21 years
Cabal-Herrera, A. M., Tassanakijpanich, N., Salcedo-Arellano, M. J., & Hagerman, R. J. (2020). Fragile X-associated tremor/ataxia
syndrome (FXTAS): pathophysiology and clinical implications. International journal of molecular sciences, 21(12), 4391.

6. Clinical Manifestation
Adapted from Leehey et al. 2007; Greco et al. 2006

7. Pathophysiology
 Repeat associated non-AUG (RAN) translation in
FXTAS
Adapted from Glineburg et al. 2018

8. Pathophysiology
 FMR1 RNA induced protein sequestration
Adapted from Hagerman and Hagerman 2016 and Glineburg et al. 2018

9. Pathophysiology
 Formation of RNA/DNA hybrids or R-loops during
transcription
Cabal-Herrera, A. M., Tassanakijpanich, N., Salcedo-Arellano, M. J., & Hagerman, R. J. (2020). Fragile X-associated tremor/ataxia
syndrome (FXTAS): pathophysiology and clinical implications. International journal of molecular sciences, 21(12), 4391.
Pathological hallmark:
Eosinophilic intranuclear inclusions in the CNS and PNS

10. Diagnosis
Adapted from Hall et al. 2014

11. Differential Diagnosis
 Late-onset cerebellar ataxia
 Spinocerebellar ataxia
 Multiple system atrophy
 Alzheimer’s disease
 Frontotemporal dementia
 Parkinson’s disease.
Cabal-Herrera, A. M., Tassanakijpanich, N., Salcedo-Arellano, M. J., & Hagerman, R. J. (2020). Fragile X-associated tremor/ataxia
syndrome (FXTAS): pathophysiology and clinical implications. International journal of molecular sciences, 21(12), 4391.

12. Management
 Selective serotonin reuptake inhibitor (SSRI) for
depression or anxiety
 A beta blocker, primidone or levetiracetam for
tremor
 Gabapentin, pregabalin or duloxetine for
neuropathic pain
Hagerman, R.J.; Hagerman, P. Fragile X-associated tremor/ataxia syndrome—Features, mechanisms and management. Nat. Rev. Neurol. 2016, 12, 403–412

13. Summary
 FXTAS is a neurodegenerative disorder that presents
mainly as intention tremor and/or ataxia with
cognitive decline, neuropathy, and autonomic
dysfunction
 Family history and genetic testing
 No targeted treatment yet

14. THANK YOU