Managing Gastrointestinal Symptoms Resulting from Treatment with Trofinetide for Rett Syndrome: Caregiver and Nurse Perspectives.

Rett syndrome (RTT) is a rare genetic neurodevelopmental disorder mainly affecting female individuals. Trofinetide was recently approved as the first treatment for RTT, largely on the basis of results from the phase 3 LAVENDER trial, in which trofinetide showed improvements in core symptoms of RTT compared with placebo. However, gastrointestinal (GI) symptoms such as diarrhea and vomiting were commonly reported side effects, and taste was also a reported issue. The objective of this article is to describe the perspectives of five caregivers of girls in trofinetide clinical trials as well as those of three nurse trial coordinators, with a focus on management of GI symptoms of trofinetide treatment.Audio Abstract available for this article. Audio Abstract: Jane Lane provides an overview and discusses key findings of the article titled "Managing Gastrointestinal Symptoms Resulting from Treatment with Trofinetide for Rett Syndrome: Caregiver and Nurse Perspectives." (MP4 83274 KB).

Trofinetide Treatment Demonstrates a Benefit Over Placebo for the Ability to Communicate in Rett Syndrome.

BACKGROUND: Trofinetide was approved by the US Food and Drug Administration for the treatment of Rett syndrome (RTT) in March 2023. Benefiting the ability to communicate in RTT is often identified as the most important caregiver goal for new therapies. This analysis reports the communication-related end points from the phase 3 LAVENDER study of trofinetide in RTT. METHODS: Females with RTT, aged five to 20 years, were randomized 1:1 to trofinetide or placebo for 12 weeks. Secondary efficacy end points related to communication were based on change from baseline to week 12 and included the caregiver-rated Communication and Symbolic Behavior Scales Developmental Profile™ Infant-Toddler Checklist (CSBS-DP-IT) Social Composite score (key secondary end point; scores ranged from 0 to 26 [higher scores indicated better communication]) and novel clinician rating scales (0 [normal] to 7 [severe impairment]) measuring the ability to communicate choices nonverbally (RTT-COMC) and verbally (RTT-VCOM). RESULTS: Trofinetide demonstrated a statistically significant difference versus placebo for the CSBS-DP-IT Social Composite score (least squares mean [LSM] difference = 1.0; 95% confidence interval [CI], 0.3 to 1.7; P = 0.0064; Cohen's d effect size = 0.43) and a nominally significant difference for the RTT-COMC (LSM difference: -0.3; 95% CI, -0.6 to -0.0; P = 0.0257; Cohen's d effect size = 0.36). As expected, there was no difference for the RTT-VCOM. CONCLUSIONS: Significant treatment benefit for trofinetide versus placebo was observed in scales measuring the ability to communicate. These scales may be appropriate for future clinical studies in RTT and other neurodevelopmental disorders.

State-of-the-art therapies for Rett syndrome.

Rett syndrome (RTT) is an X-linked neurogenetic disorder caused by mutations of the MECP2 (methyl-CpG-binding protein 2) gene. Over two decades of work established MeCP2 as a protein with pivotal roles in the regulation of the epigenome, neuronal physiology, synaptic maintenance, and behaviour. Given the genetic aetiology of RTT and the proof of concept of its reversal in a mouse model, considerable efforts have been made to design therapeutic approaches to re-express MeCP2. By being at the forefront of the development of innovative gene therapies, research on RTT is of paramount importance for the treatment of monogenic neurological diseases. Here we discuss the recent advances and challenges of promising genetic strategies for the treatment of RTT including gene replacement therapies, gene/RNA editing strategies, and reactivation of the silenced X chromosome. WHAT THIS PAPER ADDS: Recent advances shed light on the promises of gene replacement therapy with new vectors designed to control the levels of MeCP2 expression. New developments in DNA/RNA editing approaches or reactivation of the silenced X chromosome open the possibility to re-express the native MeCP2 locus at endogenous levels. Current strategies still face limitations in transduction efficiency and future work is needed to improve brain delivery.

Vitamin D modulates cortical transcriptome and behavioral phenotypes in an Mecp2 heterozygous Rett syndrome mouse model.

Rett syndrome (RTT) is an X-linked neurological disorder caused by mutations in the transcriptional regulator MECP2. Mecp2 loss-of-function leads to the disruption of many cellular pathways, including aberrant activation of the NF-κB pathway. Genetically attenuating the NF-κB pathway in Mecp2-null mice ameliorates hallmark phenotypes of RTT, including reduced dendritic complexity, raising the question of whether NF-κB pathway inhibitors could provide a therapeutic avenue for RTT. Vitamin D is a known inhibitor of NF-κB signaling; further, vitamin D deficiency is prevalent in RTT patients and male Mecp2-null mice. We previously demonstrated that vitamin D rescues the aberrant NF-κB activity and reduced neurite outgrowth of Mecp2-knockdown cortical neurons in vitro, and that dietary vitamin D supplementation rescues decreased dendritic complexity and soma size of neocortical projection neurons in both male hemizygous Mecp2-null and female heterozygous mice in vivo. Here, we have identified over 200 genes whose dysregulated expression in the Mecp2+/- cortex is modulated by dietary vitamin D. Genes normalized with vitamin D supplementation are involved in dendritic complexity, synapses, and neuronal projections, suggesting that the rescue of their expression could underpin the rescue of neuronal morphology. Further, there is a disruption in the homeostasis of the vitamin D synthesis pathway in Mecp2+/- mice, and motor and anxiety-like behavioral phenotypes in Mecp2+/- mice correlate with circulating vitamin D levels. Thus, our data indicate that vitamin D modulates RTT pathology and its supplementation could provide a simple and cost-effective partial therapeutic for RTT.

Chronic Treatment with Cannabidiolic Acid (CBDA) Reduces Thermal Pain Sensitivity in Male Mice and Rescues the Hyperalgesia in a Mouse Model of Rett Syndrome.

Rett syndrome (RTT) is a rare neurologic disorder, characterized by severe behavioural and physiological symptoms. RTT is caused by mutations in the MECP2 gene in about 95% of cases and to date no cure is available. Recent evidence suggests that non-euphoric phytocannabinoids (pCBs) extracted from Cannabis sativa may represent innovative therapeutic molecules for RTT, with the cannabinoid cannabidivarin having beneficial effects on behavioural and brain molecular alterations in RTT mouse models. The present study evaluated the potential therapeutic efficacy for RTT of cannabidiolic acid (CBDA; 0.2, 2, 20 mg/kg through intraperitoneal injections for 14 days), a pCB that has proved to be effective for the treatment of nausea and anxiety in rodents. This study demonstrates that systemic treatment with the low dose of CBDA has anti-nociceptive effects and reduces the thermal hyperalgesia in 8 month-old MeCP2-308 male mice, a validated RTT mouse model. CBDA did not affect other behavioural or molecular parameters. These results provide support to the antinociceptive effects of CBDA and stress the need for further studies aimed at clarifying the mechanisms underlying the abnormal pain perception in RTT.

Vitamin D Supplementation Rescues Aberrant NF-κB Pathway Activation and Partially Ameliorates Rett Syndrome Phenotypes in Mecp2 Mutant Mice.

Rett syndrome (RTT) is a severe, progressive X-linked neurodevelopmental disorder caused by mutations in the transcriptional regulator MECP2 We previously identified aberrant NF-κB pathway upregulation in brains of Mecp2-null mice and demonstrated that genetically attenuating NF-κB rescues some characteristic neuronal RTT phenotypes. These results raised the intriguing question of whether NF-κB pathway inhibitors might provide a therapeutic avenue in RTT. Here, we investigate whether the known NF-κB pathway inhibitor vitamin D ameliorates neuronal phenotypes in Mecp2-mutant mice. Vitamin D deficiency is prevalent among RTT patients, and we find that Mecp2-null mice similarly have significantly reduced 25(OH)D serum levels compared with wild-type littermates. We identify that vitamin D rescues aberrant NF-κB pathway activation and reduced neurite outgrowth of Mecp2 knock-down cortical neurons in vitro Further, dietary supplementation with vitamin D in early symptomatic male Mecp2 hemizygous null and female Mecp2 heterozygous mice ameliorates reduced neocortical dendritic morphology and soma size phenotypes and modestly improves reduced lifespan of Mecp2-nulls. These results elucidate fundamental neurobiology of RTT and provide foundation that NF-κB pathway inhibition might be a therapeutic target for RTT.

Effects of oral administration of common antioxidant supplements on the energy metabolism of red blood cells. Attenuation of oxidative stress-induced changes in Rett syndrome erythrocytes by CoQ10.

Nutritional supplements are traditionally employed for overall health and for managing some health conditions, although controversies are found concerning the role of antioxidants-mediated benefits in vivo. Consistently with its critical role in systemic redox buffering, red blood cell (RBC) is recognized as a biologically relevant target to investigate the effects of oxidative stress. In RBC, reduction of the ATP levels and adenylate energy charge brings to disturbance in intracellular redox status. In the present work, several popular antioxidant supplements were orally administrated to healthy adults and examined for their ability to induce changes on the energy metabolism and oxidative status in RBC. Fifteen volunteers (3 per group) were treated for 30 days per os with epigallocatechin gallate (EGCG) (1 g green tea extract containing 50% EGCG), resveratrol (325 mg), coenzyme Q10 (CoQ10) (300 mg), vitamin C (1 g), and vitamin E (400 U.I.). Changes in the cellular levels of high-energy compounds (i.e., ATP and its catabolites, NAD and GTP), GSH, GSSG, and malondialdehyde (MDA) were simultaneously analyzed by ion-pairing HPLC. Response to oxidative stress was further investigated through the oxygen radical absorptive capacity (ORAC) assay. According to our experimental approach, (i) CoQ10 appeared to be the most effective antioxidant inducing a high increase in ATP/ADP, ATP/AMP, GSH/GSSG ratio and ORAC value and, in turn, a reduction of NAD concentration, (ii) EGCG modestly modulated the intracellular energy charge potential, while (iii) Vitamin E, vitamin C, and resveratrol exhibited very weak effects. Given that, the antioxidant potential of CoQ10 was additionally assessed in a pilot study which considered individuals suffering from Rett syndrome (RTT), a severe X-linked neuro-developmental disorder in which RBC oxidative damages provide biological markers for redox imbalance and chronic hypoxemia. RTT patients (n = 11), with the typical clinical form, were supplemented for 12 months with CoQ10 (300 mg, once daily). Level of lipid peroxidation (MDA production) and energy state of RBCs were analyzed at 2 and 12 months. Our data suggest that CoQ10 may significantly attenuate the oxidative stress-induced damage in RTT erythrocytes.

L-Serine dietary supplementation is associated with clinical improvement of loss-of-function GRIN2B-related pediatric encephalopathy.

Autosomal dominant mutations in GRIN2B are associated with severe encephalopathy, but little is known about the pathophysiological outcomes and any potential therapeutic interventions. Genetic studies have described the association between de novo mutations of genes encoding the subunits of the N-methyl-d-aspartate receptor (NMDAR) and severe neurological conditions. Here, we evaluated a missense mutation in GRIN2B, causing a proline-to-threonine switch (P553T) in the GluN2B subunit of NMDAR, which was found in a 5-year-old patient with Rett-like syndrome with severe encephalopathy. Structural molecular modeling predicted a reduced pore size of the mutant GluN2B-containing NMDARs. Electrophysiological recordings in a HEK-293T cell line expressing the mutated subunit confirmed this prediction and showed an associated reduced glutamate affinity. Moreover, GluN2B(P553T)-expressing primary murine hippocampal neurons showed decreased spine density, concomitant with reduced NMDA-evoked currents and impaired NMDAR-dependent insertion of the AMPA receptor subunit GluA1 at stimulated synapses. Furthermore, the naturally occurring coagonist d-serine restored function to GluN2B(P553T)-containing NMDARs. l-Serine dietary supplementation of the patient was hence initiated, resulting in the increased abundance of d-serine in the plasma and brain. The patient has shown notable improvements in motor and cognitive performance and communication after 11 and 17 months of l-serine dietary supplementation. Our data suggest that l-serine supplementation might ameliorate GRIN2B-related severe encephalopathy and other neurological conditions caused by glutamatergic signaling deficiency.

A Coordinated Attack: Rett Syndrome Therapeutic Development.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the Methyl CpG binding protein 2 (MeCP2) gene. This Science & Society article focuses on pharmacological strategies that attack RTT treatment from multiple angles, including drug repurposing and de novo discovery efforts, and discusses the impacts of preclinical study design and translationally relevant outcome measures.

Chronic treatment with the phytocannabinoid Cannabidivarin (CBDV) rescues behavioural alterations and brain atrophy in a mouse model of Rett syndrome.

Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioural and physiological symptoms. RTT is caused by mutations in the MECP2 gene in about 95% of cases and to date no cure is available. The endocannabinoid system modulates several physiological processes and behavioural responses that are impaired in RTT and its deregulation has been associated with neuropsychiatric disorders which have symptoms in common with RTT. The present study evaluated the potential therapeutic efficacy for RTT of cannabidivarin (CBDV), a non-psychotropic phytocannabinoid from Cannabis sativa that presents antagonistic properties on the G protein-coupled receptor 55 (GPR55), the most recently identified cannabinoid receptor. Present results demonstrate that systemic treatment with CBDV (2, 20, 100 mg/Kg ip for 14 days) rescues behavioural and brain alterations in MeCP2-308 male mice, a validated RTT model. The CBDV treatment restored the compromised general health status, the sociability and the brain weight in RTT mice. A partial restoration of motor coordination was also observed. Moreover, increased levels of GPR55 were found in RTT mouse hippocampus, suggesting this G protein-coupled receptor as new potential target for the treatment of this disorder. Present findings highlight for the first time for RTT the translational relevance of CBDV, an innovative therapeutic agent that is under active investigation in the clinical setting.

Cytokine Dysregulation in MECP2- and CDKL5-Related Rett Syndrome: Relationships with Aberrant Redox Homeostasis, Inflammation, and ω-3 PUFAs.

An involvement of the immune system has been suggested in Rett syndrome (RTT), a devastating neurodevelopmental disorder related to oxidative stress, and caused by a mutation in the methyl-CpG binding protein 2 gene (MECP2) or, more rarely, cyclin-dependent kinase-like 5 (CDKL5). To date, it is unclear whether both mutations may have an impact on the circulating cytokine patterns. In the present study, cytokines involved in the Th1-, Th2-, and T regulatory (T-reg) response, as well as chemokines, were investigated in MECP2- (MECP2-RTT) (n = 16) and CDKL5-Rett syndrome (CDKL5-RTT) (n = 8), before and after ω-3 polyunsaturated fatty acids (PUFAs) supplementation. A major cytokine dysregulation was evidenced in untreated RTT patients. In MECP2-RTT, a Th2-shifted balance was evidenced, whereas in CDKL5-RTT both Th1- and Th2-related cytokines (except for IL-4) were upregulated. In MECP2-RTT, decreased levels of IL-22 were observed, whereas increased IL-22 and T-reg cytokine levels were evidenced in CDKL5-RTT. Chemokines were unchanged. The cytokine dysregulation was proportional to clinical severity, inflammatory status, and redox imbalance. Omega-3 PUFAs partially counterbalanced cytokine changes, as well as aberrant redox homeostasis and the inflammatory status. RTT is associated with a subclinical immune dysregulation as the likely consequence of a defective inflammation regulatory signaling system.

[Hyperammonemic encephalopathy in multiple myeloma]. / Hyperammonämische Enzephalopathie bei multiplem Myelom.

HISTORY AND CLINICAL FINDINGS: A 54-year old man had suffered from advanced multiple myeloma for two years. After initially good response the myeloma was refractrory to treatment with dexamethasone, cyclophosphamide, bortezomibe, zoledronate and additionally doxorubicine. The patient then complained of dyspnea without clinical signs of cardiopulmonary disease. INVESTIGATIONS: Arterial blood gas analysis showed hyperventilation with respiratory alkalosis and normal alveolo-arterial gradient as the reason for the dyspnea. With a normal MRI of the brain and lumbal puncture, a neurological disease could be excluded. Serum calcium, creatinine and serum viscosity were normal. Eventually, serum ammonia levels were found to be substantially elevated (144 µmol/l) and hyperammonemic encephalopathy was diagnosed. TREATMENT AND COURSE: Therapy with bortezomib and high dose dexamethason was repeated, and the patient also received bendamustin. Despite this treatment, he lost consciousness and died after two weeks because of aspiration pneumonia. CONCLUSION: The existence of respiratory alkalosis and multiple myeloma should prompt a search for hyperammonemia.

Effects of ω-3 PUFAs supplementation on myocardial function and oxidative stress markers in typical Rett syndrome.

Rett syndrome (RTT) is a devastating neurodevelopmental disorder with a 300-fold increased risk rate for sudden cardiac death. A subclinical myocardial biventricular dysfunction has been recently reported in RTT by our group and found to be associated with an enhanced oxidative stress (OS) status. Here, we tested the effects of the naturally occurring antioxidants ω-3 polyunsaturated fatty acids (ω-3 PUFAs) on echocardiographic parameters and systemic OS markers in a population of RTT patients with the typical clinical form. A total of 66 RTT girls were evaluated, half of whom being treated for 12 months with a dietary supplementation of ω-3 PUFAs at high dosage (docosahexaenoic acid ~71.9 ± 13.9 mg/kg b.w./day plus eicosapentaenoic acid ~115.5 ± 22.4 mg/kg b.w./day) versus the remaining half untreated population. Echocardiographic systolic longitudinal parameters of both ventricles, but not biventricular diastolic measures, improved following ω-3 PUFAs supplementation, with a parallel decrease in the OS markers levels. No significant changes in the examined echocardiographic parameters nor in the OS markers were detectable in the untreated RTT population. Our data indicate that ω-3 PUFAs are able to improve the biventricular myocardial systolic function in RTT and that this functional gain is partially mediated through a regulation of the redox balance.

Vascular dysfunction in a mouse model of Rett syndrome and effects of curcumin treatment.

Mutations in the coding sequence of the X-linked gene MeCP2 (Methyl CpG-binding protein) are present in around 80% of patients with Rett Syndrome, a common cause of intellectual disability in female and to date without any effective pharmacological treatment. A relevant, and so far unexplored feature of RTT patients, is a marked reduction in peripheral circulation. To investigate the relationship between loss of MeCP2 and this clinical aspect, we used the MeCP2 null mouse model B6.129SF1-MeCP2tm1Jae for functional and pharmacological studies. Functional experiments were performed on isolated resistance mesenteric vessels, mounted on a pressurized myograph. Vessels from female MeCP2(+/-) mice show a reduced endothelium-dependent relaxation, due to a reduced Nitric Oxide (NO) availability secondary to an increased Reactive Oxygen Species (ROS) generation. Such functional aspects are associated with an intravascular increase in superoxide anion production, and a decreased vascular eNOS expression. These alterations are reversed by curcumin administration (5% (w/w) dietary curcumin for 21 days), which restores endothelial NO availability, decreases intravascular ROS production and normalizes vascular eNOS gene expression. In conclusion our findings highlight alterations in the vascular/endothelial system in the absence of a correct function of MeCP2, and uncover related cellular/molecular mechanisms that are rescued by an anti-oxidant treatment.

Síndrome de Rett: doble catéter epidural para control del dolor postoperatorio tras cirugía de escoliosis. Revisión de la bibliografía / Rett syndrome: double epidural catheter for the control of postoperative pain after scoliosis surgery. A literature review

El síndrome de Rett es una enfermedad neurológica grave e incapacitante por un defecto estructural en el brazo corto del cromosoma X (Xq28). Afecta a mujeres y consta de múltiples discapacidades neurológicas progresivas que se manifiestan desde edades tempranas causando invalidez y dependencia de por vida. La escoliosis aparece en más del 50% de los pacientes, con necesidad de corrección quirúrgica en casos de graves angulaciones. Es imprescindible una evaluación preanestésica cuidadosa con el fin de identificar los factores de riesgo y así disminuir la morbimortalidad asociada con el procedimiento quirúrgico. Presentamos el caso de una paciente afectada por este síndrome y escoliosis, programada para la realización de una artrodesis vertebral toracolumbar mediante instrumentación con anestesia general, que transcurrió sin incidentes. Evaluamos las connotaciones específicas de este síndrome, sus potenciales complicaciones y su manejo desde un punto de vista anestésico; remarcando el control del dolor postoperatorio conseguido mediante un doble catéter epidural con infusión de anestésicos locales y fentanilo tras la cirugía(AU)

Rett syndrome is a severe and incapacitating neurological disease caused by a structural defect in the short arm of the X chromosome (Xq28). It affects females and consists of multiple and progressive neurological impairments that start from a young age, leading to lifelong disability and dependency. Scoliosis appears in more than 50% of patients and requires surgical correction in cases where the curvature is severe. Pre-anaesthetic assessment is essential in order to identify the risk factors and thus reduce the morbidity and mortality associated with the surgical procedure. We present the case of a patient affected by this syndrome and scoliosis, who was scheduled to have an instrumented thoracolumbar spine arthrodesis with general anaesthesia, which passed without incident. We evaluate the specific details of this syndrome, its potential complications, and its management from an anaesthetic point of view, emphasising the control of postoperative pain using a double epidural catheter with an infusion of local anaesthetics and fentanyl(AU)

S-adenosylmethionine and S-adenosylhomocysteine in plasma and cerebrospinal fluid in Rett syndrome and the effect of folinic acid supplementation.

Rett syndrome is a neurodevelopmental disorder characterized by cognitive and locomotor regression and stereotypic hand movements. The disorder is caused by mutations in the X chromosomal MECP2 a gene encoding methyl CpG-binding protein. It has been associated with disturbances of cerebral folate homeostasis, as well as with speculations on a compromised DNA-methylation. Folinic acid is the stable form of folate. Its derived intermediate 5-MTHF supports the conversion of homocysteine to methionine, the precursor of S-adenosylmethionine (SAM). This in turn donates its methyl group to various acceptors, including DNA, thereby being converted to S-adenosylhomocysteine (SAH). The SAM/SAH ratio reflects the methylation potential. The goal of our study was to influence DNA methylation processes and ameliorate the clinical symptoms in Rett syndrome. Therefore we examined the hypothesis that folinic acid supplementation, besides increasing cerebrospinal fluid (CSF) 5-MTHF (p = 0.003), influences SAM and SAH and their ratio. In our randomized, double-blind crossover study on folinic acid supplementation, ten female Rett patients received both folinic acid and placebo for 1 year each. It was shown that both SAM and SAH levels in the CSF remained unchanged following folinic acid administration (p = 0.202 and p = 0.097, respectively) in spite of a rise of plasma SAM and SAH (p = 0.007; p = 0.009). There was no significant change in the SAM/SAH ratio either in plasma or CSF. The apparent inability of Rett patients to upregulate SAM and SAH levels in the CSF may contribute to the biochemical anomalies of the Rett syndrome. Our studies warrant further attempts to promote DNA methylation in the true region of interest, i.e. the brain.

Neonatal exposure to low dose corticosterone persistently modulates hippocampal mineralocorticoid receptor expression and improves locomotor/exploratory behaviour in a mouse model of Rett syndrome.

Rett syndrome (RTT) is a pervasive neurodevelopmental disorder, primarily affecting girls. RTT causes a wide variety of debilitating symptoms and no cure currently exists. Mouse models bearing mutations in the Mecp2 gene recapitulate most physiological and behavioural RTT-related abnormalities. Stimulating neonatal environments (e.g. brief maternal separations or maternal low-dose corticosterone supplementation) reduce stress and fear responses at adulthood. The present study investigated whether impacting early in development the hypothalamic-pituitary-adrenal axis, by exposing Mecp2-308 mutant pups to a low dose of corticosterone (50 µg/ml, during the 1st week of life) may contrast RTT-related abnormalities in neuroendocrine regulation and behavioural adaptation at adulthood. In line with previous reports, when fully symptomatic, MeCP2-308 mice showed a reduction in the regular nocturnal hyperactivity in the home-cage and increased anxiety-like behaviours and plasma corticosterone (CORT) levels in response to restraint stress. An abnormal elevation in mRNA levels of mineralocorticoid receptors (MR) and BDNF gene was also evident in the hippocampus of fully symptomatic mutant mice. Neonatal CORT modulated MR gene expression and behavioural reactivity towards a novel object, also restoring wt-like levels of locomotor/exploratory behaviour in mutant mice. Enhanced sensitivity to the neonatal treatment (in terms of increase in GR and MR mRNA levels), was also evident in the hippocampus of MeCP2-308 mice compared to wt littermates. Present results corroborate the hypothesis that targeting the glucocorticoid system may prove valid in contrasting at least some of the RTT-related symptoms and provide evidence that pharmacological interventions during critical early time windows can persistently improve the behavioural phenotype of RTT mice. Current data also support the emerging role played by Mecp2 in mediating the epigenetic programming induced by early life events and indicate that, in the absence of functional MeCP2, programming of the central nervous system in response to early environmental stimuli is abnormally regulated. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'.

Acetyl-L-carnitine improves behavior and dendritic morphology in a mouse model of Rett syndrome.

Rett syndrome (RTT) is a devastating neurodevelopmental disorder affecting 1 in 10,000 girls. Approximately 90% of cases are caused by spontaneous mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). Girls with RTT suffer from severe motor, respiratory, cognitive and social abnormalities attributed to early deficits in synaptic connectivity which manifest in the adult as a myriad of physiological and anatomical abnormalities including, but not limited to, dimished dendritic complexity. Supplementation with acetyl-L-carnitine (ALC), an acetyl group donor, ameliorates motor and cognitive deficits in other disease models through a variety of mechanisms including altering patterns of histone acetylation resulting in changes in gene expression, and stimulating biosynthetic pathways such as acetylcholine. We hypothesized ALC treatment during critical periods in cortical development would promote normal synaptic maturation, and continuing treatment would improve behavioral deficits in the Mecp2(1lox) mouse model of RTT. In this study, wildtype and Mecp2(1lox) mutant mice received daily injections of ALC from birth until death (postnatal day 47). General health, motor, respiratory, and cognitive functions were assessed at several time points during symptom progression. ALC improved weight gain, grip strength, activity levels, prevented metabolic abnormalities and modestly improved cognitive function in Mecp2 null mice early in the course of treatment, but did not significantly improve motor or cognitive functions assessed later in life. ALC treatment from birth was associated with an almost complete rescue of hippocampal dendritic morphology abnormalities with no discernable side effects in the mutant mice. Therefore, ALC appears to be a promising therapeutic approach to treating early RTT symptoms and may be useful in combination with other therapies.

Oxidative stress in Rett syndrome: natural history, genotype, and variants.

OBJECTIVES: Rett syndrome (RTT) is an X-linked autism spectrum disorder caused by mutations in the MeCP2 gene in the great majority of cases. Evidence suggests a potential role of oxidative stress (OS) in its pathogenesis. Here, we investigated the potential value of OS markers (non-protein-bound iron (NPBI) and F2-isoprostanes (F2-IsoPs)) in explaining natural history, genotype-phenotype correlation, and clinical heterogeneity of RTT, and gauging the response to omega-3 polyunsaturated fatty acids (ω-3 PUFAs). METHODS: RTT patients (n=113) and healthy controls were assayed for plasma NPBI and F2-IsoPs, and intraerythrocyte NPBI. Forty-two patients with typical RTT were randomly assigned to ω-3 PUFAs supplementation for 12 months. NPBI was measured by HPLC and F2-IsoPs using a gas chromatography/negative ion chemical ionization tandem mass spectrometry (GC/NICI-MS/MS) technique. RESULTS: F2-IsoPs were significantly higher in the early stages as compared with the late natural progression of classic RTT. MeCP2 mutations related to more severe phenotypes exhibited higher OS marker levels than those of milder phenotypes. Higher OS markers were observed in typical RTT and early seizure variant as compared with the preserved speech and congenital variants. Significant reduction in OS markers levels and improvement of severity scores were observed after ω-3 PUFAs supplementation. DISCUSSION: OS is a key modulator of disease expression in RTT.