The Spectrum of Neurological and White Matter Changes and Premutation Status Categories of Older Male Carriers of the Alleles Are Linked to Genetic (CGG and FMR1 MRNA) and Cellular Stress (AMPK) Markers

Overview

Journal Front Genet

Date 2018 Nov 29

PMID 30483310

Citations 7

Authors

Danuta Z Loesch

Nicholas Trost

Minh Q Bui

Eleanor Hammersley

Sui T Lay

Sarah J Annesley

Oana Sanislav

Claire Y Allan

Flora Tassone

Zhi-Ping Chen

Kevin R W Ngoei

Bruce E Kemp

David Francis

Paul R Fisher

Elsdon Storey

Affiliations

Soon will be listed here.

Abstract

The fragile X premutation (PM) allele contains a CGG expansion of 55-200 repeats in the gene's promoter. Male PM carriers have an elevated risk of developing neurological and psychiatric changes, including an approximately 50% risk of the fragile X-associated tremor/ataxia syndrome (FXTAS). The aim of this study was to assess the relationships of regional white matter hyperintensities () semi-quantitative scores, clinical status, motor (UPDRS, ICARS, Tremor) scales, and cognitive impairments, with -specific genetic changes, in a sample of 32 unselected male PM carriers aged 39-81 years. Half of these individuals were affected with FXTAS, while the non-FXTAS group comprised subcategories of non-affected individuals and individuals affected with non-syndromic changes. The dynamics of pathological processes at the cellular level relevant to the clinical status of PM carriers was investigated using the enzyme AMP-activated protein kinase (AMPK), which is a highly sensitive cellular stress-sensing alarm protein. This enzyme, as well as genetic markers - CGG repeat number and the levels of the mRNA - were assessed in blood lymphoblasts. The results showed that the repeat distribution for FXTAS individuals peaked at 85-90 CGGs; non-FXTAS carriers were distributed within the lowest end of the PM repeat range, and non-syndromic carriers assumed an intermediate position. The size of the CGG expansion was significantly correlated, across all three categories, with infratentorial and total and with all motor scores, and the mRNA levels with all the scores, whilst AMPK activity showed considerable elevation in the non-FXTAS combined group, decreasing in the FXTAS group, proportionally to increasing severity of the and tremor/ataxia. We conclude that the size of the CGG expansion relates to the risk for FXTAS, to severity of infratentorial lesions, and to all three motor scale scores. mRNA shows a strong association with the extent of , which is the most sensitive marker of the pathological process. However, the AMPK activity findings - suggestive of a role of this enzyme in the risk of FXTAS - need to be verified and expanded in future studies using larger samples and longitudinal assessment.

Citing Articles

Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on Premutation.

Tassone F, Protic D, Allen E, Archibald A, Baud A, Brown T Cells. 2023; 12(18).

PMID: 37759552 PMC: 10529056. DOI: 10.3390/cells12182330.

Relationships of Motor Changes with Cognitive and Neuropsychiatric Features in FMR1 Male Carriers Affected with Fragile X-Associated Tremor/Ataxia Syndrome.

Hocking D, Loesch D, Stimpson P, Tassone F, Atkinson A, Storey E Brain Sci. 2022; 12(11).

PMID: 36421873 PMC: 9688438. DOI: 10.3390/brainsci12111549.

Cellular Bioenergetics and AMPK and TORC1 Signalling in Blood Lymphoblasts Are Biomarkers of Clinical Status in FMR1 Premutation Carriers.

Loesch D, Kemp B, Bui M, Fisher P, Allan C, Sanislav O Front Psychiatry. 2021; 12:747268.

PMID: 34880790 PMC: 8645580. DOI: 10.3389/fpsyt.2021.747268.

Relationships between Mitochondrial Function, AMPK, and TORC1 Signaling in Lymphoblasts with Premutation Alleles of the FMR1 Gene.

Fisher P, Allan C, Sanislav O, Atkinson A, Ngoei K, Kemp B Int J Mol Sci. 2021; 22(19).

PMID: 34638732 PMC: 8508849. DOI: 10.3390/ijms221910393.

Lymphoblastoid Cell Lines as Models to Study Mitochondrial Function in Neurological Disorders.

Annesley S, Fisher P Int J Mol Sci. 2021; 22(9).

PMID: 33926115 PMC: 8123577. DOI: 10.3390/ijms22094536.

References

Bokko P, Francione L, Bandala-Sanchez E, Ahmed A, Annesley S, Huang X . Diverse cytopathologies in mitochondrial disease are caused by AMP-activated protein kinase signaling. Mol Biol Cell. 2007; 18(5):1874-86. PMC: 1855013. DOI: 10.1091/mbc.e06-09-0881. View

Boivin M, Willemsen R, Hukema R, Sellier C . Potential pathogenic mechanisms underlying Fragile X Tremor Ataxia Syndrome: RAN translation and/or RNA gain-of-function?. Eur J Med Genet. 2017; 61(11):674-679. DOI: 10.1016/j.ejmg.2017.11.001. View

Loesch D, Annesley S, Trost N, Bui M, Lay S, Storey E . Novel Blood Biomarkers Are Associated with White Matter Lesions in Fragile X- Associated Tremor/Ataxia Syndrome. Neurodegener Dis. 2016; 17(1):22-30. PMC: 10964908. DOI: 10.1159/000446803. View

Loesch D, Kotschet K, Trost N, Greco C, Kinsella G, Slater H . White matter changes in basis pontis in small expansion FMR1 allele carriers with parkinsonism. Am J Med Genet B Neuropsychiatr Genet. 2011; 156B(4):502-6. PMC: 4148303. DOI: 10.1002/ajmg.b.31189. View

Apartis E, Blancher A, Meissner W, Guyant-Marechal L, Maltete D, de Broucker T . FXTAS: new insights and the need for revised diagnostic criteria. Neurology. 2012; 79(18):1898-907. DOI: 10.1212/WNL.0b013e318271f7ff. View

Loesch D, Litewka L, Brotchie P, Huggins R, Tassone F, Cook M . Magnetic resonance imaging study in older fragile X premutation male carriers. Ann Neurol. 2005; 58(2):326-30. DOI: 10.1002/ana.20542. View

van Straaten E, Harvey D, Scheltens P, Barkhof F, Petersen R, Thal L . Periventricular white matter hyperintensities increase the likelihood of progression from amnestic mild cognitive impairment to dementia. J Neurol. 2008; 255(9):1302-8. PMC: 2879405. DOI: 10.1007/s00415-008-0874-y. View

Loesch D, Churchyard A, Brotchie P, Marot M, Tassone F . Evidence for, and a spectrum of, neurological involvement in carriers of the fragile X pre-mutation: FXTAS and beyond. Clin Genet. 2005; 67(5):412-7. DOI: 10.1111/j.1399-0004.2005.00425.x. View

Loesch D, Bui Q, Huggins R, Mitchell R, Hagerman R, Tassone F . Transcript levels of the intermediate size or grey zone fragile X mental retardation 1 alleles are raised, and correlate with the number of CGG repeats. J Med Genet. 2006; 44(3):200-4. PMC: 2598026. DOI: 10.1136/jmg.2006.043950. View

10.

Tassone F, Hagerman R, Taylor A, Gane L, Godfrey T, Hagerman P . Elevated levels of FMR1 mRNA in carrier males: a new mechanism of involvement in the fragile-X syndrome. Am J Hum Genet. 2000; 66(1):6-15. PMC: 1288349. DOI: 10.1086/302720. View

11.

He H, Liu X, Lv L, Liang H, Leng B, Zhao D . Calcineurin suppresses AMPK-dependent cytoprotective autophagy in cardiomyocytes under oxidative stress. Cell Death Dis. 2014; 5:e997. PMC: 4040710. DOI: 10.1038/cddis.2013.533. View

12.

Storey E, Tuck K, Hester R, Hughes A, Churchyard A . Inter-rater reliability of the International Cooperative Ataxia Rating Scale (ICARS). Mov Disord. 2004; 19(2):190-2. DOI: 10.1002/mds.10657. View

13.

Richards M, Marder K, Cote L, Mayeux R . Interrater reliability of the Unified Parkinson's Disease Rating Scale motor examination. Mov Disord. 1994; 9(1):89-91. DOI: 10.1002/mds.870090114. View

14.

Peixoto C, Oliveira W, Araujo S, Nunes A . AMPK activation: Role in the signaling pathways of neuroinflammation and neurodegeneration. Exp Neurol. 2017; 298(Pt A):31-41. DOI: 10.1016/j.expneurol.2017.08.013. View

15.

Wang J, Hessl D, Hagerman R, Tassone F, Rivera S . Age-dependent structural connectivity effects in fragile x premutation. Arch Neurol. 2012; 69(4):482-9. PMC: 3979438. DOI: 10.1001/archneurol.2011.2023. View

16.

Wahlund L, Barkhof F, Fazekas F, Bronge L, Augustin M, Sjogren M . A new rating scale for age-related white matter changes applicable to MRI and CT. Stroke. 2001; 32(6):1318-22. DOI: 10.1161/01.str.32.6.1318. View

17.

Ross-Inta C, Omanska-Klusek A, Wong S, Barrow C, Garcia-Arocena D, Iwahashi C . Evidence of mitochondrial dysfunction in fragile X-associated tremor/ataxia syndrome. Biochem J. 2010; 429(3):545-52. PMC: 4011071. DOI: 10.1042/BJ20091960. View

18.

Debrey S, Leehey M, Klepitskaya O, Filley C, Shah R, Kluger B . Clinical Phenotype of Adult Fragile X Gray Zone Allele Carriers: a Case Series. Cerebellum. 2016; 15(5):623-31. DOI: 10.1007/s12311-016-0809-6. View

19.

Tassone F, Hagerman R, Garcia-Arocena D, Khandjian E, Greco C, Hagerman P . Intranuclear inclusions in neural cells with premutation alleles in fragile X associated tremor/ataxia syndrome. J Med Genet. 2004; 41(4):e43. PMC: 1735735. DOI: 10.1136/jmg.2003.012518. View

20.

Hagerman R, Hagerman P . Fragile X-associated tremor/ataxia syndrome - features, mechanisms and management. Nat Rev Neurol. 2016; 12(7):403-12. DOI: 10.1038/nrneurol.2016.82. View