Treatment including psychopharmacology
Currently there is no treatment targeting the pathophysiological mechanisms underlying FXTAS. Treatment is symptomatic, addressing specific motor, cognitive or psychiatric signs (Hall et al., 2006). A randomised controlled trial exploring treatment efficacy of Memantine, a glutamate receptor antagonist approved for use in the management of Alzheimer’s disease, suggested no significant improvement in intention tremor or executive function (Seritan et al., 2014) and limited benefit for language and memory function (Hall et al., 2014; Yang, Niu, Simon, Chen, Seritan & Schneider, 2013b) compared to placebo. An open-label trial of the neurosteroid allopregnanolone (administered via intravenous infusions) also showed improvements in executive function and episodic memory, but with no significant impact on structural brain MRI outcomes (Wang et al., 2017). It has been suggested that other therapeutic modalities may improve motor, cognitive or psychiatric symptoms (Hagerman et al., 2008), although these have not been the subject of clinical trials. Potentially beneficial interventions include cholinesterase inhibitors, levodopa, antidepressants, antipsychotics, N-methyl-D-aspartate (NMDA) receptor antagonists, dietary supplements and aerobic exercise (ibid.). Current clinical best practice involves implementing individual treatment programs comprising a combination of these management strategies (Hagerman et al., 2009; Polussa, Schneider & Hagerman, 2014). A greater understanding of the pathogenic mechanisms of FXTAS (e.g. CGG expansion, mRNA toxicity, protein dysregu- lation) and their relationships to clinical manifestations is required to inform the development of targeted disease-modifying therapies.
Fragile X-associated tremor ataxia syndrome is an inherited neurodegenerative disorder affecting up to 45% of men and 8-16% of women who cany premutation expansions of the FMR1 gene. Onset of symptoms is typically from the age of 50 years and the overall penetrance increases with advancing age. Motor, cognitive, and psychiatric signs are consistent with subcortical and white matter pathology seen on brain MRI. Several studies provide evidence of possible biological determinants of clinical features among PM carriers, including FMR/-related measures (e.g. longer CGG repeat length, elevated FMR1 mRNA, depleted FMRP) and neural markers (e.g. structural and functional alterations in frontal, subcortical and cerebellar brain regions). Some of these markers have been observed in PM carriers prior to the onset of symptoms, suggesting potential utility as early markers of increased risk. Currently there are no disease-modifying therapies available for FXTAS but individualised treatment plans (incorporating multidisciplinary teams where appropriate) should be implemented to manage symptoms of concern. Further research is required to develop a greater understanding of the pathological mechanisms underlying the development of FXTAS, and to facilitate the identification of specific risk or protective factors related to symptom onset. This will inform the development of targeted treatments to slow the progression of FXTAS, or even to prevent onset in those at risk.
ADLs activities of daily living
FMR 1 Fragile X Mental Retardation 1
FMRP Fragile X Mental Retardation Protein
FXPOI fragile X-associated primary ovarian insufficiency
FXS fragile X syndrome
FXTAS fragile X-associated tremor ataxia syndrome MCP middle cerebellar peduncles
RNA ribonucleic acid
Birch, R. C., Cornish, К. M., Hocking, D. R. & Trollor, J. N. (2014) Understanding the neuropsychiatric phenotype of fragile X-associated tremor ataxia syndrome: A systematic review. Neuropsychology Review, 24, 401-513.
Hagerman, R. & Hagerman, P. (2013) Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome. Lancet Neurology, 12, 786-798.
Hall, D. A., Robertson, E., Shelton, A. L., Losh, M. C., Mila, M., Moreno, E. G., . . . O’Keefe, J. (2016) Update on the clinical, radiographic, and neurobehavioral manifestations in FXTAS and FMR1 premutation carriers. The Cerebellum, 15, 578-586.
Robertson, E. E., Hall, D. A., McAsey, A. R. & O’Keefe, J. (2016) Fragile X-associated tremor/ataxia syndrome: Phenotypic comparisons with other movement disorders. The Clinical Neuropsychologist, 30, 849-900.
Wang, J. Y., Hessl, D., Hagerman, R. J., Simon, T. J., Tasone, F., Ferrer, E. & Rivera, S. M. (2017) Abnormal trajectories in cerebellum and brainstem volumes in carriers of the fragile X premutation. Neurobiology of Aging, 55, 11-19.