Update on the Clinical, Radiographic, and Neurobehavioral Manifestations in FXTAS and FMR1 Premutation Carriers

doi:10.1007/s12311-016-0799-4

Review

. 2016 Oct;15(5):578-86.

doi: 10.1007/s12311-016-0799-4.

Update on the Clinical, Radiographic, and Neurobehavioral Manifestations in FXTAS and FMR1 Premutation Carriers

Deborah A Hall¹, Erin Robertson², Annie L Shelton³, Molly C Losh⁴, Montserrat Mila⁵, Esther Granell Moreno^{6

7}, Beatriz Gomez-Anson^{6

7

8}, Verónica Martínez-Cerdeño⁹, Jim Grigsby¹⁰, Reymundo Lozano¹¹, Randi Hagerman¹², Lorena Santa Maria¹³, Elizabeth Berry-Kravis^{1

14}, Joan A O'Keefe^{15

16}

Affiliations

¹ Department of Neurological Sciences, Rush University, Chicago, IL, USA.
² Department of Anatomy and Cell Biology, Rush University, 507 Academic Facility, 600 South Paulina Street, Chicago, IL, 60612, USA.
³ School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne, Australia.
⁴ Roxelyn and Richard Pepper Department of Communication Sciences and Disorders, Northwestern University, Evanston, IL, USA.
⁵ Servei de Bioquímica i Genètica Molecular. Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain.
⁶ Neuroradiology Unit, Hospital Santa Creu i Sant Pau, Barcelona, Spain.
⁷ Neuroimaging Research Group, Hospital Sant Pau, IIB-Sant Pau, UAB, Barcelona, Spain.
⁸ Universitat Autonoma Barcelona, Barcelona, Spain.
⁹ Department of Pathology and Laboratory Medicine, University of California at Davis Medical Center, Sacramento, CA, USA.
¹⁰ Departments of Medicine and Psychology at the University of Colorado Denver, Aurora, CO, USA.
¹¹ Seaver Autism Center for Research and Treatment, Departments of Genetics and Genomic Sciences, Psychiatry, and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹² Department of Pediatrics & MIND Institute, University of California at Davis Medical Center, Sacramento, CA, USA.
¹³ Cytogenetics and Molecular Laboratory, Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago, Chile.
¹⁴ Departments of Pediatrics and Biochemistry, Rush University, Chicago, IL, USA.
¹⁵ Department of Neurological Sciences, Rush University, Chicago, IL, USA. joan_a_okeefe@rush.edu.
¹⁶ Department of Anatomy and Cell Biology, Rush University, 507 Academic Facility, 600 South Paulina Street, Chicago, IL, 60612, USA. joan_a_okeefe@rush.edu.

PMID: 27287737
PMCID: PMC7608648
DOI: 10.1007/s12311-016-0799-4

Review

Update on the Clinical, Radiographic, and Neurobehavioral Manifestations in FXTAS and FMR1 Premutation Carriers

Deborah A Hall et al. Cerebellum. 2016 Oct.

. 2016 Oct;15(5):578-86.

doi: 10.1007/s12311-016-0799-4.

Authors

Affiliations

¹ Department of Neurological Sciences, Rush University, Chicago, IL, USA.
² Department of Anatomy and Cell Biology, Rush University, 507 Academic Facility, 600 South Paulina Street, Chicago, IL, 60612, USA.
³ School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne, Australia.
⁴ Roxelyn and Richard Pepper Department of Communication Sciences and Disorders, Northwestern University, Evanston, IL, USA.
⁵ Servei de Bioquímica i Genètica Molecular. Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain.
⁶ Neuroradiology Unit, Hospital Santa Creu i Sant Pau, Barcelona, Spain.
⁷ Neuroimaging Research Group, Hospital Sant Pau, IIB-Sant Pau, UAB, Barcelona, Spain.
⁸ Universitat Autonoma Barcelona, Barcelona, Spain.
⁹ Department of Pathology and Laboratory Medicine, University of California at Davis Medical Center, Sacramento, CA, USA.
¹⁰ Departments of Medicine and Psychology at the University of Colorado Denver, Aurora, CO, USA.
¹¹ Seaver Autism Center for Research and Treatment, Departments of Genetics and Genomic Sciences, Psychiatry, and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹² Department of Pediatrics & MIND Institute, University of California at Davis Medical Center, Sacramento, CA, USA.
¹³ Cytogenetics and Molecular Laboratory, Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago, Chile.
¹⁴ Departments of Pediatrics and Biochemistry, Rush University, Chicago, IL, USA.
¹⁵ Department of Neurological Sciences, Rush University, Chicago, IL, USA. joan_a_okeefe@rush.edu.
¹⁶ Department of Anatomy and Cell Biology, Rush University, 507 Academic Facility, 600 South Paulina Street, Chicago, IL, 60612, USA. joan_a_okeefe@rush.edu.

PMID: 27287737
PMCID: PMC7608648
DOI: 10.1007/s12311-016-0799-4

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disorder caused by a repeat expansion in the fragile X mental retardation 1 (FMR1) gene. The disorder is characterized by kinetic tremor and cerebellar ataxia, shows age-dependent penetrance, and occurs more frequently in men. This paper summarizes the key emerging issues in FXTAS as presented at the Second International Conference on the FMR1 Premutation: Basic Mechanisms & Clinical Involvement in 2015. The topics discussed include phenotype-genotype relationships, neurobehavioral function, and updates on FXTAS genetics and imaging.

Keywords: Cognition; FMR1 genetics; FMR1 premutation; Fragile X-associated tremor/ataxia syndrome (FXTAS); Neuroimaging.

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Conflict of interest statement

Conflict of Interests Randi Hagerman has received funding from Novartis, Roche, Neuren, and Alcobra for treatment trials in fragile X syndrome (FXS). She has also consulted with Roche/Genentech, Alcobra and Novartis regarding treatment trials in FXS. Elizabeth Berry-Kravis has received funding from Neuren and Alcobra to carry out treatment studies in patients with FXS. She has also received funding from Vtesse to carry out a clinical trial in Niemann-Pick type C. She has also consulted with Neuren, Alcobra, and Neurotrope regarding treatment studies in patients with FXS. Deborah Hall has received research funds from NINDS, Shapiro Foundation, National Parkinson Disease Foundation, Pfizer, and Neurocrine. Dr. Lozano has consulted for Ambry genetics, Courtagen and ClearView Healthcare Partners. The authors declare that they have no conflict of interest.

Figures

**Fig. 1**
Illustration of the fragile X mental retardation 1 (*FMR1*) gene

**Fig. 2**
Summary of expanded fragile X-associated tremor/ataxia syndrome (FXTAS) and premutation phenotypes. *PSP* progressive supranuclear gaze palsy; *FMR1 fragile X mental retardation 1* gene; PC premutation carrier; *BAP* broad autism phenotype; AR activation ratio; *MCP* middle cerebellar peduncles. *Asterisk* indicates that this study was conducted in individuals with normal *FMR1* repeat size

See this image and copyright information in PMC

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References

1. Murray A, Webb J, MacSwiney F, Shipley E, Morton N, Conway G. Serum concentrations of follicle stimulating hormone may predict premature ovarian failure in FRAXA premutation women. Hum Reprod. 1999;14:1217–8. - PMC - PubMed
1. Sherman S. Premature ovarian failure in the fragile X syndrome. Am J Med Genet. 2000;97:189–94. - PubMed
1. Hagerman RJ, Leehey M, Heinrichs W, Tassone F, Wilson R, Hills J, et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology. 2001;57:127–30. - PubMed
1. Fraint A, Vittal P, Szewka A. New observations in the fragile X-associated tremor/ataxia syndrome (FXTAS) phenotype. Front Genet. 2014;5:365. - PMC - PubMed
1. Leehey M, Berry-Kravis E, Goetz C, Zhang L, Hall D, Li L, et al. FMR1 CGG repeat length predicts motor dysfunction in premutation carriers. Neurology. 2008;70:1397–402. - PMC - PubMed

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[1] Murray A, Webb J, MacSwiney F, Shipley E, Morton N, Conway G. Serum concentrations of follicle stimulating hormone may predict premature ovarian failure in FRAXA premutation women. Hum Reprod. 1999;14:1217–8. - PMC - PubMed

[2] Murray A, Webb J, MacSwiney F, Shipley E, Morton N, Conway G. Serum concentrations of follicle stimulating hormone may predict premature ovarian failure in FRAXA premutation women. Hum Reprod. 1999;14:1217–8. - PMC - PubMed

[3] Sherman S. Premature ovarian failure in the fragile X syndrome. Am J Med Genet. 2000;97:189–94. - PubMed

[4] Sherman S. Premature ovarian failure in the fragile X syndrome. Am J Med Genet. 2000;97:189–94. - PubMed

[5] Hagerman RJ, Leehey M, Heinrichs W, Tassone F, Wilson R, Hills J, et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology. 2001;57:127–30. - PubMed

[6] Hagerman RJ, Leehey M, Heinrichs W, Tassone F, Wilson R, Hills J, et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology. 2001;57:127–30. - PubMed

[7] Fraint A, Vittal P, Szewka A. New observations in the fragile X-associated tremor/ataxia syndrome (FXTAS) phenotype. Front Genet. 2014;5:365. - PMC - PubMed

[8] Fraint A, Vittal P, Szewka A. New observations in the fragile X-associated tremor/ataxia syndrome (FXTAS) phenotype. Front Genet. 2014;5:365. - PMC - PubMed

[9] Leehey M, Berry-Kravis E, Goetz C, Zhang L, Hall D, Li L, et al. FMR1 CGG repeat length predicts motor dysfunction in premutation carriers. Neurology. 2008;70:1397–402. - PMC - PubMed

[10] Leehey M, Berry-Kravis E, Goetz C, Zhang L, Hall D, Li L, et al. FMR1 CGG repeat length predicts motor dysfunction in premutation carriers. Neurology. 2008;70:1397–402. - PMC - PubMed

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Update on the Clinical, Radiographic, and Neurobehavioral Manifestations in FXTAS and FMR1 Premutation Carriers

Affiliations

Update on the Clinical, Radiographic, and Neurobehavioral Manifestations in FXTAS and FMR1 Premutation Carriers

Authors

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Abstract

Conflict of interest statement

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