Impact of FMR1 Premutation on Neurobehavior and Bioenergetics in Young Monozygotic Twins

Abstract

Mitochondrial dysfunction (MD) has been identified in lymphocytes, fibroblasts and brain samples from adults carrying a 55–200 CGG expansion in the fragile X mental retardation 1 (FMR1) gene (premutation; PM); however, limited data are available on the bioenergetics of pediatric carriers. Here we discuss a case report of three PM carriers: two monozygotic twins (aged 8 years) harboring an FMR1 allele with 150–180 CGG repeats, with no cognitive or intellectual issues but diagnosed with depression, mood instability and ADHD, and their mother (asymptomatic carrier with 78 CGG repeats). Fibroblasts and lymphocytes from the twins presented a generalized OXPHOS deficit, altered mitochondrial network, accumulation of depolarized mitochondria, and increased mitochondrial ROS production, outcomes distinct and more severe than the mother’s ones, suggesting the involvement of modulatory effects mediated by CGG expansion, X-activation ratio, sex hormones and epigenetic factors (chronic inflammation, consequence of Lyme disease). The degree of the severity of MD appeared to segregate with the morbidity of the phenotype. The mitochondrial ROS-mediated HIF-1α stabilization was identified as a key player at contributing to the MD, pointing it as a novel target for future therapeutical intervention.

Characterization of the Metabolic, Clinical and Neuropsychological Phenotype of Female Carriers of the Premutation in the X-Linked FMR1 Gene

“…Mitochondrial dysfunction has been reported not only in neurodegeneration (Friedland et al, 1983;Minoshima et al, 1997;Chiaravalloti et al, 2015) but also in pre-symptomatic, genetically-susceptible individuals (Small et al, 1995;Reiman et al, 1996;Mosconi et al, 2006;Ossenkoppele et al, 2013). In line with these studies and our previous reports on the PM (Napoli et al, 2016a(Napoli et al, , 2018, our study strongly indicates that global impairment of bioenergetics, and likely the subsequent energy depletion, is one of the earliest functional changes prior to the onset of overt clinical symptoms. This is supported by the relatively milder mitochondrial dysfunction in PM carriers without FXTAS and FXPOI which is enhanced with the diagnosis and progression of FXTAS.…”

“…Our team was the first to report mitochondrial dysfunction as a common feature in biological samples from PM carriers (Napoli et al, 2013(Napoli et al, , 2016a(Napoli et al, ,b, 2018Song et al, 2016) as well as in murine models of the PM (Napoli et al, 2016a). This decreased mitochondrial bioenergetics is present in PM carriers with and without FXTAS and even in some pediatric carriers (Napoli et al, 2018). However, to our knowledge, no study has to date characterized the metabolic footprint of the PM and related clinical and cognitive features in female carriers of the PM.…”

“…Generally, PM carriers show lower performance in neuropsychological testing including full-scale intellectual quotient (FSIQ) and working memory (WM) subtests on the Wechsler Adult Intelligence Scale (Lozano et al, 2016). In the case of children with the PM, they are often diagnosed with ADHD, autism, anxiety, and other psychopathologies (Napoli et al, 2018). The PM has also been associated with conditions beyond those involving the CNS, such as hypertension, hypothyroidism, high blood glucose, as well as a higher incidence of thyroid, prostate and other cancers (Lozano et al, 2016).…”

Human Cerebral Cortex Proteome of Fragile X-Associated Tremor/Ataxia Syndrome

“…Abundant Proteins and Fragile X-Associated Tremor/Ataxia Syndrome-Associated Dysfunction, mRNA, and Proteins Surprisingly, we did not identify differential abundance of mitochondrial proteins or those associated with mitochondrial dysfunction in FXTAS cortexes. Despite the evidence demonstrating altered mitochondrial dysfunction and decreased mitochondrial protein expression in PM subjects (Ross-Inta et al, 2010;Napoli et al, 2016Napoli et al, , 2018, dysfunction was not found in association with our DAPs in late-stage FXTAS. This may be the result of late-stage disease progression and the overall cellular abundance of proteins outweighing those specifically associated with mitochondria.…”

Molecular Biomarkers in Fragile X Syndrome

“…FMR1 -related measures, including CGG repeat number, percent of methylation, FMR1 mRNA and FMRP expression levels have been correlated to neurocognitive and social–affective functioning assessments and mental health problems in individuals with FXS [30,31,32,33,34,35,36,37,38]. The magnitude of the observed correlations generally suggests that these molecular biomarkers are likely accounting only for a proportion of the phenotypic variability of this disorder.…”