Fragile X syndrome: a pilot proton magnetic resonance spectroscopy study in premutation carriers

Journal of Neurodevelopmental Disorders

Declan D G Murphy³  Kieran C Murphy¹  Caroline J Moore³  Andrew Simmons²  Eileen M Daly³  Brian P Hallahan³ 

[1] Department of Psychiatry, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland;NIHR Biomedical Research Centre for Mental Health, London, UK;Section of Brain Maturation, Department of Forensic and Neurodevelopmental Science, Institute of Psychiatry, King’s College London, London, UK

关键词: NAA;    MRS;    Premutation carriers;    Fragile X;   

Others  :  811676
DOI  :  10.1186/1866-1955-4-23

 received in 2012-03-22, accepted in 2012-08-13,  发布年份 2012

【 摘 要 】

Purpose

There is increasing evidence that neurodevelopmental differences in people with Fragile X syndrome (FraX) may be explained by differences in glutamatergic metabolism. Premutation carriers of FraX were originally considered to be unaffected although several recent reports demonstrate neuroanatomical, cognitive, and emotional differences from controls. However there are few studies on brain metabolism in premutation carriers of FraX.

Methods

We used proton magnetic resonance spectroscopy to compare neuronal integrity of a number of brain metabolites including N-Acetyl Aspartate, Creatine + Phosphocreatinine, Choline, myoInositol, and Glutamate containing substances (Glx) in 17 male premutation carriers of FraX and 16 male healthy control individuals.

Results

There was no significant between-group difference in the concentration of any measured brain metabolites. However there was a differential increase in N-acetyl aspartate with aging in premutation FraX individuals compared to controls.

Conclusions

This is the first ¹ H-MRS study to examine premutation FraX individuals. Although we demonstrated no difference in the concentration of any of the metabolites examined between the groups, this may be due to the large age ranges included in the two samples. The differential increase in NAA levels with aging may reflect an abnormal synaptic pruning process.

【 授权许可】

   
2012 Hallahan et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Verkerk AJMH, Pieretti M, Sutcliffe JS, Fu Y-H, Kuhl DPA, Pizzuti A, Reiner O, Richards S, Victoria MF, Zhang F, Eussen BE, van Ommen GJB, Blonden LAJ, Riggins GJ, Chastain JL, Kunst CB, Galjaard H, Caskey CT, Nelson DL, Oostra BA, Warren ST: Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in Fragile-X syndrome. Cell 1991, 65:905-914.
• [2]Yu S, Pritchard M, Kremer E, Lynch M, Nancarrow J, Baker E, Holman K, Mulley JC, Warren ST, Schlessinger D: Fragile X genotype characterized by an unstable region of DNA. Science 1991, 252:1179-1181.
• [3]Tassone F, Haegerman RJ, Taylor AK, Mills JB, Harris SW, Gane LW, Hagerman PJ: Clinical involvement and protein expression in individuals with the FMR1 premutation. Am J Med Genet 2000, 91:144-152.
• [4]Hagerman RJ, Leehey M, Heinrichs W, Tassone F, Wildon R, Hills J, Grigsby J, Gage B, Hagerman PJ: Intention tremor, parkinsonism, and generalised brain atrophy in male carriers of fragile X. Neurology 2001, 57:127-130.
• [5]Tassone F, Haegerman RJ, Taylor AK, Gane LW, Godfrey TE, Haegerman PJ: Elevated levels of FMR1 mRNA in carrier males; a new mechanism of involvement in the fragile-X syndrome. Am J Hum Genet 2000, 66:6-15.
• [6]Bennetto L, Pennington BF: Neuropsychology. In Fragile X syndrome: Diagnosis, treatment and research. 3rd edition. Edited by Hagerman RJ, Hagerman PJ. The Johns Hopkins University Press, Baltimore; 2002.
• [7]Turk J: The fragile X syndrome: on the way to a behavioural phenotype. Br J Psychiatry 1992, 160:24-35.
• [8]Gothelf D, Furfaro JA, Penniman LC, Glover GH, Reiss AL: The contribution of novel brain imaging techniques to understanding the neurobiology of mental retardation and developmental disabilities. MRDD Research Reviews 2005, 11:331-339.
• [9]Hessl D, Nguyen DV, Green C, Chavez A, Tassone F, Hagerman RJ, Senturk D, Schneider A, Lightbody A, Reiss AL, Hall S: A solution to limitations of cognitive testing in children with intellectual disabilities: the case of fragile X syndrome. J Neurodevelop Disord 2008, 1:33-45.
• [10]Schapiro MB, Murphy DG, Hagerman RJ, Azari NP, Alexander GE, Miezejeski CM, Hinton VJ, Horwitz B, Haxby JV, Kumar A, White B, Grady CL: Adult fragile X syndrome: neuropsychology, brain anatomy, and metabolism. Am J Med Genet 1995, 60:480-493.
• [11]Levitas A: Neuropsychiatric aspects of fragile X syndrome. Semin Clin Neuropsychiatry 1996, 1:154-167.
• [12]Riddle JE, Cheema A, Sobesky WE, Gardner SC, Taylor AK, Pennington BF, Hagerman RJ: Phenotypic involvement in females with the FMR1 gene mutation. Am J Ment Retard 1998, 102:590-601.
• [13]Roberts JE, Bailey DB, Mankowski J, Ford A, Sideris J, Weisenfeld LA, Heath TM, Golden RN: Mood and anxiety disorders in females with the FMR1 premutation. Am J Med Genet 2009, 150B:130-139.
• [14]Moore CJ, Daly E, Schmitz N, Tassone F, Tysoe C, Hagerman RJ, Hagerman PJ, Morris RG, Murphy KC, Murphy DG: A neuropsychological investigation of male premutation carriers of fragile X syndrome. Neuropsychologia 2004, 42:1934-1947.
• [15]Moore CJ, Daly EM, Tassone F, Tysoe C, Schmitz N, Ng V, Chitnis X, McGuire P, Suckling J, Davies KE, Hagerman RJ, Hagerman PJ, Murphy KC, Murphy DGM: The effect of pre-mutation of X chromosome CGG trinucleotide repeats on brain anatomy. Brain 2004, 127:2672-2681.
• [16]Jacquemont S, Hagerman RJ, Leehey M, Grigsby J, Zhang L, Brunberg JA, Greco C, Des Portes V, Jardini T, Levine R, Berry-Kravis E, Brown WT, Schaeffer S, Kissel J, Tassone F, Hagerman PJ: Fragile X premutation tremor/ataxia syndrome: molecular, clinical and neuroimaging correlates. Am J Hum Genet 2003, 72:869-878.
• [17]Cornish KM, Kogan CS, Li L, Turk J, Jacquemont S, Hagerman RJ: Lifespan changes in working memory in fragile X premutation males. Brain Cogn 2009, 69:551-558.
• [18]Hull C, Hagerman RJ: A study of the physical, behavioral, and medical phenotype, including anthropometric measures of females with fragile X syndrome. Am J Dis Child 1993, 147:1236-1241.
• [19]Hundscheid RD, Braat DD, Kiemeney LA, Smits A, Thomas CM: Increased serum FSH in female fragile X premutation carriers with either regular menstrual cycles or on oral contraceptives. Hum Reprod 2001, 16:457-462.
• [20]Allingham-Hawkins DJ, Babul-Hirji R, Chitayat D, Holden JJ, Yang KT, Lee C, Hudson R, Gorwill H, Nolin SL, Glicksman A, Jenkins EC, Brown WT, Howard-Peebles PN, Becchi C, Cummings E, Fallon L, Seitz S, Black SH, Vianna-Morgante AM, Costa SS, Otto PA, Mingroni-Netto RC, Murray A, Webb J, Vieri F, Krekewich K, Humphries T, 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.
• [21]Conway GS, Hettitarachein S, Murray A, Jacobs PA: Fragile X premutations in familial premature ovarian failure. Lancet 1995, 346:309-310.
• [22]Adams PE, Adams JS, Nguyen DV, Hessl D, Brunberg JA, Tassone F, Zhang W, Koldewyn K, Rivera SM, Grigsby J, Zhang L, Decarli C, Hagerman PJ, Hagerman RJ: Psychological symptoms correlate with reduced hippocampal volume in fragile X premutation carriers. Am J Med Genet B Neuropsychiatr Genet 2010, 153B:775-785.
• [23]Cordeiro L, Ballinger E, Hagerman R, Hessl D: Clinical assessment of DSM-IV anxiety disorders in fragile X syndrome: prevalence and characterization. J Neurodevelop Disord 2011, 3:1-11.
• [24]Coffey SM, Cook K, Tartaglia N, Tassone F, Nguyen DV, Pan R, Bronsky HE, Yuhas J, Borodyanskaya M, Grigsby J, Doerflinger M, Hagerman PJ, Hagerman RJ: Expanded clinical phenotype of women with the FMR1 premutation. Am J Med Genet 2008, 146A:1009-1016.
• [25]Danielson ER, Ross B: Magnetic Resonance Spectroscopy Diagnosis of Neurological Diseases. Marcel Dekker, Inc., New York, NY; 1999.
• [26]Koller KJ, Zacsek R, Coyle JT: N-acetyl-aspartyl-glutamate: regional levels in rat brain and the effects of brain lesions as determined by a new HPLC method. J Neurochem 1984, 43:1136-1142.
• [27]Bhakoo K, Craig T, Styles P: Cellular and developmental tissue distribution of NAA catabolic enzyme, aspartoacylase. Insights into NAA Function. Proc Intl Soc Mag Reson Med 2001, 9:490.
• [28]Brandao L, Domingues RC: MR Spectroscopy of the Brain. Lippincott Williams & Wilkins, Philadelphia, PA; 2004.
• [29]Clark JB: N-acetyl aspartate: a marker for neuronal loss or mitochondrial dysfunction. Dev Neurosci 1998, 20:271-276.
• [30]Gill SS, Thomas GT, Van Bruggen N, Gadian DG, Peden CJ, Bell JD, Cox IJ, Menon DK, Iles RA, Bryant DJ: Proton NR spectroscopy of intracranial tumours: in vivo and in vitro studies. J Comput Assist Tomogr 1990, 14:497-504.
• [31]Bruhn H, Frahm J, Gyngell ML, Merboldt KD, Hanicke W, Sauter R: Cerebral metabolism in man after acute stroke: new observations using localized proton NMR spectroscopy. Magn Reson Med 1989, 9:126-131.
• [32]Davie CA, Hawkins CP, Barker GJ, Brennan A, Tofts PS, Miller DH, McDonald WI: Serial proton magnetic resonance spectroscopy in acute multiple sclerosis lesions. Brain 1994, 117:49-58.
• [33]Nishizuka Y: The molecular heterogeneity of protein kinase C and its implications for cellular regeneration. Nature 1998, 334:661-665.
• [34]Huang W, Alexander G, Chang L, Shetty H, Krasuski J, Rapoport S, Schapiro M: Brain metabolite concentration and dementia severity in Alzheimer’s disease: a (1)H MRS study. Neurology 2001, 57:626-632.
• [35]Martinez-Hernandez A, Bell KP, Norenberg MD: Glutamine synthetase: glial localization in brain. Science 1977, 195:1356-1358.
• [36]Bear MF, Dolen G, Osterweil E, Nagarajan N: Fragile X: translation in action. Neuropsychopharmacology 2008, 33:84-87.
• [37]Aschrafi A, Cunningham BA, Edelman GM, Vanderklish PW: The Fragile X mental retardation protein and group I metabotropic glutamate receptors regulate levels of mRNA granules in brain. Proc Natl Acad Sci USA 2005, 102:2180-2185.
• [38]Grossman AW, Aldridge GM, Weiler IJ, Greenough WT: Local protein synthesis and spine morphogenesis: Fragile X syndrome and beyond. J Neurosci 2006, 26:7151-7155.
• [39]Silverman JL, Tolu S, Barkan C, Crawley J: Repetitive self-grooming behavior in the BTBR mouse model of autism is blocked by the mGluR5 antagonist MPEP. Neuropsychopharmacology 2010, 35:976-989.
• [40]Jacquemont S, Curie A, Portes V, Torriolo MG, Berry-Kravis E, Hagerman RJ, Ramos FJ, Cornish K, He Y, Paulding C, Neri G, Chen F, Hadjikhani N, Martinet D, Meyer J, Beckerman JS, Delange K, Brun A, Bussy G, Gasparini F, Hilse T, Floesser A, Branson J, Bilbe G, Johns D, Gomez-Mancilla B: Epigenetic modification of the FMR1 gene in Fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci Transl Med 2011, 3:64ra1.
• [41]Ginestroni A, Guerrini L, Della Nave R, Tessa C, Cellini E, Dotti MT, Brunori P, De Stefano N, Piacentini S, Mascalchi M: Morphometry and 1 H-MR spectroscopy of the brain stem and cerebellum in three patients with fragile X-associated tremor/ataxia syndrome. Am J Neuroradiol 2007, 28:486-488.
• [42]Rizzo G, Pizza F, Scaglione C: A case of Fragile X premutation tremor/ataxia syndrome with evidence of mitochondrial dysfunction. Mov Disord 2006, 21:1541-1542.
• [43]Murphy DGM, Mentis MJ, Pietrini P, Grady G, Daly E, Haxby JV, De La Granja M, Allen G, Largay K, White BJ, Powell CM, Horwitz B, Rapoport SI, Schapiro MB: A PET study if Turner’s syndrome: effects of sex steroids and the X chromosome on brain. Biol Psychiatry 1997, 41:285-298.
• [44]Murphy DGM, Mentis MJ, Pietrini P, Grady CL, Moore CJ, Horowitz B, Hinton V, Dobkin CS, Schapiro MB, Rapoport SI: Premutation female carriers of fragile x syndrome: a pilot study on brain anatomy and metabolism. J Am Acad Child Adolesc Psychiatry 1999, 38:1294-1301.
• [45]American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. DSM-IV. 4th edition. American Psychiatric Association, Washington, DC; 1994.
• [46]Wechsler D: Wechsler Adult Intelligence Scale-Revised. Psychological Corporation, New York, NY; 1987.
• [47]Annet N: A classification of hand preferences by association analysis. Br J Psychol 1970, 61:303-321.
• [48]Beck AT: Beck Depression Inventory. The Psychological Corporation, San Antonio, TX; 1987.
• [49]Beck AT: Beck Anxiety Inventory. The Psychological Corporation, San Antonio, TX; 1987.
• [50]Hamilton M: The assessment of anxiety states by rating. Br J Med Psychol 1959, 32:50-55.
• [51]Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL, Heninger GR, Charney DS: The Yale-Brown Obsessive Compulsive Scale. I. Development, use and reliability. Arch Gen Psychiatry 1989, 46:1006-1011.
• [52]Brown WT, Houck GE, Jeziorowska A, Levinson FN, Ding X, Dobkin C, Zhong N, Henderson J, Brooks SS, Jenkins EC: Rapid fragile X carrier screening and prenatal diagnosis using a non-radioactive PCR test. JAMA 1993, 270:1569-1575.
• [53]Simmons A, Arridge SR, Barker GJ, Williams SCR: Simulation of MRI cluster plots and application to neurological segmentation. Magnetic Resonance Imaging 1996, 14:73-92.
• [54]Simmons A, Smail M, Moore E, Williams SCR: Serial Precision of metabolite peak area ratios and water referenced metabolite peak areas in Proton MR spectroscopy of the human brain. Magnetic Resonance Imaging 1998, 16:319-330.
• [55]Provencher SW: Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med 1993, 30:672-679.
• [56]Pallant J: SPSS survival manual. A step by step guide on data analysis using SPSS for Windows Version 11. Open University Press, Maidenhead: Buckingham; 2001.
• [57]Horska A, Kaufmann WE, Brant LJ, Naidu S, Jarris JC, Barker PB: In vivo qualitative proton MRS study of brain development from childhood to adolescence. J Magn Reson Imaging 2002, 15:137-143.
• [58]Kadota T, Horinouchi T, Kuroda C: Development and aging of the cerebrum: assessment with proton MR spectroscopy. Am J Neuroradiol 2001, 22:128-135.
• [59]Kreis R, Ernst T, Ross BD: Development of the human brain: in vivo quantification of metabolite and water content with proton magnetic resonance spectroscopy. Magn Reson Med 1993, 30:424-437.
• [60]Kostovic I, Judas M, Petanjek Z, Simic G: Ontogenesis of goal directed behaviour: anatomo-functional considerations. Int J Psychophysiol 1995, 19:85-102.
• [61]Huttenlocher PR: Synaptic density in human frontal cortex: developmental changes and effects of aging. Brain Res 1979, 163:195-205.
• [62]Huttenlocher PR, Dabholkar AS: Regional differences in synaptogenesis in human cerebral cortex. J Comp Neuro 1997, 387:167-178.
• [63]Irwin SA, Galvez R, Greenough WT: Dendritic spine structural anomalies in fragile-X mental retardation syndrome. Cereb Cortex 2000, 10:1038-1044.
• [64]Gao FB: Understanding fragile X: insights from retarded flies. Neuron 2002, 34:859-862.
• [65]Hinton VJ, Brown WT, Wisniewski K, Rudelli RD: Analysis of neocortex in three males with the fragile X syndrome. Am J Med Genet 1991, 41:289-294.
• [66]Irwin SA, Idupulapati M, Gilbert ME, Harris JB, Chakravarti AB, Rogers EJ, Crisostomo RA, Larsen BP, Mehta A, Alcantara CJ, Patel B, Swain RA, Weiler IJ, Oostra BA, Greenough WT: Dendritic spine and dendritic field characteristics of layer V pyramidal neurons in the visual cortex of fragile-X knockout mice. Am J Med Genet 2002, 111:140-146.
• [67]Palmfeldt J, Vang S, Stengroen V, Pedersen CB, Christensen JH, Bross P, Gregersen N, et al.: Mitochondrial proteomics on human fibroblasts for identification of metabolic imbalance and cellular stress. Proteome Sci 2009, 7:20. BioMed Central Full Text
• [68]Yan QJ, Rammal M, Tranfaglia M, Bauchwitz RP: Suppression of two major Fragile X syndrome mouse model phenotypes by the mGluR5 antagonist MPEP. Neuropharmacology 2005, 49:1053-1066.
• [69]McBride SM, Choi CH, Wang Y, Liebelt D, Braunstein E, Ferreiro D, Sehgal A, Siwicki KK, Dockendorff TC, Nguyen HT, McDonald TV, Jongens TA: Pharmacological rescue of synaptic plasticity, courtship behaviour, and mushroom body defects in a Drosophila model of fragile X syndrome. Neuron 2005, 45:753-764.