Rett Syndrome and Mitochondrial Enzyme Deficiencies

Coker, Steven B.; Melnyk, Andrew R.

doi:10.1177/088307389100600216

Cited by 61 publications

(39 citation statements)

References 8 publications

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“…It was recently noted, however, that a patient with symptoms normally associated with mitochondrial disorders (hypotonia, small stature, developmental delay, and a slight decrease in respiratory chain enzyme activity) harbored mutations in the MECP2 gene (11). This overlap between symptoms of RTT and mitochondrial disorders recalls early reports of structural abnormalities (4,8,9,34) and defects in the electron transport chain (7,8) in mitochondria from skin and muscle biopsies of RTT patients. Moreover, about half of RTT patients were reported to have elevated levels of circulatory lactic or pyruvic acid, which might be caused by defects in the efficiency of the respiratory chain and urea cycle complexes, both of which are mitochondrial (21,25).…”

Section: Discussionmentioning

confidence: 86%

Gene Expression Analysis Exposes Mitochondrial Abnormalities in a Mouse Model of Rett Syndrome

Kriaucionis

Paterson

Curtis

et al. 2006

Molecular and Cellular Biology

193

144

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Rett syndrome (RTT) is a severe neurological disorder caused by mutations in the X-linked MECP2 gene, which encodes a methyl-CpG binding transcriptional repressor. Using the Mecp2-null mouse (an animal model for RTT) and differential display, we found that mice with neurological symptoms overexpress the nuclear gene for ubiquinol-cytochrome c reductase core protein 1 (Uqcrc1). Chromatin immunoprecipitation demonstrated that MeCP2 interacts with the Uqcrc1 promoter. Uqcrc1 encodes a subunit of mitochondrial respiratory complex III, and isolated mitochondria from the Mecp2-null brain showed elevated respiration rates associated with respiratory complex III and an overall reduction in coupling. A causal link between Uqcrc1 gene overexpression and enhanced complex III activity was established in neuroblastoma cells. Our findings raise the possibility that mitochondrial dysfunction contributes to pathology of the Mecp2-null mouse and may contribute to the long-known resemblance between Rett syndrome and certain mitochondrial disorders.

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Section: Discussionmentioning

confidence: 86%

Gene Expression Analysis Exposes Mitochondrial Abnormalities in a Mouse Model of Rett Syndrome

Kriaucionis

Paterson

Curtis

et al. 2006

Molecular and Cellular Biology

193

144

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“…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. Furthermore a reduced NADH cytochrome c reductase, succinate cytochrome c reductase, and cytochrome c oxidase activity has been shown in muscle and frontal cortex biopsies of RTT patients [54,55] as well as an alteration of mitochondrial respiration efficiency [56]. Indeed, biochemical analyses on muscle biopsy material confirmed reduced activities of NADH cytochrome c reductase, succinate cytochrome c reductase and cytochrome c oxidase, even in mitochondria of physiological appearance [54].…”

Section: Discussionmentioning

confidence: 93%

“…Furthermore a reduced NADH cytochrome c reductase, succinate cytochrome c reductase, and cytochrome c oxidase activity has been shown in muscle and frontal cortex biopsies of RTT patients [54,55] as well as an alteration of mitochondrial respiration efficiency [56]. Indeed, biochemical analyses on muscle biopsy material confirmed reduced activities of NADH cytochrome c reductase, succinate cytochrome c reductase and cytochrome c oxidase, even in mitochondria of physiological appearance [54]. These data correlate with a recent microarray analyses on RTT patient blood samples where we have noticed an up-regulation of several mitochondria-related genes [57].…”

Section: Discussionmentioning

confidence: 97%

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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“…greater height and weight are associated with lower seizure prevalence) is intriguing, particularly because growth is a modifiable risk factor in Rett syndrome. While the source of the association remains unknown, individuals with Rett syndrome often exhibit a secondary mitochondrial dysfunction, and hypothalamic abnormalities have been reported in MECP2-deficient mice (Eeg-Olofsson et al, 1990;Coker and Melnyk, 1991;Ben-Shachar et al, 2009;Garcia-Rudaz et al, 2009;Grosser et al, 2012;Torres-Andrade et al, 2014). Recent evidence supports the association between mitochondrial dysfunction and epilepsy, and nutritional intervention has been a fundamental component of managing mitochondrial disease (Yuen and Sander, 2011;Kim do et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Longitudinal course of epilepsy in Rett syndrome and related disorders

Tarquinio

Hou

Berg

et al. 2016

Brain

100

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Epilepsy is common in Rett syndrome, an X-linked dominant disorder caused by mutations in the MECP2 gene, and in Rett-related disorders, such as MECP2 duplication. However, neither the longitudinal course of epilepsy nor the patterns of seizure onset and remission have been described in Rett syndrome and related conditions. The present study summarizes the findings of the Rett syndrome Natural History study. Participants with clinical Rett syndrome and those with MECP2 mutations without the clinical syndrome were recruited through the Rett Natural History study from 2006 to 2015. Clinical details were collected, and cumulative lifetime prevalence of epilepsy was determined using the Kaplan-Meier estimator. Risk factors for epilepsy were assessed using Cox proportional hazards models. Of 1205 participants enrolled in the study, 922 had classic Rett syndrome, and 778 of these were followed longitudinally for 3939 person-years. The diagnosis of atypical Rett syndrome with a severe clinical phenotype was associated with higher prevalence of epilepsy than those with classic Rett syndrome. While point prevalence of active seizures ranged from 30% to 44%, the estimated cumulative lifetime prevalence of epilepsy using Kaplan-Meier approached 90%. Specific MECP2 mutations were not significantly associated with either seizure prevalence or seizure severity. In contrast, many clinical features were associated with seizure prevalence; frequency of hospitalizations, inability to walk, bradykinesia, scoliosis, gastrostomy feeding, age of seizure onset, and late age of diagnosis were independently associated with higher odds of an individual having epilepsy. Aggressive behaviour was associated with lower odds. Three distinct patterns of seizure prevalence emerged in classic Rett syndrome, including those who did not have seizures throughout the study, those who had frequent relapse and remission, and those who had relentless seizures. Although 248 of those with classic Rett syndrome and a history of seizures were in terminal remission at last contact, only 74 (12% of those with a history of epilepsy) were seizure free and off anti-seizure medication. When studied longitudinally, point prevalence of active seizures is relatively low in Rett syndrome, although lifetime risk of epilepsy is higher than previously reported. While daily seizures are uncommon in Rett syndrome, prolonged remission is less common than in other causes of childhood onset epilepsy. Complete remission off anti-seizure medications is possible, but future efforts should be directed at determining what factors predict when withdrawal of medications in those who are seizure free is propitious.

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Rett Syndrome and Mitochondrial Enzyme Deficiencies

Cited by 61 publications

References 8 publications

Gene Expression Analysis Exposes Mitochondrial Abnormalities in a Mouse Model of Rett Syndrome

Gene Expression Analysis Exposes Mitochondrial Abnormalities in a Mouse Model of Rett Syndrome

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

Longitudinal course of epilepsy in Rett syndrome and related disorders

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