Subclinical myocardial dysfunction in Rett syndrome

Felice, Claudio De; Maffei, Silvia; Signorini, Cinzia; Leoncini, Silvia; Lunghetti, Stefano; Valacchi, Giuseppe; D’Esposito, Maurizio; Filosa, Stefania; Ragione, Floriana Della; Butera, Gianfranco; Favilli, Roberto; Ciccoli, Lucia; Hayek, Joussef

doi:10.1093/ejechocard/jer256

Cited by 43 publications

(46 citation statements)

References 34 publications

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“…Mitochondrial dysfunction and its derived oxidative stress may contribute to RTT pathogenesis. Indeed, some RTT clinical signs such as hypotonia [49] and myocardial dysfunctions [50] correlate with mitochondrial dysfunctions and oxidative stress. In muscle and frontal lobe biopsies of RTT patients [48,51,52] and in cortex and hippocampus of MeCP2−/y mice [53], morphological alterations of mitochondria have been found.…”

Section: Discussionmentioning

confidence: 99%

Impaired enzymatic defensive activity, mitochondrial dysfunction and proteasome activation are involved in RTT cell oxidative damage

Cervellati

Sticozzi

Romani

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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A strong correlation between oxidative stress (OS) and Rett syndrome (RTT), a rare neurodevelopmental disorder affecting females in the 95% of the cases, has been well documented although the source of OS and the effect of a redox imbalance in this pathology has not been yet investigated. Using freshly isolated skin fibroblasts from RTT patients and healthy subjects, we have demonstrated in RTT cells high levels of H2O2 and HNE protein adducts. These findings correlated with the constitutive activation of NADPH-oxidase (NOX) and that was prevented by a NOX inhibitor and iron chelator pre-treatment, showing its direct involvement. In parallel, we demonstrated an increase in mitochondrial oxidant production, altered mitochondrial biogenesis and impaired proteasome activity in RTT samples. Further, we found that the key cellular defensive enzymes: glutathione peroxidase, superoxide dismutase and thioredoxin reductases activities were also significantly lower in RTT. Taken all together, our findings suggest that the systemic OS levels in RTT can be a consequence of both: increased endogenous oxidants as well as altered mitochondrial biogenesis with a decreased activity of defensive enzymes that leads to posttranslational oxidant protein modification and a proteasome activity impairment.

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Section: Discussionmentioning

confidence: 99%

Impaired enzymatic defensive activity, mitochondrial dysfunction and proteasome activation are involved in RTT cell oxidative damage

Cervellati

Sticozzi

Romani

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Onset of symptoms and regression typically occur at 6 to 18 months of age after a period of apparently normal development [109]. Individuals with MECP2 -related disorder demonstrate autistic symptoms [110,111] as well as distinct features that include respiratory rhythm abnormalities, gait impairment, and cardiac complications [112,113]. …”

Section: Single Gene Disordersmentioning

confidence: 99%

Autism spectrum disorder and epilepsy: Disorders with a shared biology

Lee

Smith

Paciorkowski

2015

Epilepsy & Behavior

139

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There is an increasing recognition of clinical overlap in patients presenting with epilepsy and autism spectrum disorder (ASD), and a great deal of new information is available regarding the genetic causes of both disorders. Several biological pathways appear to be involved in both disease processes, including gene transcription regulation, cellular growth, synaptic channel function, and maintenance of synaptic structure. We review several genetic disorders where ASD and epilepsy frequently co-occur, and we discuss the screening tools available to practicing neurologists and epileptologists to help determine which patients should be referred for formal ASD diagnostic evaluation. Finally, we make recommendations regarding the workflow of genetic diagnostic testing available for children with both ASD and epilepsy.

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“…Several previous studies reported cardiac abnormalities in both RTT patients and animal models1718. In our laboratory, Mecp2 -null mice exhibited reduced spontaneous movement between 3 and 8 weeks of age.…”

Section: Resultsmentioning

confidence: 64%

“…In RTT patients, recurrent apnea and breath-holding leads to significant hypoxic and oxidative stress, both of which are detrimental to many neuronal and cardiovascular functions4447. In fact, recent studies demonstrated that the levels of oxidative stress markers are increased, and correlated to LV systolic dysfunction, in RTT patients18. Those findings suggested that increased oxidative stress via respiratory depression may lead to aberrant ion channel and Cx43 expression, and predisposes the animal to arrhythmia and sudden death.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have suggested that cardiac dysfunction in RTT may be secondary to abnormal nervous system control14151617. However, accumulating evidence indicates that the cardiac dysfunction observed in RTT may also result from MeCP2 deficiency in the cardiovascular system itself18. Recent studies have elucidated the role of MeCP2 in cardiovascular development and cardiomyocyte maturation.…”

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confidence: 99%

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Disturbance of cardiac gene expression and cardiomyocyte structure predisposes Mecp2-null mice to arrhythmias

Hara

Takahashi

Mitsumasu

et al. 2015

Sci Rep

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Methyl-CpG-binding protein 2 (MeCP2) is an epigenetic regulator of gene expression that is essential for normal brain development. Mutations in MeCP2 lead to disrupted neuronal function and can cause Rett syndrome (RTT), a neurodevelopmental disorder. Previous studies reported cardiac dysfunction, including arrhythmias in both RTT patients and animal models of RTT. In addition, recent studies indicate that MeCP2 may be involved in cardiac development and dysfunction, but its role in the developing and adult heart remains unknown. In this study, we found that Mecp2-null ESCs could differentiate into cardiomyocytes, but the development and further differentiation of cardiovascular progenitors were significantly affected in MeCP2 deficiency. In addition, we revealed that loss of MeCP2 led to dysregulation of endogenous cardiac genes and myocardial structural alterations, although Mecp2-null mice did not exhibit obvious cardiac functional abnormalities. Furthermore, we detected methylation of the CpG islands in the Tbx5 locus, and showed that MeCP2 could target these sequences. Taken together, these results suggest that MeCP2 is an important regulator of the gene-expression program responsible for maintaining normal cardiac development and cardiomyocyte structure.

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Subclinical myocardial dysfunction in Rett syndrome

Abstract: These data indicate a previously unrecognized subclinical systo-diastolic biventricular myocardial dysfunction in typical and atypical RTT patients. A reduced preload is evidenced. The biventricular dysfunction is partially related to OS damage.

Cited by 43 publications

References 34 publications

Impaired enzymatic defensive activity, mitochondrial dysfunction and proteasome activation are involved in RTT cell oxidative damage

Impaired enzymatic defensive activity, mitochondrial dysfunction and proteasome activation are involved in RTT cell oxidative damage

Autism spectrum disorder and epilepsy: Disorders with a shared biology

Disturbance of cardiac gene expression and cardiomyocyte structure predisposes Mecp2-null mice to arrhythmias

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