Interrater agreement of classification of photoparoxysmal electroencephalographic response.

Our goal was to assess the interrater agreement (IRA) of photoparoxysmal response (PPR) using the classification proposed by a task force of the International League Against Epilepsy (ILAE), and a simplified classification system proposed by our group. In addition, we evaluated IRA of epileptiform discharges (EDs) and the diagnostic significance of the electroencephalographic (EEG) abnormalities. We used EEG recordings from the European Reference Network (EpiCARE) and Standardized Computer-based Organized Reporting of EEG (SCORE). Six raters independently scored EEG recordings from 30 patients. We calculated the agreement coefficient (AC) for each feature. IRA of PPR using the classification proposed by the ILAE task force was only fair (AC = 0.38). This improved to a moderate agreement by using the simplified classification (AC = 0.56; P = .004). IRA of EDs was almost perfect (AC = 0.98), and IRA of scoring the diagnostic significance was moderate (AC = 0.51). Our results suggest that the simplified classification of the PPR is suitable for implementation in clinical practice.

Developmental loss of MeCP2 from VIP interneurons impairs cortical function and behavior.

Rett Syndrome is a devastating neurodevelopmental disorder resulting from mutations in the gene MECP2. Mutations of Mecp2 that are restricted to GABAergic cell types largely replicate the behavioral phenotypes associated with mouse models of Rett Syndrome, suggesting a pathophysiological role for inhibitory interneurons. Recent work has suggested that vasoactive intestinal peptide-expressing (VIP) interneurons may play a critical role in the proper development and function of cortical circuits, making them a potential key point of vulnerability in neurodevelopmental disorders. However, little is known about the role of VIP interneurons in Rett Syndrome. Here we find that loss of MeCP2 specifically from VIP interneurons replicates key neural and behavioral phenotypes observed following global Mecp2 loss of function.

Sleep-Disordered Breathing in Pediatric Patients With Rett Syndrome.

STUDY OBJECTIVES: Although respiratory abnormalities occurring during wakefulness are well recognized in patients with Rett syndrome (RS), less has been reported regarding sleep-disordered breathing (SDB) in this population. This study aims to characterize the presenting complaints, types and severity of SDB, and treatment modalities of patients with RS and sleep concerns. METHODS: Retrospective chart review of pediatric patients with RS referred to our academic tertiary care institution from January 2007 to July 2017. RESULTS: Thirteen patients were identified, 11 female (84.6%); mean age at polysomnography (PSG) was 10.3 years (standard deviation 4.94). Eleven were white (84.6%), 2 were black (15.4%). The most common presenting symptoms were snoring (10/13, 77%) and witnessed apnea (7/13, 53.8%). On baseline PSG, all patients (100%) exhibited hyperapneas followed by a central apnea during wake. Nine (69.2%) had obstructive sleep apnea (OSA) (obstructive apnea-hypopnea index (oAHI) > 1); four had severe OSA (oAHI ≥ 10). One had central sleep apnea (central apnea index > 5) and severe OSA. No patients exhibited hypoventilation on baseline PSG. Mean AHI of all patients was 8.77 ± 8.82 (oAHI 6.51 ± 6.91) events/h. Mean oxyhemoglobin nadir was 88.52 ± 5.6%. Treatment modalities included observation: 5 (38%), acetazolamide: 2 (15%), nasal mometasone: 1 (7.7%), adenotonsillectomy: 3 (23.1%), and positive airway pressure: 2 (15%). CONCLUSIONS: Regarding patients with RS referred to the sleep medicine clinic, snoring and witnessed apneas were the most common presenting complaints. In addition to breathing abnormalities during wake, OSA was very common in our cohort. Further studies are needed to examine the pathogenesis of OSA in RS and relationships between disease genotype and respiratory abnormality phenotype.

Senescence Phenomena and Metabolic Alteration in Mesenchymal Stromal Cells from a Mouse Model of Rett Syndrome.

Chromatin modifiers play a crucial role in maintaining cell identity through modulation of gene expression patterns. Their deregulation can have profound effects on cell fate and functions. Among epigenetic regulators, the MECP2 protein is particularly attractive. Mutations in the Mecp2 gene are responsible for more than 90% of cases of Rett syndrome (RTT), a progressive neurodevelopmental disorder. As a chromatin modulator, MECP2 can have a key role in the government of stem cell biology. Previously, we showed that deregulated MECP2 expression triggers senescence in mesenchymal stromal cells (MSCs) from (RTT) patients. Over the last few decades, it has emerged that senescent cells show alterations in the metabolic state. Metabolic changes related to stem cell senescence are particularly detrimental, since they contribute to the exhaustion of stem cell compartments, which in turn determine the falling in tissue renewal and functionality. Herein, we dissect the role of impaired MECP2 function in triggering senescence along with other senescence-related aspects, such as metabolism, in MSCs from a mouse model of RTT. We found that MECP2 deficiencies lead to senescence and impaired mitochondrial energy production. Our results support the idea that an alteration in mitochondria metabolic functions could play an important role in the pathogenesis of RTT.

A clinical case-control comparison of epidermal innervation density in Rett syndrome.

INTRODUCTION: Rett syndrome (RTT), a rare neurodevelopmental disorder occurring primarily in females (1:10-15,000 female live births), is most often caused by loss-of-function mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2). Clinical observations and preclinical findings indicate apparent abnormal sensory and nociceptive function. There have been no direct investigations of epidermal sensory innervation in patients with RTT. METHODS: We compared 3 mm epidermal punch biopsy specimens from adolescent female RTT patients (N = 4, aged 12-19 years) against an archived approximate age-, sex-, body-site matched comparison sample of healthy adolescent females (N = 8, ages 11-17). RESULTS: Confocal imaging revealed, on average, statistically significant increased epidermal nerve fiber (ENF) peptidergic (co-stained calcitonin gene-related protein [CGRP]) innervation density compared with healthy female control individuals. CONCLUSIONS: Given the clinical phenotype of disrupted sensory function along with diagnostic criteria specific to cold hands/feet and insensitivity to pain, our preliminary observations of ENF peptidergic fiber density differences warrants further investigation of the peripheral neurobiology in RTT.

Polysomnographic findings in Rett syndrome.

INTRODUCTION: Rett syndrome (RS) is a severe neurodevelopment disorder associated with abnormal breathing during wakefulness and disturbed nocturnal behaviour. Breathing abnormalities during daytime have been extensively reported but polysomnographic (PSG) findings have been poorly studied. MATERIALS AND METHODS: Consecutive patients with RS carrying distinct mutations in MECP2 gene, who underwent a PSG between October 2014 and January 2018, were included in the study. Clinical and PSG data were collected. RESULTS: Seventeen RS girls, mean age 9.5 ± 2.8 years, were included in the study. Mean total sleep time was 366 ± 102 min. Mean sleep efficiency was reduced (66 ± 19%) with only 3 girls presenting a sleep efficiency above 80%. Wake after sleep onset was increased (33 ± 20%) with an arousal index of 7 ± 6 events/hour. Sleep stages were altered with a normal N1 (2 ± 3%), a decreased N2 (34 ± 20%), an increase of N3 (51 ± 23%) and a decrease of REM sleep (12 ± 9%). Mean apnea hypopnea index (AHI) was increased at 19 ± 37 events/hour, with a predominance of obstructive events. Thirteen patients had an AHI > 1.5 event/hour. Four patients had an obstructive AHI >10 events/hour with one patient having associated tonsillar hypertrophy. Two patients had predominant severe central apneas (central AHI 53 and 132 events/hour) which resolved with noninvasive ventilation and nocturnal oxygen therapy respectively. CONCLUSION: Girls with RS have poor sleep quality with alterations in slow wave and REM sleep stages. Obstructive respiratory events are uncommon in patients without adenotonsillar hypertrophy. Central respiratory events are rare. Longitudinal studies should help understanding the natural history of sleep disturbances in RS and their relationship with the neurocognitive decline.

The Way Forward for Mechanism-Based Therapeutics in Genetically Defined Neurodevelopmental Disorders.

Rare genetically defined neurodevelopmental disorders with increased risk of autism have recently become an entry point for autism-related drug discovery. Through exploration of downstream effects of the pathological mutations, specific mechanistic pathways have been identified as dysregulated. The identification of shared mechanisms across forms of autism opens the door for the development of novel "mechanism-based therapeutics." However, confidence in the therapeutic mechanism does not diminish the need for well-designed clinical trials.

MeCP2 isoform e1 mutant mice recapitulate motor and metabolic phenotypes of Rett syndrome.

Mutations in the X-linked gene MECP2 cause the majority of Rett syndrome (RTT) cases. Two differentially spliced isoforms of exons 1 and 2 (MeCP2-e1 and MeCP2-e2) contribute to the diverse functions of MeCP2, but only mutations in exon 1, not exon 2, are observed in RTT. We previously described an isoform-specific MeCP2-e1-deficient male mouse model of a human RTT mutation that lacks MeCP2-e1 while preserving expression of MeCP2-e2. However, RTT patients are heterozygous females that exhibit delayed and progressive symptom onset beginning in late infancy, including neurologic as well as metabolic, immune, respiratory and gastrointestinal phenotypes. Consequently, we conducted a longitudinal assessment of symptom development in MeCP2-e1 mutant females and males. A delayed and progressive onset of motor impairments was observed in both female and male MeCP2-e1 mutant mice, including hind limb clasping and motor deficits in gait and balance. Because these motor impairments were significantly impacted by age-dependent increases in body weight, we also investigated metabolic phenotypes at an early stage of disease progression. Both male and female MeCP2-e1 mutants exhibited significantly increased body fat compared to sex-matched wild-type littermates prior to weight differences. Mecp2e1-/y males exhibited significant metabolic phenotypes of hypoactivity, decreased energy expenditure, increased respiratory exchange ratio, but decreased food intake compared to wild-type. Untargeted analysis of lipid metabolites demonstrated a distinguishable profile in MeCP2-e1 female mutant liver characterized by increased triglycerides. Together, these results demonstrate that MeCP2-e1 mutation in mice of both sexes recapitulates early and progressive metabolic and motor phenotypes of human RTT.

Correcting deregulated Fxyd1 expression rescues deficits in neuronal arborization and potassium homeostasis in MeCP2 deficient male mice.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the MECP2 gene. In the absence of MeCP2, expression of FXYD domain-containing transport regulator 1 (FXYD1) is deregulated in the frontal cortex (FC) of mice and humans. Because Fxyd1 is a membrane protein that controls cell excitability by modulating Na+, K+-ATPase activity (NKA), an excess of Fxyd1 may reduce NKA activity and contribute to the neuronal phenotype of Mecp2 deficient (KO) mice. To determine if Fxyd1 can rescue these RTT deficits, we studied the male progeny of Fxyd1 null males bred to heterozygous Mecp2 female mice. Maximal NKA enzymatic activity was not altered by the loss of MeCP2, but it increased in mice lacking one Fxyd1 allele, suggesting that NKA activity is under Fxyd1 inhibitory control. Deletion of one Fxyd1 allele also prevented the increased extracellular potassium (K+) accumulation observed in cerebro-cortical neurons from Mecp2 KO animals in response to the NKA inhibitor ouabain, and rescued the loss of dendritic arborization observed in FC neurons of Mecp2 KO mice. These effects were gene-dose dependent, because the absence of Fxyd1 failed to rescue the MeCP2-dependent deficits, and mimicked the effect of MeCP2 deficiency in wild-type animals. These results indicate that excess of Fxyd1 in the absence of MeCP2 results in deregulation of endogenous K+ conductances functionally associated with NKA and leads to stunted neuronal growth.

Functional assessment of MeCP2 in Rett syndrome and cancers of breast, colon, and prostate.

Ever since the first report that mutations in methyl-CpG-binding protein 2 (MeCP2) causes Rett syndrome (RTT), a severe neurological disorder in females world-wide, there has been a keen interest to gain a comprehensive understanding of this protein. While the classical model associated with MeCP2 function suggests its role in gene suppression via recruitment of co-repressor complexes and histone deacetylases to methylated CpG-sites, recent discoveries have brought to light its role in transcription activation, modulation of RNA splicing, and chromatin compaction. Various post-translational modifications (PTMs) of MeCP2 further increase its functional versatility. Involvement of MeCP2 in pathologies other than RTT, such as tumorigenesis however, remains poorly explored and understood. This review provides a survey of the literature implicating MeCP2 in breast, colon and prostate cancer.

IGF1 neuronal response in the absence of MECP2 is dependent on TRalpha 3.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder in which the MECP2 (methyl CpG-binding protein 2) gene is mutated. Recent studies showed that RTT-derived neurons have many cellular deficits when compared to control, such as: less synapses, lower dendritic arborization and reduced spine density. Interestingly, treatment of RTT-derived neurons with Insulin-like Growth Factor 1 (IGF1) could rescue some of these cellular phenotypes. Given the critical role of IGF1 during neurodevelopment, the present study used human induced pluripotent stem cells (iPSCs) from RTT and control individuals to investigate the gene expression profile of IGF1 and IGF1R on different developmental stages of differentiation. We found that the thyroid hormone receptor (TRalpha 3) has a differential expression profile. Thyroid hormone is critical for normal brain development. Our results showed that there is a possible link between IGF1/IGF1R and the TRalpha 3 and that over expression of IGF1R in RTT cells may be the cause of neurites improvement in neural RTT-derived neurons.

Bases moleculares del síndrome de Rett, una mirada actual / Molecular basis of Rett syndrome: A current look

El síndrome de Rett (SR) es un trastorno del neurodesarrollo que afecta casi exclusivamente a niñas y cursa secundariamente con autismo. Es poco frecuente y consta de 5 formas clínicas, una clásica y el resto atípicas que comprometen de manera general la habilidad manual, el lenguaje y la motricidad amplia unida a la aparición de estereotipias y epilepsia precoz. Con el objetivo de actualizar la información sobre SR, se aplicaron los descriptores de búsqueda Síndrome de Rett, genes y «Síndrome de Rett¼, «Rett Syndrome gene¼, «Rett Syndrome¼, «Rett Syndrome gene therapy¼ y «Rett Syndrome review¼. Se investigó en los archivos digitales PubMed, Hinari, SCIELO y Medline, y se consultaron los sitios web OMIM, ORPHANET, GeneMap, Genetests, Proteins y Gene, entre otros. Entre 1.348 artículos se seleccionaron 42, los cuales reportan 3 genes causantes del síndrome: MECP2, CDKL5 y FOXG. El gen MECP2 está mutado en el 80% de los pacientes con SR clásico así como en el 40% de los afectados con alguna de sus formas atípicas. El SR con epilepsia precoz y la variante congénita se deben fundamentalmente a variaciones en los genes CDKL5 y FOXG1 respectivamente. Conclusiones: El diagnóstico del SR se basa en criterios clínicos, sin embargo, los avances en la biología molecular y en la genética en particular han abierto el abanico de posibilidades diagnósticas a las diferentes formas clínicas que antes quedaban sin clasificar, a la vez que el análisis molecular permite confirmar el criterio clínico y aportar información en cuanto al pronóstico del paciente.

Rett syndrome (RS) is a neurodevelopmental disorder that exclusively affects girls, and occurs along with autism. It is very uncommon, and has five distinct forms, one classic and the others atypical, which generally compromise manual skills, language, and mobility, and widely associated with the appearance of stereotypy and early epilepsy. With the aim of updating the information about RS, a search was performed in the computer data bases of PubMed, Hinari, SCIELO and Medline, as well as consulting other web sites including OMIM, ORPHANET, GeneMap, Genetests, Proteins and Gene, using the descriptors "Síndrome de Rett", "genes y Síndrome de Rett", "Rett Syndrome gene", "Rett Syndrome", "Rett Syndrome gene therapy", and "Rett Syndrome review". Of the 1,348 articles found, 42 articles were selected, which reported 3 genes causing the syndrome: MECP2, CDKL5 and FOXG. The MECP2 gene is mutated in 80% of patients with classic RS, as well as in 40% of those affected by any of its atypical forms. RS with early epilepsy and the congenital variant are mainly due to variations in the CDKL5 and FOXG1 genes, respectively. Conclusions: The diagnosis of RS is based on clinical criteria. However, the advances in molecular biology and genetics have opened a wide range of possibilities for diagnosing the different clinical forms that could not be classified before. Molecular analysis can help confirm the clinical criteria and provided information as regards the prognosis of the patient.

The eye-tracking of social stimuli in patients with Rett syndrome and autism spectrum disorders: a pilot study / Rastreamento do olhar para estímulos sociais em pacientes com síndrome de Rett e transtornos do espectro do autismo: estudo piloto

Objective To compare visual fixation at social stimuli in Rett syndrome (RT) and autism spectrum disorders (ASD) patients. Method Visual fixation at social stimuli was analyzed in 14 RS female patients (age range 4-30 years), 11 ASD male patients (age range 4-20 years), and 17 children with typical development (TD). Patients were exposed to three different pictures (two of human faces and one with social and non-social stimuli) presented for 8 seconds each on the screen of a computer attached to an eye-tracker equipment. Results Percentage of visual fixation at social stimuli was significantly higher in the RS group compared to ASD and even to TD groups. Conclusion Visual fixation at social stimuli seems to be one more endophenotype making RS to be very different from ASD. .

Objetivo Comparar a fixação visual em estímulos sociais em pacientes com síndrome de Rett (SR) e com transtornos do espectro do autismo (TEA). Método Fixação visual em estímulos sociais foi analisada em 14 pacientes do sexo feminino com SR (idades entre 4 e 30 anos), 11 pacientes do sexo masculino com TEA (idades entre 4 e 20 anos), e 17 crianças do sexo feminino com desenvolvimento típico (DT). Os participantes foram expostos a três figuras diferentes (duas figuras de faces humanas e uma figura contendo estímulo social e não social) apresentadas por 8 segundos cada uma no monitor de um computador acoplado a um equipamento de rastreamento de olhar. Resultados A porcentagem de fixação visual em estímulos sociais foi significativamente maior no grupo SR do que no grupo TEA e mesmo no grupo DT. Conclusão A fixação visual em estímulos sociais parece ser mais um dos endofenótipos que esclarecem as diferenças entre SR e TEA. .

Impacto da ativação da intenção na prática da atividade física em diabéticos tipo II: ensaio clínico randomizado / Impact of the activation of intention to perform physical activity in type II diabetics: a randomized clinical trial

O diabetes mellitus, tipo II, é uma doença com alta prevalência na população adulta brasileira e que pode ser controlada, dentre outras intervenções, por meio da atividade física. Este estudo teve como objetivo avaliar o impacto de uma estratégia motivacional tradicional, bem como sua associação à estratégia de ativação da intenção, na adesão à atividade física, nos portadores do diabetes mellitus, tipo II, usuários do Sistema Único de Saúde (SUS), por meio de um ensaio clínico randomizado. Os participantes foram alocados em Grupo Controle (GC) e Grupo Intervenção (GI). Ambos os grupos receberam uma estratégia motivacional tradicional, porém, somente o GI recebeu a estratégia de ativação da intenção. Após dois meses de seguimento, observaram-se diferenças estatisticamente significativas entre os grupos, relativas à prática de caminhada (p = 0,0050), número de dias por semana (p = 0,0076), minutos por dia (p = 0,0050) e minutos por semana (p = 0,0015) de caminhada. Ao final das intervenções, observaram-se, também, diferenças na circunferência abdominal (p = 0,0048) entre os grupos. Conclui-se que a estratégia de ativação da intenção teve maior impacto na adesão à prática de atividade física e diminuição da circunferência abdominal de diabéticos, tipo II, do que a estratégia motivacional tradicional.

Type II diabetes mellitus is a highly prevalent disease among the adult Brazilian population, and one that can be controlled by interventions such as physical activity, among others. The aim of this randomized controlled study was to evaluate the impact of a traditional motivational strategy, associated with the activation of intention theory, on adherence to physical activity in patients with type II, diabetes mellitus who are part of the Unified Health System (SUS). Participants were divided into a control group (CG) and an intervention group (IG). In both groups, the traditional motivational strategy was applied, but the activation of intention strategy was only applied to the IG Group. After a two-month follow-up, statistically significant differences were verified between the groups, related to the practice of walking (p = 0.0050), number of days per week (p = 0.0076), minutes per day (p = 0.0050) and minutes walking per week (p = 0.0015). At the end of the intervention, statistically significant differences in abdominal circumference (p = 0.0048) between the groups were observed. The conclusion drawn is that the activation of intention strategy had greater impact on adherence to physical activity and reduction in abdominal circumference in type II diabetics, than traditional motivational strategy.

Rett-like onset in late-infantile neuronal ceroid lipofuscinosis (CLN7) caused by compound heterozygous mutation in the MFSD8 gene and review of the literature data on clinical onset signs.

BACKGROUND: We present clinical and molecular findings of a patient with ceroid-lipofuscinosis CLN7, with a compound heterozygous mutation of the MFSD8 gene, with Rett syndrome clinical signs onset and a later development of full picture of vLINCL. CASE PRESENTATION: A 7 years-old female patient with normal development until the age 12 months, developed Rett like clinical picture (psychomotor regression, microcephaly, stereotypic hands movements in the midline, hyperventilation episodes) present at the onset of her condition (age 18 months), features still present at the initial evaluation in our clinic at age 5 years. RESULTS: MECP2 (methyl CpG binding protein 2) gene mutation was negative. At age 6 years she was readmitted for severe ataxia and blindness, seizures, and severe developmental regression leading to NCL (neuronal ceroid lipofuscinosis) suspicion. EEG showed slow background with IRDA (intermittent rhythmic delta activity). A conjunctive biopsy showed abnormal curvilinear and fingerprint lysosomal deposits, and genetic analysis revealed two heterozygous mutations of MFSD8 gene (c.881C > A p.Thr294Lys and c.754 + 2T > A) each inherited from carrier parents and a heterozygous variant (c.470A>C p.Asp157Ala) of CLN5 gene. CONCLUSION: NCL should be suspected and MFSD8 genetic testing should also be considered in patients with Rett like phenotype at onset and negative MECP2 mutation. Such cases should be carefully and frequently re-evaluated in order to avoid delayed diagnosis and offer proper genetic advice to the family. In our knowledge, this might be the first case of CLN7 disease with Rett like onset described in the literature, which developed typical vLINCL clinical phenotype after age 5.5 years. A short review of the literature showing NCL onset modalities is presented.

Anaplerotic triheptanoin diet enhances mitochondrial substrate use to remodel the metabolome and improve lifespan, motor function, and sociability in MeCP2-null mice.

Rett syndrome (RTT) is an autism spectrum disorder (ASD) caused by mutations in the X-linked MECP2 gene that encodes methyl-CpG binding protein 2 (MeCP2). Symptoms range in severity and include psychomotor disabilities, seizures, ataxia, and intellectual disability. Symptom onset is between 6-18 months of age, a critical period of brain development that is highly energy-dependent. Notably, patients with RTT have evidence of mitochondrial dysfunction, as well as abnormal levels of the adipokines leptin and adiponectin, suggesting overall metabolic imbalance. We hypothesized that one contributor to RTT symptoms is energy deficiency due to defective nutrient substrate utilization by the TCA cycle. This energy deficit would lead to a metabolic imbalance, but would be treatable by providing anaplerotic substrates to the TCA cycle to enhance energy production. We show that dietary therapy with triheptanoin significantly increased longevity and improved motor function and social interaction in male mice hemizygous for Mecp2 knockout. Anaplerotic therapy in Mecp2 knockout mice also improved indicators of impaired substrate utilization, decreased adiposity, increased glucose tolerance and insulin sensitivity, decreased serum leptin and insulin, and improved mitochondrial morphology in skeletal muscle. Untargeted metabolomics of liver and skeletal muscle revealed increases in levels of TCA cycle intermediates with triheptanoin diet, as well as normalizations of glucose and fatty acid biochemical pathways consistent with the improved metabolic phenotype in Mecp2 knockout mice on triheptanoin. These results suggest that an approach using dietary supplementation with anaplerotic substrate is effective in improving symptoms and metabolic health in RTT.

Low bone mineral mass is associated with decreased bone formation and diet in girls with Rett syndrome.

OBJECTIVE: The aim of the present study was to characterize biomarkers of bone turnover and their relation with bone mineral mass in a cross-sectional cohort of girls with Rett syndrome (RTT) and to examine the role of dietary, biochemical, hormonal, and inflammatory factors on bone mineral mass and bone biomarkers in this disorder. METHODS: Total body bone mineral content (BMC) and bone mineral density (BMD) were determined by dual-energy x-ray absorptiometry. Dietary nutrient intakes were determined from 3-day food records. Biomarkers of bone turnover, bone metabolites, vitamin D metabolites, hormones, and inflammatory markers were measured by standard clinical laboratory methods. RESULTS: Serum osteocalcin, bone alkaline phosphatase, and C-telopeptide showed significant inverse relations with age in the RTT cohort. Mean osteocalcin concentrations were significantly lower and mean bone alkaline phosphatase concentrations were significantly higher for individual age groups in the RTT cohort than mean values for their respective age ranges in the reference population. Significant inverse associations were identified between urinary calcium losses, expressed as calcium:creatinine ratios, and total body BMC and BMD z scores. Dietary protein, calcium, and phosphorus intakes, expressed as a proportion of Dietary Reference Intakes for age and sex, showed significant positive associations with total body BMD z scores. CONCLUSIONS: The present study suggests decreased bone formation instead of increased bone resorption may explain in part the deficits in bone mineral mass in RTT and that attention to the adequacy of dietary protein, calcium, and phosphorus intakes may offer an opportunity to improve bone health in RTT.

Twenty years of surveillance in Rett syndrome: what does this tell us?

BACKGROUND: The clinical characteristics of children diagnosed with Rett syndrome are well described. Survival and how these characteristics persist or change in adulthood are less well documented. This study aimed to describe overall survival and adult health in those with Rett syndrome. METHODS: Using the Kaplan-Meier method, we estimated survival of individuals registered with the Australian Rett syndrome Database (ARSD) who had been followed for up to 20 years (n = 396). We then conducted logistic and linear regression analyses investigating epilepsy, musculoskeletal, gastrointestinal, autonomic dysfunction and behaviour of individuals aged 18 years and over using cross sectional cohorts from the ARSD (n = 150) and the international database InterRett (n = 273). RESULTS: The likelihood of survival was 77.6% at 20 years, 71.5% at 25 years and 59.8% at 37 years. The median age of the combined cross-sectional cohort was 25 years (range 18 to 54 years), the majority (71%) were living in their parental home and the remainder being cared for in group homes or other institutions. Just over half walked either independently (18%) or with assistance (43%). The majority (86%) had scoliosis with 40% of those having undergone corrective surgery. Almost two-thirds (64%) of the women were taking anti-epileptic medications at the time of data collection. Constipation was highly prevalent (83%) and many experienced bloating (53%). Biliary dyskinesia, inflammation or infection of the gallbladder was reported for 20 women (5%) and of those 13 had undergone gallbladder surgery. Sleep disturbance was relatively common (63%), and adverse mood events and anxiety were slightly more prevalent in those aged 26-30 years in comparison to the younger and older age groups. Other frequently reported medical conditions included urinary tract infections, pneumonia and other respiratory conditions. CONCLUSIONS: Survival in Rett syndrome has now been estimated with the most accurate follow up to date. During adulthood, continuation of multidisciplinary services and programs is necessary to optimise health and wellbeing.

Inflammatory lung disease in Rett syndrome.

Rett syndrome (RTT) is a pervasive neurodevelopmental disorder mainly linked to mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2). Respiratory dysfunction, historically credited to brainstem immaturity, represents a major challenge in RTT. Our aim was to characterize the relationships between pulmonary gas exchange abnormality (GEA), upper airway obstruction, and redox status in patients with typical RTT (n = 228) and to examine lung histology in a Mecp2-null mouse model of the disease. GEA was detectable in ~80% (184/228) of patients versus ~18% of healthy controls, with "high" (39.8%) and "low" (34.8%) patterns dominating over "mixed" (19.6%) and "simple mismatch" (5.9%) types. Increased plasma levels of non-protein-bound iron (NPBI), F2-isoprostanes (F2-IsoPs), intraerythrocyte NPBI (IE-NPBI), and reduced and oxidized glutathione (i.e., GSH and GSSG) were evidenced in RTT with consequently decreased GSH/GSSG ratios. Apnea frequency/severity was positively correlated with IE-NPBI, F2-IsoPs, and GSSG and negatively with GSH/GSSG ratio. A diffuse inflammatory infiltrate of the terminal bronchioles and alveoli was evidenced in half of the examined Mecp2-mutant mice, well fitting with the radiological findings previously observed in RTT patients. Our findings indicate that GEA is a key feature of RTT and that terminal bronchioles are a likely major target of the disease.