Novel Blood Biomarkers Are Associated with White Matter Lesions in Fragile X- Associated Tremor/Ataxia Syndrome.
The need for accessible cellular biomarkers of neurodegeneration in carriers of the fragile X mental retardation 1 (FMR1) premutation (PM) alleles.



To assess the mitochondrial status and respiration in blood lymphoblasts from PM carriers manifesting the fragile X-associated tremor/ataxia syndrome (FXTAS) and non-FXTAS carriers, and their relationship with the brain white matter lesions.



Oxygen consumption rates (OCR) and ATP synthesis using a Seahorse XFe24 Extracellular Flux Analyser, and steady-state parameters of mitochondrial function were assessed in cultured lymphoblasts from 16 PM males (including 11 FXTAS patients) and 9 matched controls. The regional white matter hyperintensity (WMH) scores were obtained from MRI.



Mitochondrial respiratory activity was significantly elevated in lymphoblasts from PM carriers compared with controls, with a 2- to 3-fold increase in basal and maximum OCR attributable to complex I activity, and ATP synthesis, accompanied by unaltered mitochondrial mass and membrane potential. The changes, which were more advanced in FXTAS patients, were significantly associated with the WMH scores in the supratentorial regions.



The dramatic increase in mitochondrial activity in lymphoblasts from PM carriers may represent either the early stages of disease (specific alterations in short-lived blood cells) or an activation of the lymphocytes under pathological situations. These changes may provide early, convenient blood biomarkers of clinical involvements.
Department of Psychology and Counselling, School of Psychology and Public Health, La Trobe University, Melbourne, Vic., Australia.
Danuta Z
DZ
Loesch
Sarah J
SJ
Annesley
Nicholas
N
Trost
Minh Q
MQ
Bui
Sui T
ST
Lay
Elsdon
E
Storey
Shawn W
SW
De Piazza
Oana
O
Sanislav
Lisa M
LM
Francione
Eleanor M
EM
Hammersley
Flora
F
Tassone
David
D
Francis
Paul R
PR
Fisher
D000293:Adolescent; D000368:Aged; D000369:Aged, 80 and over; D001259:Ataxia / Q000097:blood* / Q000000981:diagnostic imaging* / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D001921:Brain / Q000000981:diagnostic imaging*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000097:blood* / Q000000981:diagnostic imaging* / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D010101:Oxygen Consumption; D012044:Regression Analysis; D014202:Tremor / Q000097:blood* / Q000000981:diagnostic imaging* / Q000235:genetics; D066127:White Matter / Q000000981:diagnostic imaging*
D015415:Biomarkers; D051860:Fragile X Messenger Ribonucleoprotein 1; C497683:FMR1 protein, human