MECP2 Mutations Research Articles

MeCP2+/− mouse model of RTT reproduces auditory phenotypes associated with Rett syndrome and replicate select EEG endophenotypes of autism spectrum disorder

Impairments in cortical sensory processing have been demonstrated in Rett syndrome (RTT) and Autism Spectrum Disorders (ASD) and are thought to contribute to high-order phenotypic deficits. However, underlying pathophysiological mechanisms for these abnormalities are unknown. This study investigated auditory sensory processing in a mouse model of RTT with a heterozygous loss of MeCP2 function. Cortical abnormalities in a number of neuropsychiatric disorders, including ASD are reflected in auditory evoked potentials and fields measured by EEG and MEG. One of these abnormalities, increased latency of cortically sourced components, is associated with language and developmental delay in autism. Additionally, gamma-band abnormalities have recently been identified as an endophenotype of idiopathic autism. Both of these cortical abnormalities are potential clinical endpoints for assessing treatment. While ascribing similar mechanisms of idiopathic ASD to Rett syndrome (RTT) has been controversial, we sought to determine if mouse models of RTT replicate these intermediate phenotypes. Mice heterozygous for the null mutations of the gene MeCP2, were implanted for EEG. In response to auditory stimulation, these mice recapitulated specific latency differences as well as select gamma and beta band abnormalities associated with ASD. MeCP2 disruption is the predominant cause of RTT, and reductions in MeCP2 expression predominate in ASD. This work further suggests a common cortical pathophysiology for RTT and ASD, and indicates that the MeCP2+/− model may be useful for preclinical development targeting specific cortical processing abnormalities in RTT with potential relevance to ASD.

Hippocampal CA1 pyramidal neurons of Mecp2 mutant mice show a dendritic spine phenotype only in the presymptomatic stage.

Alterations in dendritic spines have been documented in numerous neurodevelopmental disorders, including Rett Syndrome (RTT). RTT, an X chromosome-linked disorder associated with mutations in MECP2, is the leading cause of intellectual disabilities in women. Neurons in Mecp2-deficient mice show lower dendritic spine density in several brain regions. To better understand the role of MeCP2 on excitatory spine synapses, we analyzed dendritic spines of CA1 pyramidal neurons in the hippocampus of Mecp2tm1.1Jae male mutant mice by either confocal microscopy or electron microscopy (EM). At postnatal-day 7 (P7), well before the onset of RTT-like symptoms, CA1 pyramidal neurons from mutant mice showed lower dendritic spine density than those from wildtype littermates. On the other hand, at P15 or later showing characteristic RTT-like symptoms, dendritic spine density did not differ between mutant and wildtype neurons. Consistently, stereological analyses at the EM level revealed similar densities of asymmetric spine synapses in CA1 stratum radiatum of symptomatic mutant and wildtype littermates. These results raise caution regarding the use of dendritic spine density in hippocampal neurons as a phenotypic endpoint for the evaluation of therapeutic interventions in symptomatic Mecp2-deficient mice. However, they underscore the potential role of MeCP2 in the maintenance of excitatory spine synapses.

Autism: Where Genetics Meets the Immune System

Individuals with autism often display immune abnormalities in the form of altered cytokine profiles, autoantibodies, and changes in immune cell function. Are they mere “smoke” or real “fire”? Given what we now know about the cross-talk between the immune and nervous systems, one must ask: are these immune abnormalities simply bystander effects of genetic/genomic variants directly responsible for abnormal neurodevelopment, or is there a sizable subgroup of patients with autism spectrum disorder (ASD), in which a dysfunctional immune system plays a critical mediator role in the pathogenic chain of events leading to the disorder? Is autism one of many genetic/genomic conditions, Down syndrome representing the best-known example, accompanied by immune abnormalities not primarily responsible for changing the trajectory of neurodevelopment? Or could conceivably an unfortunate combination of genetic/genomic susceptibility and environmental factors converging onto the same individual affect neurodevelopment through immune-mediated mechanisms, such as fetomaternal incompatibility, autoimmunity, abnormal neuroinflammation, and so on? This special issue contains six contributions aimed at addressing different aspects of this question. The paper by N. Momeni et al. documents significantly elevated plasma levels of factor I among ASD children compared to controls. Factor I is a plasma enzyme responsible for degrading complement factor 3b, which in turn is the major opsonin in the complement system enabling phagocytosis of microbial agents. Higher factor I levels can be interpreted as either primary (i.e., conferring vulnerability toward microbial infections) or as a secondary event part of a broader immunomodulatory response aiming to blunt an inflammatory process. F1 plasma levels suggest that this process could play a more relevant role in males and in small ASD children. The contribution by S. Rose et al. describes reduced glutathione-mediated redox/antioxidant capacity both inside primary leukocytes and in the plasma of ASD children. Consistently with this intracellular and extracellular imbalance of the glutathione redox status, intracellular production of free radicals is also enhanced, especially in 30% of ASD cases. This and several previous studies provide converging evidence of excessive oxidative stress likely leading to abnormal mitochondrial function in a similar percentage of autistic individuals. Along similar lines, M. I. Waly et al. direct their attention on the complex array of pathophysiological consequences produced by enhanced oxidative stress. In addition to imbalanced glutathione redox status, reduced methionine synthase activity is particularly interesting, as it results in lower availability of S-adenosyl-methionine and consequently blunted DNA methylation. Curiously, a similar abnormality underlies autistic features also in two entirely different contexts, namely, children exposed prenatally to valproic acid and in Rett syndrome girls, carrying MECP2 mutations. The review by S. D. Bilbo et al. presents a stimulating hypothesis, linking ASD to inflammatory, allergic, and autoimmune diseases. These “hyperimmune” disorders are known to share steeply increasing incidence rates over the last decades, as well as significant loading in many families with children with autism. In the authors' view, they also share an inappropriate activation of the immune system due to biome depletion in postindustrial societies, possibly suggesting preventive strategies based on biome reconstitution. The paper by C. Onore et al. reports an impressive threefold decrease in EGF plasma levels among small ASD children compared to controls. EGF is involved in wound healing in the skin, in the gastrointestinal, and respiratory systems, as well as in the central nervous system where this neurotrophic factor supports both adult subventricular zone and midbrain dopaminergic neurons, in addition to stem cell proliferation. A. R. Torres et al. review immune abnormalities in autism, focusing on HLA gene roles as potential contributors to autism pathogenesis through several distinct mechanisms. HLA genes or haplotypes have been found associated with several autoimmune diseases, but strong associations with autism have also been reported. These contributions, while not providing the ultimate answers, do add some new pieces to the autism puzzle, providing further support to the idea that immune abnormalities may play a pathophysiologically relevant role in a subgroup of families with autistic children. Future studies of the interaction of the immune and central nervous system are needed to clarify in more detail how neuroimmune mechanisms influence the enhancement of the neurodevelopmental disarray and disturbances of neurobehavioral trajectories determined by genetic and environmental factors. The heuristic potential of this line of investigation, both in terms of prevention and clinical therapeutics, ensures continued efforts until a more definitive answer can be given to our initial question, so crucial in today's autism field. Antonio M. Persico Judy Van de Water Carlos A. Pardo

Molecular analysis of MECP2 gene in Egyptian patients with Rett syndrome

Rett syndrome (RTT) is a progressive neurodevelopmental disorder that affects mainly females comprising one of the most common causes of mental retardation in females. Mutations in the X-linked MECP2 gene have been identified to be the major cause for RTT. This study represents one of the limited MECP2 molecular analyses done on Egyptian patients with RTT, in which direct sequencing of MECP2 coding region in 10 female Egyptian patients provisionally diagnosed to have RTT was carried out. Four different pathogenic mutations were identified in four patients; three missense (C380T, C397T and C916T) and one nonsense (C382T). The four mutations, C→T transitions, were located in exon four. Patients with MECP2 mutation showed the clinical course of typical RTT. Analysis of X chromosome inactivation (XCI) pattern of genomic DNA in patients proved to be positive for MECP2 mutations identifying one patient with skewed inactivation pattern.

Mutations in MECP2 exon 1 in classical rett patients disrupt MECP2_e1 transcription, but not transcription of MECP2_e2

The overwhelming majority of Rett syndrome cases are caused by mutations in the gene MECP2. MECP2 has two isoforms, termed MECP2_e1 and MECP2_e2, which differ in their N-terminal amino acid sequences. A growing body of evidence has indicated that MECP2_e1 may be the etiologically relevant isoform in Rett Syndrome based on its expression profile in the brain and because, strikingly, no mutations have been discovered that affect MECP2_e2 exclusively. In this study we sought to characterize four classical Rett patients with mutations that putatively affect only the MECP2_e1 isoform. Our hypothesis was that the classical Rett phenotype seen here is the result of disrupted MECP2_e1 expression, but with MECP2_e2 expression unaltered. We used quantitative reverse transcriptase PCR to assay mRNA expression for each isoform independently, and used cytospinning methods to assay total MECP2 in peripheral blood lymphocytes (PBL). In the two Rett patients with identical 11 bp deletions within the coding portion of exon 1, MECP2_e2 levels were unaffected, whilst a significant reduction of MECP2_e1 levels was detected. In two Rett patients harboring mutations in the exon 1 start codon, MECP2_e1 and MECP2_e2 mRNA amounts were unaffected. In summary, we have shown that patients with exon 1 mutations transcribe normal levels of MECP2_e2 mRNA, and most PBL are positive for MeCP2 protein, despite them theoretically being unable to produce the MECP2_e1 isoform, and yet still exhibit the classical RTT phenotype. Altogether, our work further supports our hypothesis that MECP2_e1 is the predominant isoform involved in the neuropathology of Rett syndrome.

Genotype–phenotype relationships as prognosticators in Rett syndrome should be handled with care in clinical practice

Rett syndrome (RTT; OMIM 312750) is an X-linked dominant neurodevelopmental disorder leading to cognitive and motor impairment, epilepsy, and autonomic dysfunction in females. Since the discovery that RTT is caused by mutations in MECP2, large retrospective genotype-phenotype correlation studies have been performed. A number of general genotype-phenotype relationships were confirmed and specific disorder profiles were described. Nevertheless, conflicting results are still under discussion, partly due to the variability in classification of mutations, assessment tools, and structure of the data sets. The aim of this study was to investigate relationships between genotype and specific clinical data collected by the same experienced physician in a well-documented RTT cohort, and evaluate its prognostic value in counseling young parents with a newly diagnosed RTT girl regarding her future outcome. The Maastricht-Leuven Rett Syndrome Database is a register of 137 molecularly confirmed clinical RTT cases, containing both molecular and clinical data on examination and follow up by the same experienced physician. Although the general genotype-phenotype relationships were confirmed, the clinical severity was still found to be very variable. We therefore recommend caution in using genotype-phenotype data in the prognosis of outcome for children in Rett syndrome. Early diagnosis, early intervention, and preventive management are imperative for better outcomes and better quality of daily life for RTT females and their families.

Pharmacological interference with the glucocorticoid system influences symptoms and lifespan in a mouse model of Rett syndrome

Rett syndrome (RTT) is caused by loss-of-function mutations in the X-linked gene MECP2 coding for methyl CpG-binding protein 2 (MeCP2). This protein can act as transcriptional repressor, and we showed in a previous study that glucocorticoid-inducible genes are up-regulated in an RTT mouse model and that these genes are direct MeCP2 targets. Here, we report that pharmacological intervention with the glucocorticoid system has an impact on the symptoms and lifespan in an RTT mouse model. Our data support a functional implication of the stress hormone system in RTT and suggest this hormone system as potential therapeutic target.

FOXG1 mutations in Japanese patients with the congenital variant of Rett syndrome

Rett syndrome (RTT) is a severe neurodevelopmental disorder characterized by microcephaly, psychomotor regression, seizures and stereotypical hand movements. Recently, deletions and inactivating mutations in FOXG1, encoding a brain-specific transcription factor that is critical for forebrain development, have been found to be associated with the congenital variant of RTT. Here we report the clinical features and molecular characteristics of two cases of the congenital variant of RTT. We conducted mutation screenings of FOXG1 in a cohort of 15 Japanese patients with a clinical diagnosis of atypical RTT but without MECP2 and CDKL5 mutations. Two unrelated female patients had heterozygous mutations (c.256dupC, p.Gln86ProfsX35 and c.689G>A, pArg230His). Both showed neurological symptoms from the neonatal period, including hypotonia, irritability and severe microcephaly. Further, their psychomotor development was severely impaired, as indicated by their inability to sit unaided or acquire speech sounds, and they had a hyperkinetic movement disorder, because both displayed hand stereotypies and jerky movements of the upper limbs. Brain magnetic resonance imaging scans revealed delayed myelination with hypoplasia of the corpus callosum and frontal lobe. These cases confirm the involvement of FOXG1 in the molecular etiology of the congenital variant of RTT and show the characteristic features of FOXG1-related disorder.

Methodological note: Video analysis of the early development of Rett syndrome—one method for many disciplines

Rett syndrome is a profoundly disabling X-linked neurodevelopmental disorder that predominantly, but not exclusively, occurs in females. It is mainly caused by mutations in the gene MECP2 for methy...

Normal mitral cell dendritic development in the setting of Mecp2 mutation

Rett syndrome (RTT) is an autism spectrum disorder caused by mutation in the gene encoding methyl CpG binding protein 2 (MECP2). Evidence to date suggests that these disorders display defects in synaptic organization and plasticity. A hallmark of the pathology in RTT has been identified as decreased dendritic arborization, which has been interpreted to represent abnormal dendritic formation and pruning during development. Our previous studies revealed that olfactory axons display defective pathfinding and targeting in the setting of Mecp2 mutation. In the present work, we use Mecp2 mutant mouse models and the olfactory system to investigate dendritic development. Here, we demonstrate that mitral cell dendritic development proceeds normally in mutant mice, resulting in typical dendritic morphology at early postnatal ages. We also failed to detect abnormalities in dendritic inputs at symptomatic stages when glomeruli from mutant mice appear smaller in area than the wild type (WT) (6 weeks postnatally). Collectively, these findings suggest that the initial defects in glomeruli impairment seen with Mecp2 mutation do not result from abnormal dendritic development. Our results using the olfactory system indicate that dendritic abnormalities are not an early feature in the abnormalities incurred by Mecp2 mutation.

Rett syndrome mutation MeCP2 T158A disrupts DNA binding, protein stability and ERP responses

Mutations in the MECP2 gene cause the autism spectrum disorder Rett Syndrome (RTT). One of the most common mutations associated with RTT occurs at MeCP2 Threonine 158 converting it to Methionine (T158M) or Alanine (T158A). To understand the role of T158 mutation in the pathogenesis of RTT, we generated knockin mice recapitulating MeCP2 T158A mutation. Here we show a causal role for T158A mutation in the development of RTT-like phenotypes including developmental regression, motor dysfunction, and learning and memory deficits. These phenotypes resemble those in Mecp2-null mice and manifest through a reduction in MeCP2 binding to methylated DNA and a decrease in MeCP2 protein stability. Importantly, the age-dependent development of event-related neuronal responses are disrupted by MeCP2 mutation, suggesting that impaired neuronal circuitry underlies the pathogenesis of RTT and that assessment of event-related potentials may serve as a biomarker for RTT and treatment evaluation.

Asking the right questions

Rett syndrome is a rare neurodevelopmental disorder affecting 1:1,000 female children. Revision of the diagnostic criteria in 2010 reflected a growing understanding of the heterogeneity of the disorder.1 Slowed head growth in infancy, for example, is no longer a criterion for diagnosis. Classic Rett syndrome (RTT) is determined by regression of language and fine motor skills and all 4 main criteria: 1) partial or complete loss of purposeful hand skills, 2) partial or complete loss of acquired speech, 3) gait abnormalities (e.g., dyspraxic gait) or inability to walk, and 4) characteristic midline hand movements. Exclusionary criteria include brain injury such as trauma, infection, or neurometabolic disease and markedly abnormal development in the first 6 months. Atypical Rett syndrome is diagnosed when there are at least 2 of the 4 main criteria and 5 of the 11 supporting criteria categorizing the behavioral features, neuromotor findings, and physical symptoms. Abnormalities of the MECP2 gene are found in 95% of affected girls2 with other genes contributing to infrequent subtypes. Mutations of MECP2 may be found in children with other neurodevelopmental disorders such as autism. It is likely that …

Clinical severity and quality of life in children and adolescents with Rett syndrome

The clinical features and genetics of Rett syndrome (RTT) have been well studied, but examination of quality of life (QOL) is limited. This study describes the impact of clinical severity on QOL among female children and adolescents with classic RTT. Cross-sectional and longitudinal analyses were conducted on data collected from an NIH-sponsored RTT natural history study. More than 200 participants from 5 to 18 years of age with classic RTT finished their 2-year follow-up at the time of analysis. Regression models after adjustment for their MECP2 mutation type and age at enrollment were used to examine the association between clinical status and QOL. Severe clinical impairment was highly associated with poor physical QOL, but worse motor function and earlier age at onset of RTT stereotypies were associated with better psychosocial QOL; conversely, better motor function was associated with poorer psychosocial QOL. Standard psychosocial QOL assessment for children and adolescents with RTT differs significantly with regard to their motor function severity. As clinical trials in RTT emerge, the Child Health Questionnaire 50 may represent one of the important outcome measures.

MECP2 mutations and clinical correlations in Greek children with Rett syndrome and associated neurodevelopmental disorders

Background: Mutations in the MECP2 gene (methyl-CpG-binding protein-2) are responsible for 60–95% of cases of Rett syndrome (RTT), an X-linked dominant neurodevelopmental disorder affecting mostly girls. Classic RTT is characterized by normal early development followed by psychomotor regression and onset of microcephaly, although variant forms are also observed. MECP2 has also been implicated in variable mental retardation (MR) phenotypes, including X-linked Mental Retardation (XLMR), Fragile-X-like Syndrome (FXS) and Angelman-like (AS) phenotypes. Aim: The aim of the study was: (a) to evaluate the incidence and spectrum of MECP2 mutations in children with RTT and variant MR; (b) to evaluate phenotype-genotype correlations. Methods: Exons 3–4 were analyzed for mutations in 281 MR patients (aged 13months–27years old, 144 males–137 females) consisting of 88 patients referred for RTT and 193 patients referred for AS-like and FXS-like types of MR. Statistical analysis included correlation between classic MECP2-positive and MECP2-negative and variant RTT patients, and frequency of MECP2 mutations in the various categories. Results: Mutations were detected in ≈70% of classic and ≈21% of variant RTT, respectively. Amongst MR cases, 2.1% carried MECP2 mutations. MECP2-positive females had more problems in ambulation, muscle tone, tremor and ataxia, respiratory disturbances, head growth, hand use and stereotypies. Classic RTT-positive versus negative had significant respiratory and sitting problems and versus variant RTT-positive females ambulatory, hand and stereotypies problems. Conclusion: The analysis of the MECP2 gene could provide a diagnostic tool for RTT and non-specific MR research.

Genome-Wide Activity-Dependent MeCP2 Phosphorylation Regulates Nervous System Development and Function

Autism spectrum disorders such as Rett syndrome (RTT) have been hypothesized to arise from defects in experience-dependent synapse maturation. RTT is caused by mutations in MECP2, a nuclear protein that becomes phosphorylated at S421 in response to neuronal activation. We show here that disruption of MeCP2 S421 phosphorylation invivo results in defects in synapse development and behavior, implicating activity-dependent regulation of MeCP2 in brain development and RTT. We investigated the mechanism by which S421 phosphorylation regulates MeCP2 function and show by chromatin immunoprecipitation-sequencing that this modification occurs on MeCP2 bound across the genome. The phosphorylation of MeCP2 S421 appears not to regulate the expression of specific genes; rather, MeCP2 functions as a histone-like factor whose phosphorylation may facilitate a genome-wide response of chromatin to neuronal activity during nervous system development. We propose that RTT results in part from a loss of this experience-dependent chromatin remodeling.

Temporal and Regional Alterations in NMDA Receptor Expression in Mecp2‐Null Mice

Our previous postmortem study of girls with Rett Syndrome (RTT), a development disorder caused by MECP2 mutations, found increases in the density of N-Methyl-D-aspartate (NMDA) receptors in the prefrontal cortex of 2-8-year-old girls, whereas girls older than 10 years had reductions in NMDA receptors compared with age-matched controls (Blue et al., Ann Neurol 1999b;45:541-545). Using [(3)H]-CGP to label NMDA-type glutamate receptors in 2- and 7-week old wild-type (WT), Mecp2-null, and Mecp2-heterozygous (HET) mice (Bird model), we found that frontal areas of the brain also exhibited a bimodal pattern in NMDA expression, with increased densities of NMDA receptors in Mecp2-null mice at 2 weeks of age but decreased densities at 7 weeks of age. Visual cortex showed a similar pattern, while other cortical regions only exhibited changes in NMDA receptor densities at 2 weeks (retrosplenial granular) or 7 weeks (somatosensory). In thalamus of null mice, NMDA receptors were increased at 2 and 7 weeks. No significant differences in density were found between HET and WT mice at both ages. Western blots for NMDAR1 expression in frontal brain showed higher levels of expression in Mecp2-null mice at 2 weeks of age but not at 1 or 7 weeks of age. Our mouse data support the notion that deficient MeCP2 function is the primary cause of the NMDA receptor changes we observed in RTT. Furthermore, the findings of regional and temporal differences in NMDA expression illustrate the importance of age and brain region in evaluating different genotypes of mice.

IPS cells to model CDKL5-related disorders

Rett syndrome (RTT) is a progressive neurologic disorder representing one of the most common causes of mental retardation in females. To date mutations in three genes have been associated with this condition. Classic RTT is caused by mutations in the MECP2 gene, whereas variants can be due to mutations in either MECP2 or FOXG1 or CDKL5. Mutations in CDKL5 have been identified both in females with the early onset seizure variant of RTT and in males with X-linked epileptic encephalopathy. CDKL5 is a kinase protein highly expressed in neurons, but its exact function inside the cell is unknown. To address this issue we established a human cellular model for CDKL5-related disease using the recently developed technology of induced pluripotent stem cells (iPSCs). iPSCs can be expanded indefinitely and differentiated in vitro into many different cell types, including neurons. These features make them the ideal tool to study disease mechanisms directly on the primarily affected neuronal cells. We derived iPSCs from fibroblasts of one female with p.Q347X and one male with p.T288I mutation, affected by early onset seizure variant and X-linked epileptic encephalopathy, respectively. We demonstrated that female CDKL5-mutated iPSCs maintain X-chromosome inactivation and clones express either the mutant CDKL5 allele or the wild-type allele that serve as an ideal experimental control. Array CGH indicates normal isogenic molecular karyotypes without detection of de novo CNVs in the CDKL5-mutated iPSCs. Furthermore, the iPS cells can be differentiated into neurons and are thus suitable to model disease pathogenesis in vitro.

Effects of Creatine Supplementation in Rett Syndrome: A Randomized, Placebo-Controlled Trial

To evaluate the effects of creatine monohydrate (CMH) supplementation on global DNA methylation and disease-specific clinical symptoms in female patients with Rett syndrome (RTT). Double-blind, randomized, placebo-controlled crossover trial of female patients with RTT. Participants received 200 mg/kg of either CMH or placebo daily for 6 months and switched following a 4-week washout period. Primary endpoints were change in global DNA methylation and in a RTT-specific symptom score as defined by medical history and clinical evaluation with Rett Syndrome Motor and Behavioral Assessment. Secondary endpoints were changes in biochemical markers of methionine metabolism. Eighteen female patients aged 3 to 25 years with clinically diagnosed typical RTT and MECP2 mutation at clinical Stages III or IV were studied. CMH supplementation resulted in a statistically significant increase of global methylation by 0.11 (95% confidence interval 0.03-0.19, p = .009) compared with placebo. Total and subscores of Rett Syndrome Motor and Behavioral Assessment tended to improve but without statistical significance. CMH supplementation increases global DNA methylation statistically significantly. Scores were lower for creatine than for placebo reflecting clinical improvement but not reaching statistical significance. Biochemical variables of methionine-homocysteine remethylation are unaffected. Multicenter studies are urgently warranted to evaluate the long-term effects of CMH supplementation in an optimally homogenous RTT population over a prolonged period.

Oxidative stress in Rett syndrome: Natural history, genotype, and variants

ObjectivesRett 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).MethodsRTT 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.ResultsF2-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.DiscussionOS is a key modulator of disease expression in RTT.

Late-onset mental deterioration and fluctuating dystonia in a female patient with a truncating MECP2 mutation

A 26-year-old woman with psychomotor developmental delay since late infancy showed rapid deterioration of her psychomotor abilities at the 11 years of age. She had gained the ability to verbally express herself and perform motor activities such as running and dancing in early childhood, but she lost the ability to verbally communicate and was unable to walk independently after this period. She also presented with dystonia in the right extremities, which markedly fluctuated with a periodicity of hours to months. Sleep disturbance and epileptic seizures also emerged during adolescence. Frontal lobe atrophy and hypoperfusion of the left cerebral hemisphere were noted on neuroimaging examinations. Analysis of the MECP2 gene revealed a late truncating mutation of c.1196_1200delCCACC (p.P399QfsX4) near the 3'-terminal of the coding region. The phenotype of this patient corresponds to the rare, unestablished variant of "late childhood deterioration" in MECP2-related disorders. For the first time, MECP2 mutation was confirmed to be the genetic basis of this condition.