RESUMO
BACKGROUND: Rett syndrome is a progressive neurological disorder associated to several comorbidities that contribute significantly to impair lung function. Respiratory morbidity represents a major cause of death in this population. Little is known about the benefit of noninvasive ventilation. METHODS: We retrospectively enrolled patients with Rett syndrome who underwent a pneumological evaluation combined with a cardiorespiratory polygraphy and/or a pulse oximetry and capnography from 2012 to 2022. RESULTS: Medical records of 11 patients with Rett syndrome, mean age 13 ± 6 years, were evaluated. Most patients presented with both epilepsy and scoliosis. Five patients showed a pathologic sleep study and/or impaired night gas exchange: mean obstructive apnea-hypopnea index was 4 ± 3 events/hour; mean and minimal SpO2 were, respectively, 93% ± 2% and 83% ± 6%, while mean and maximal transcutaneous carbon dioxide monitoring (PtcCO2) were, respectively, 51 ± 5 mm Hg and 55 ± 8 mm Hg; and mean oxygen desaturation index was 13 ± 11 events/hour. These patients started noninvasive ventilation with clinical benefit and improved gas exchange mostly in terms of PtcCO2 (mean PtcCO2 51 ± 5 mm Hg before and 46 ± 6 mm Hg after noninvasive ventilation). CONCLUSIONS: Noninvasive ventilation is a suitable option for patients with Rett syndrome.
Assuntos
Hipoventilação , Ventilação não Invasiva , Síndrome de Rett , Humanos , Síndrome de Rett/complicações , Síndrome de Rett/terapia , Síndrome de Rett/fisiopatologia , Feminino , Hipoventilação/terapia , Hipoventilação/etiologia , Estudos Retrospectivos , Adolescente , Criança , Adulto Jovem , Oximetria , Pré-Escolar , Polissonografia , Resultado do TratamentoRESUMO
STUDY DESIGN: Retrospective database cohort study. OBJECTIVE: To evaluate U.S. treatment trends and inpatient outcomes for children undergoing posterior spinal fusion (PSF) for Rett syndrome (RTT)-associated scoliosis (RAS). SUMMARY OF BACKGROUND DATA: RTT is a rare, sporadic neurodevelopmental disorder presenting in childhood with developmental regression, ataxia, and seizures. RAS occurs in 50% to 80% of cases of RTT, but little is known about the case volume and perioperative experience for children undergoing PSF. MATERIALS AND METHODS: Using the International Classification of Diseases Ninth and 10th revision codes in the national Kids' Inpatient Database, we identified children with RTT who underwent PSF from 2000 to 2019. Annual case volumes were analyzed. Clinical characteristics and outcomes were compared with those of a cohort of patients with neuromuscular scoliosis (NMS). RESULTS: Among 220 patients with RAS, 216 (98.2%) were females (mean age at surgery: 12.3±3.3 yr). Surgical case incidence steadily increased over 19 years, with more RAS admissions in the South (31.4%). Overall, patients with RAS demonstrated a higher mean Elixhauser Comorbidity Index score (2 vs . 1, P < 0.001) and had more perioperative complications (41.4% vs . 18%, P < 0.001) than patients with NMS. RTT diagnosis independently predicted higher odds of any complications (odds ratio: 1.98, P < 0.001) and increased length of stay (odds ratio: 1.18, P = 0.009) for admissions for PSF. CONCLUSIONS: Surgical treatment for RAS is rare but increased over a 19-year period. Cases appear to be clustering by region, with the highest proportion in the South. The higher Elixhauser Comorbidity Index in RAS patients predicted higher costs, longer hospital stays, more complications (particularly respiratory), and more nonroutine discharge disposition than in other patients with NMS. RTT was independently associated with higher odds of complications and longer length of stay. Because RAS cases appear to be increasing in number, future studies should emphasize methods to reduce morbidity and investigate deformity-specific metrics to help better understand this population.
Assuntos
Síndrome de Rett , Escoliose , Fusão Vertebral , Criança , Feminino , Humanos , Masculino , Escoliose/epidemiologia , Escoliose/cirurgia , Escoliose/complicações , Síndrome de Rett/complicações , Síndrome de Rett/epidemiologia , Síndrome de Rett/cirurgia , Estudos de Coortes , Estudos Retrospectivos , Tempo de Internação , Fusão Vertebral/métodos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Resultado do TratamentoRESUMO
BACKGROUND: Identification of genetic causes of central precocious puberty have revealed epigenetic mechanisms as regulators of human pubertal timing. MECP2, an X-linked gene, encodes a chromatin-associated protein with a role in gene transcription. MECP2 loss-of-function mutations usually cause Rett syndrome, a severe neurodevelopmental disorder. Early pubertal development has been shown in several patients with Rett syndrome. The aim of this study was to explore whether MECP2 variants are associated with an idiopathic central precocious puberty phenotype. METHODS: In this translational cohort study, participants were recruited from seven tertiary centres from five countries (Brazil, Spain, France, the USA, and the UK). Patients with idiopathic central precocious puberty were investigated for rare potentially damaging variants in the MECP2 gene, to assess whether MECP2 might contribute to the cause of central precocious puberty. Inclusion criteria were the development of progressive pubertal signs (Tanner stage 2) before the age of 8 years in girls and 9 years in boys and basal or GnRH-stimulated LH pubertal concentrations. Exclusion criteria were the diagnosis of peripheral precocious puberty and the presence of any recognised cause of central precocious puberty (CNS lesions, known monogenic causes, genetic syndromes, or early exposure to sex steroids). All patients included were followed up at the outpatient clinics of participating academic centres. We used high-throughput sequencing in 133 patients and Sanger sequencing of MECP2 in an additional 271 patients. Hypothalamic expression of Mecp2 and colocalisation with GnRH neurons were determined in mice to show expression of Mecp2 in key nuclei related to pubertal timing regulation. FINDINGS: Between Jun 15, 2020, and Jun 15, 2022, 404 patients with idiopathic central precocious puberty (383 [95%] girls and 21 [5%] boys; 261 [65%] sporadic cases and 143 [35%] familial cases from 134 unrelated families) were enrolled and assessed. We identified three rare heterozygous likely damaging coding variants in MECP2 in five girls: a de novo missense variant (Arg97Cys) in two monozygotic twin sisters with central precocious puberty and microcephaly; a de novo missense variant (Ser176Arg) in one girl with sporadic central precocious puberty, obesity, and autism; and an insertion (Ala6_Ala8dup) in two unrelated girls with sporadic central precocious puberty. Additionally, we identified one rare heterozygous 3'UTR MECP2 insertion (36_37insT) in two unrelated girls with sporadic central precocious puberty. None of them manifested Rett syndrome. Mecp2 protein colocalised with GnRH expression in hypothalamic nuclei responsible for GnRH regulation in mice. INTERPRETATION: We identified rare MECP2 variants in girls with central precocious puberty, with or without mild neurodevelopmental abnormalities. MECP2 might have a role in the hypothalamic control of human pubertal timing, adding to the evidence of involvement of epigenetic and genetic mechanisms in this crucial biological process. FUNDING: Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico, and the Wellcome Trust.
Assuntos
Puberdade Precoce , Síndrome de Rett , Animais , Criança , Feminino , Humanos , Masculino , Camundongos , Brasil , Estudos de Coortes , Hormônio Foliculoestimulante , Hormônio Liberador de Gonadotropina , Hormônio Luteinizante/metabolismo , Puberdade Precoce/genética , Puberdade Precoce/diagnóstico , Síndrome de Rett/genética , Síndrome de Rett/complicaçõesRESUMO
Genital warts (GWs) are the most common sexually transmitted infections worldwide, caused by the human papillomavirus (HPV). The increasing prevalence of GWs in children has renewed the interest in therapeutic management which still presents a unique challenge, being influenced by many variables including size, quantity, and location of warts, as well as the presence of comorbidities. Conventional photodynamic therapy (C-PDT) has already shown encouraging results in the treatment of viral warts in adult patients, but its use is still not standardized in the pediatric population. On this topic, we report our experience with C-PDT in a difficult-to-treat area like the perianal region in a 12-year-old girl affected by Rett syndrome, an X-linked dominant neurological disorder, with a 10-month history of florid genital condylomatosis. After the third session of C-PDT, complete clearance of the lesions was achieved. Our case is paradigmatic of the potentiality of PDT to treat difficult lesions in difficult patients. Despite being expensive and time-consuming, this procedure has been demonstrated to be safe and well-tolerated. Lastly, the therapy is also well accepted by parents, due to its minimal invasiveness and the few side effects, compared to the other therapeutic options.
Assuntos
Condiloma Acuminado , Infecções por Papillomavirus , Fotoquimioterapia , Síndrome de Rett , Verrugas , Adulto , Feminino , Humanos , Criança , Síndrome de Rett/complicações , Síndrome de Rett/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Fotoquimioterapia/métodos , Verrugas/tratamento farmacológico , Condiloma Acuminado/tratamento farmacológico , Infecções por Papillomavirus/tratamento farmacológicoRESUMO
BACKGROUND: Neuromuscular scoliosis in Rett syndrome (RS) is common, progressive, and often requires posterior spinal fusion (PSF). While PSF is associated with improved overall outcomes, there is a paucity of information describing complications. We aimed to report the postoperative complications, readmissions, and reoperations for patients with RS undergoing PSF. METHODS: Female pediatric patients with RS treated by PSF with segmental instrumentation, with or without concurrent pelvis fixation, during January 2012 to August 2022 were included. Preoperative patient characteristics, intraoperative data (estimated blood loss, cell saver, packed red blood cells transfused), postoperative complications according to the Modified Clavien-Dindo-Sink classification within 90 days, unplanned readmissions within 30 days, and unplanned reoperations within 90 days were recorded. RESULTS: A total of 25 females were included. The mean (SD) age at surgery was 12.9 (1.8) years and the mean follow-up of 38.6 (24.9) months. The mean preoperative major coronal curve was 79 degrees (23 degrees) which decreased to 32 degrees (15 degrees) by the last follow-up ( P <0.001). The median estimated blood loss was 600 mL and length of stay was 7 days. There were 81 total postoperative complications (3.2 complications/patient). Eight (32%) had grade IVa complications (disseminated intravascular coagulopathy, hypotensive shock, respiratory failure, chronic urosepsis). Five (20%) patients experienced seizures, 48% had pulmonary complications, and 56% had gastrointestinal complications. There were 3 readmissions (12%) within 30 days for pneumonia and 2 (8%) reoperations (an incision and drainage and C2-T2 fusion for significant kyphosis) within 90 days. One patient also had their fusion extended to the pelvis 1 year later. There were more nonambulatory patients in the group fused to the pelvis, but otherwise no differences between those fused and unfused to the pelvis. CONCLUSIONS: This is the largest review of early postoperative complications for patients with RS who underwent PSF. PSF effectively reduced the major coronal curve, but surgeons and families should be aware of a high postoperative seizure and respiratory complication rate, as well as 8% having reoperations within 90 days and 12% being readmitted within 30 days. LEVEL OF EVIDENCE: Level IV-therapeutic study.
Assuntos
Síndrome de Rett , Escoliose , Fusão Vertebral , Humanos , Feminino , Criança , Síndrome de Rett/complicações , Síndrome de Rett/cirurgia , Fusão Vertebral/efeitos adversos , Estudos Retrospectivos , Escoliose/etiologia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Resultado do TratamentoRESUMO
STUDY DESIGN: This was a retrospective case series. OBJECTIVE: The objective of this study was to discuss the treatment challenges in scoliosis patients with Rett syndrome (RTT) in a national referral centre for RTT. We describe structural characteristics of curves, age of onset, genetic mutation, ambulation status, and treatment through RTT progression. Based on this unique experience, we aimed to suggest guidelines for scoliosis treatment in RTT patients. SUMMARY OF BACKGROUND DATA: RTT is a neurodevelopmental disorder associated with a mutation in the methyl-CpG binding protein 2 (MECP2) gene, primarily in females with significant features of growth failure, gastrointestinal and pulmonary dysfunction, ataxia, seizures, and intellectual disability. Scoliosis is the most common orthopedic manifestation of RTT and is present in 64%-75% of patients. No clear guidelines for scoliosis treatment in RTT are available, and typically patients are treated according to guidelines of another neuromuscular scoliosis. METHODS: Clinical and radiographic data were gathered, including MECP2 mutation type, scoliosis characteristics, preoperative treatment, surgical treatment, functional status, and postoperative follow-up. RESULTS: Our cohort included 102 patients with RTT. They were 36 who presented with scoliosis; 18 were treated surgically. C-curve was found in 17 patients and S-type in 19. Scoliosis treatment onset was 8.76 years in the C-type group and 13.88 years in the S-type group. The average curve at the time of surgery was 52.42 degrees. The average time until surgery was 2.44 years. Seventeen patients underwent posterior spinal fusion, and 1 patient underwent posterior spinal fusion+anterior spinal fusion with an average correction of 40 degrees. The most common mutation was R255X nucleotide (30% of cases). The most severe curves had mutations R168X and R270X nucleotides. CONCLUSIONS: We advise early monitoring for patients with RTT and scoliosis due to early and rapid progression. Common mutations found were R255X, R168X, R270X, and T158M. We recommend surgical treatment in every curve above 45 degrees, independently of age.
Assuntos
Síndrome de Rett , Escoliose , Feminino , Humanos , Síndrome de Rett/complicações , Síndrome de Rett/genética , Escoliose/complicações , Escoliose/diagnóstico por imagem , Escoliose/genética , Estudos Retrospectivos , MutaçãoRESUMO
Rett syndrome is an X-linked dominant disorder, and the typical phenotype includes intractable epileptic seizures and severe mental retardation, in particular, a rapid regression in language and limited progress in psychomotor development. Premature breast and pubic hair development and advanced bone age are signs of precocious puberty (PP), defined as puberty occurring before 8 years of age in girls. There are rare reports about precious puberty associated with Rett syndrome. Herein, we report the case of a patient with Rett syndrome with precocious puberty. Her first signs of PP occurred 6 months prior to presentation (at 7.5 years old), and the laboratory measurements, including tests of bone age and gonadotropin-releasing hormone stimulation, were positive for PP. PP was controlled after treatment with leuprorelin 3.75 mg for one year. In addition, the genetic and phenotypic spectrum of previously reported cases of Rett syndrome with precocious puberty are reviewed and summarized.
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Puberdade Precoce , Síndrome de Rett , Feminino , Hormônio Liberador de Gonadotropina , Humanos , Puberdade Precoce/diagnóstico , Puberdade Precoce/genética , Síndrome de Rett/complicaçõesRESUMO
Rett syndrome (RTT) is a progressive neurological disorder, affecting females with mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2). While MECP2 has been implicated in cancers of the breast, colon, and prostrate, cancer in patients with RTT is rare. We present a case of malignant melanoma in a patient with RTT, which additionally, displayed hitherto undescribed nuclear features, resembling herpes simplex virus cytopathic effects.
Assuntos
Efeito Citopatogênico Viral/genética , Melanoma/patologia , Síndrome de Rett/patologia , Simplexvirus/metabolismo , Neoplasias Cutâneas/patologia , Adulto , Progressão da Doença , Feminino , Humanos , Melanoma/diagnóstico , Melanoma/metabolismo , Melanoma/cirurgia , Proteína 2 de Ligação a Metil-CpG/genética , Mutação , Síndrome de Rett/complicações , Síndrome de Rett/genética , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/cirurgia , Melanoma Maligno CutâneoRESUMO
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.
Assuntos
Síndrome de Rett/complicações , Síndromes da Apneia do Sono/complicações , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Polissonografia , Estudos Retrospectivos , Síndrome de Rett/fisiopatologia , Índice de Gravidade de Doença , Síndromes da Apneia do Sono/diagnóstico , Síndromes da Apneia do Sono/fisiopatologia , Síndromes da Apneia do Sono/terapiaRESUMO
STUDY DESIGN: Retrospective cohort. OBJECTIVE: To determine how respiratory failure rates and duration of intensive care unit (ICU) stay after posterior spinal fusion (PSF) for neuromuscular scoliosis compare between children with Rett syndrome (RS) versus cerebral palsy (CP). SUMMARY OF BACKGROUND DATA: Rett syndrome and CP are associated with high incidence of neuromuscular scoliosis and respiratory dysfunction. METHODS: We included 21 patients with RS (mean age, 13â±â3.1 yrs) and 124 with CP (mean age, 14â±â3.2 yrs) who underwent PSF by one surgeon from 2004 to 2017. Preoperative motor function was assessed using the Gross Motor Function Classification System (GMFCS). Primary outcomes were respiratory failure and duration of ICU stay. Secondary outcomes were pneumonia and prolonged use of positive pressure ventilation (PPV). Using multivariate regression, we identified associations of age, intraoperative vital signs, duration of hospital stay, number of vertebral levels fused, anesthesia and surgery durations, and estimated blood loss with longer ICU stay and respiratory failure. RESULTS: A greater proportion of CP patients (96%) than RS patients (66%) were in GMFCS IV or V (Pâ<â0.01). Respiratory failure was more common in RS patients (43% vs. 19%; Pâ=â0.02), as was PPV (67% vs. 31%; Pâ<â0.01). RS patients had shorter median durations of anesthesia and surgery (Pâ<â0.01). RS patients had a longer median (interquartile range) ICU stay (4 days [1-5] vs. 2 days [2-19]; Pâ=â0.01). Incidence of pneumonia did not differ between groups (Pâ=â0.69). Only RS diagnosis (Pâ=â0.02) and prolonged PPV (Pâ<â0.01) were associated with longer ICU stay. CONCLUSION: Despite better preoperative motor function and shorter anesthesia and surgery durations, patients with RS experienced more respiratory failure, prolonged PPV use, and longer ICU stays after PSF than did children with CP. LEVEL OF EVIDENCE: 4.
Assuntos
Paralisia Cerebral , Pneumonia , Complicações Pós-Operatórias/epidemiologia , Síndrome de Rett , Escoliose , Fusão Vertebral , Adolescente , Paralisia Cerebral/complicações , Paralisia Cerebral/epidemiologia , Criança , Humanos , Pneumonia/epidemiologia , Pneumonia/etiologia , Estudos Retrospectivos , Síndrome de Rett/complicações , Síndrome de Rett/epidemiologia , Escoliose/complicações , Escoliose/epidemiologia , Escoliose/cirurgia , Fusão Vertebral/efeitos adversos , Fusão Vertebral/estatística & dados numéricosRESUMO
OBJECTIVE: We reviewed medical records and conducted a nationwide survey to characterize the clinical features and determine the prevalence of biliary tract disease in girls and women with Rett syndrome (RTT). METHODS: Sixty-two individuals with RTT and biliary tract disease were identified from the membership of Rett Syndrome Organization and patient files of the principal investigator. Medical records of 46 individuals were reviewed for presenting features, diagnostic tests, and treatment outcomes of biliary tract disease. We designed a questionnaire that probed the frequency of risk factors and treatment outcomes of biliary tract disease in RTT. The questionnaire was completed by 271 parents whose daughters met the clinical criteria for RTT and/or had MECP2 mutations and participated in the Natural History of Rett Syndrome Study. RESULTS: Presenting symptoms identified by record review included abdominal pain (94%), irritability (88%), weight loss (64%), and vomiting (52%). Biliary dyskinesia, cholecystitis, and cholelithiasis were identified in 90%, 77%, and 70%, respectively, by cholescintigraphy, surgical pathology, and abdominal ultrasound. The prevalence of biliary tract disease was 4.4% (nâ=â12) in the RTT cohort. Risk factors included older age (Pâ<â0.001) and a positive family history (Pâ<â0.01). Diagnoses included cholecystitis (nâ=â5), biliary dyskinesia (nâ=â6), and cholelithiasis (nâ=â7). Ten individuals underwent surgery; 7 had resolution of symptoms after surgical intervention. CONCLUSIONS: Biliary tract disease is not unique to RTT, but may be under-recognized because of the cognitive impairment of affected individuals. Early diagnostic evaluation and intervention may improve the health and quality of life of individuals affected with RTT and biliary tract disease.
Assuntos
Doenças Biliares/epidemiologia , Síndrome de Rett/complicações , Adolescente , Doenças Biliares/genética , Criança , Feminino , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Mutação , Prevalência , Estudos Prospectivos , Estudos Retrospectivos , Síndrome de Rett/genética , Fatores de Risco , Inquéritos e Questionários , Adulto JovemRESUMO
Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutation of the methyl-CpG-binding protein 2 (MECP2) gene. Although RTT has been associated with obesity, the underlying mechanism has not yet been elucidated. In this study, female heterozygous Mecp2-null mice (Mecp2+/- mice), a model of RTT, were fed a normal chow diet or high-fat diet (HFD), and the changes in molecular signaling pathways were investigated. Specifically, we examined the expression of genes related to the hypothalamus and dopamine reward circuitry, which represent a central network of feeding behavior control. In particular, dopamine reward circuitry has been shown to regulate hedonic feeding behavior, and its disruption is associated with HFD-related changes in palatability. The Mecp2+/- mice that were fed the normal chow showed normal body weight and food consumption, whereas those fed the HFD showed extreme obesity with hyperphagia, an increase of body fat mass, glucose intolerance, and insulin resistance compared with wild-type mice fed the HFD (WT-HFD mice). The main cause of obesity in Mecp2+/--HFD mice was a remarkable increase in calorie intake, with no difference in oxygen consumption or locomotor activity. Agouti-related peptide mRNA and protein levels were increased, whereas proopiomelanocortin mRNA and protein levels were reduced in Mecp2+/--HFD mice with hyperleptinemia, which play an essential role in appetite and satiety in the hypothalamus. The conditioned place preference test revealed that Mecp2+/- mice preferred the HFD. Tyrosine hydroxylase and dopamine transporter mRNA levels in the ventral tegmental area, and dopamine receptor and dopamine- and cAMP-regulated phosphoprotein mRNA levels in the nucleus accumbens were significantly lower in Mecp2+/--HFD mice than those of WT-HFD mice. Thus, HFD feeding induced dysregulation of food intake in the hypothalamus and dopamine reward circuitry, and accelerated the development of extreme obesity associated with addiction-like eating behavior in Mecp2+/- mice.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Hiperfagia/etiologia , Proteína 2 de Ligação a Metil-CpG/genética , Obesidade/etiologia , Síndrome de Rett/complicações , Animais , Apetite/fisiologia , Modelos Animais de Doenças , Dopamina/metabolismo , Comportamento Alimentar/fisiologia , Feminino , Heterozigoto , Humanos , Hiperfagia/diagnóstico , Hiperfagia/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/diagnóstico , Obesidade/fisiopatologia , Síndrome de Rett/genética , Recompensa , Índice de Gravidade de Doença , Fatores de Tempo , Área Tegmentar Ventral/metabolismo , Área Tegmentar Ventral/fisiopatologiaRESUMO
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.
Assuntos
Síndrome de Rett/complicações , Transtornos do Sono-Vigília/etiologia , Criança , Feminino , Humanos , Estudos Longitudinais , Polissonografia , Síndrome de Rett/fisiopatologia , Transtornos do Sono-Vigília/fisiopatologiaRESUMO
Rett syndrome is a neurodevelopmental disorder affecting the nervous, musculoskeletal and gastroenteric systems. Affected individuals show normal neonatal development for 6-18â¯months followed by sudden growth arrest, psychomotor retardation and a broad spectrum of clinical features. Sequence variants in MECP2 gene have been identified as the major genetic etiology accounting for 90-95% of patients. Apart from MECP2, pathogenic sequence variants and copy number variants of FOXG1 gene lead to congenital type of Rett syndrome which is a more severe form and characterised by absence of early normal development as seen in classical Rett syndrome. In this report we describe a female child with global developmental delay, microcephaly and myoclonic seizures harbouring a 5â¯Mb deletion in 14q12 locus resulting in deletion of single copy of brain specific genes FOXG1, PRKD1 and NOVA1. Whole exome sequencing ruled out any possible role of other pathogenic single nucleotide variants and/or indels as the etiology for the observed phenotype. However, copy number variation analysis from the whole exome data detected a ~ 5â¯Mb microdeletion at the long arm of chromosome 14q12 region. The deletion was confirmed through array Comparative Genomic Hybridization and validated by quantitative PCR. Further, parents were analysed for mosaicism through metaphase Fluorescence in-situ Hybridisation. Our report broadens the phenotype of atypical Rett syndrome and reiterates the role of exome sequencing not only in detection of point mutation/small indels but also for detection of large deletions/duplication in coding regions.
Assuntos
Deleção Cromossômica , Deficiências do Desenvolvimento/genética , Exoma , Microcefalia/genética , Convulsões/genética , Pré-Escolar , Cromossomos Humanos Par 14/genética , Deficiências do Desenvolvimento/complicações , Feminino , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Microcefalia/complicações , Proteínas do Tecido Nervoso/genética , Antígeno Neuro-Oncológico Ventral , Fenótipo , Polimorfismo de Nucleotídeo Único , Proteína Quinase C/genética , Proteínas de Ligação a RNA/genética , Síndrome de Rett/complicações , Síndrome de Rett/genética , Convulsões/complicações , Análise de Sequência de DNARESUMO
Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioral and physiological symptoms. Mutations in the methyl CpG binding protein 2 gene (MECP2) cause more than 95% of classic cases, and currently there is no cure for this devastating disorder. Recently we have demonstrated that neurobehavioral and brain molecular alterations can be rescued in a RTT mouse model, by pharmacological stimulation of the brain serotonin receptor 7 (5-HT7R). This member of the serotonin receptor family, crucially involved in the regulation of brain structural plasticity and cognitive processes, can be stimulated by systemic repeated treatment with LP-211, a brain-penetrant selective agonist. The present study extends previous findings by demonstrating that LP-211 treatment (0.25 mg/kg, once per day for 7 days) rescues mitochondrial respiratory chain impairment, oxidative phosphorylation deficiency and the reduced energy status in the brain of heterozygous female mice from two highly validated mouse models of RTT (MeCP2-308 and MeCP2-Bird mice). Moreover, LP-211 treatment completely restored the radical species overproduction by brain mitochondria in the MeCP2-308 model and partially recovered the oxidative imbalance in the more severely affected MeCP2-Bird model. These results provide the first evidence that RTT brain mitochondrial dysfunction can be rescued targeting the brain 5-HT7R and add compelling preclinical evidence of the potential therapeutic value of LP-211 as a pharmacological approach for this devastating neurodevelopmental disorder.
Assuntos
Encéfalo/metabolismo , Doenças Mitocondriais/terapia , Receptores de Serotonina/metabolismo , Síndrome de Rett/complicações , Trifosfato de Adenosina/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Glucosefosfato Desidrogenase/metabolismo , Ácido Glutâmico/metabolismo , Antígenos de Histocompatibilidade/metabolismo , Peroxidase do Rábano Silvestre/metabolismo , Proteína 2 de Ligação a Metil-CpG/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Doenças Mitocondriais/metabolismo , NADP/metabolismo , Piperazinas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Síndrome de Rett/genética , Agonistas do Receptor de Serotonina/uso terapêutico , Superóxido Dismutase/metabolismoRESUMO
Autism spectrum disorder (ASD) is a neurobehavioral disorder with a heterogeneous genetic etiology. Based on the literature, several single-gene disorders, including Rett syndrome, Smith-Lemli-Opitz syndrome, PTEN hamartoma tumor syndrome and tuberous sclerosis, are associated with a high prevalence of ASD. We estimated the prevalence of these four conditions in a large cohort of patients using whole-exome sequencing data from 2392 families (1800 quads and 592 trios) with ASD from the National Database for Autism Research. Seven patients carried a pathogenic or likely pathogenic variant in either TSC1, TSC2, PTEN, DHCR7 or MECP2, with 6 out of 7 reportable variants occurring in PTEN (1 in 399).
Assuntos
Transtorno do Espectro Autista/genética , Síndrome do Hamartoma Múltiplo/genética , Síndrome de Rett/genética , Síndrome de Smith-Lemli-Opitz/genética , Esclerose Tuberosa/genética , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/patologia , Feminino , Síndrome do Hamartoma Múltiplo/complicações , Síndrome do Hamartoma Múltiplo/patologia , Humanos , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Mutação , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , PTEN Fosfo-Hidrolase/genética , Síndrome de Rett/complicações , Síndrome de Rett/patologia , Síndrome de Smith-Lemli-Opitz/patologia , Esclerose Tuberosa/complicações , Esclerose Tuberosa/patologia , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genética , Sequenciamento do Exoma/métodosRESUMO
BACKGROUND: Scoliosis is prominent in Rett syndrome (RTT). Following the prior report from the US Natural History Study, the onset and progression of severe scoliosis (≥40° Cobb angle) and surgery were examined regarding functional capabilities and specific genotypes, addressing the hypothesis that abnormal muscle tone, poor oral feeding, puberty, and delays or absence of sitting balance and ambulation may be responsible for greater risk in RTT. METHODS: The multicenter RTT Natural History Study gathered longitudinal data for classic RTT, including mutation type, scoliosis, muscle tone, sitting, ambulation, hand function, and feeding. Cox regression models were used to examine the association between scoliosis and functional characteristics. All analyses utilized SAS 9.4; two-sided P values of <0.05 were considered significant. RESULTS: A total of 913 females with classic RTT were included. Scoliosis frequency and severity increased with age. Severe scoliosis was found in 251 participants (27%), 113 of whom developed severe scoliosis during the follow-up assessments; 168 (18%) had surgical correction. Severe MECP2 mutations (R106W, R168X, R255X, R270X, and large deletions) showed a higher proportion of scoliosis. Individuals developing severe scoliosis or requiring surgery were less likely to sit, ambulate, or use their hands and were more likely to have begun puberty. Significant differences were absent for epilepsy rates, sleep problems, or constipation. DISCUSSION: Scoliosis requires vigilance regarding the risk factors noted, particularly specific mutations and the role of puberty and motor abilities. Bracing is recommended for moderate curves and surgery for severe curves in accordance with published guidelines for scoliosis management.
Assuntos
Proteína 2 de Ligação a Metil-CpG/genética , Mutação/genética , Síndrome de Rett , Escoliose/epidemiologia , Escoliose/etiologia , Adolescente , Fatores Etários , Criança , Pré-Escolar , Comorbidade , Progressão da Doença , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Valor Preditivo dos Testes , Prevalência , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Síndrome de Rett/complicações , Síndrome de Rett/epidemiologia , Síndrome de Rett/genética , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND: Rett syndrome is associated with severe motor and communicative impairment making optimal postoperative pain management a challenge. There are case reports documenting reduced postoperative analgesic requirement in Rett syndrome. AIM: The goal of this preliminary investigation was to compare postoperative analgesic management among a sample of girls with Rett syndrome compared to girls with and without developmental disability undergoing spinal fusion surgery. METHOD: The medical records of eight girls with Rett syndrome (mean age = 13.2 years, sd = 1.9), eight girls with developmental disability (cerebral palsy; mean age = 13.1 years, sd = 2.0), and eight girls without developmental disability (adolescent idiopathic scoliosis; mean age = 13.4, sd = 1.8) were reviewed. Data related to demographics, medications, and route of drug administration were recorded. RESULTS: Girls with Rett syndrome received significantly fewer morphine equivalent opioids postoperatively (M = 0.26 mg·kg-1 ·day-1 , sd = 0.10) compared to girls with adolescent idiopathic scoliosis (M = 0.47mg·kg-1 ·day-1 , sd = 0.13; 95% CI -0.34 to -0.08; P = 0.001) and girls with CP (M = 0.40 mg·kg-1 per day, sd = 0.14; 95% CI -0.27 to -0.02; P = 0.01). Girls with Rett syndrome received significantly fewer opioid patient-controlled analgesic (PCA) bolus doses (given by proxy; M = 42.63, sd = 17.84) compared to girls with adolescent idiopathic scoliosis (M = 98.25, sd = 52.77; 95% CI -96.42 to -14.83; P = 0.01). There was also some evidence indicating girls with Rett syndrome received fewer bolus doses compared to girls with CP (M = 80.88, sd = 38.93; 95% CI -79.05 to 2.55; P = 0.06). On average, girls with Rett syndrome also received smaller total doses of acetaminophen, diazepam, and hydroxyzine. CONCLUSION: This study highlights possible discrepancies in postoperative pain management specific to girls with Rett syndrome and suggests further investigation is warranted to determine best practice for postoperative analgesic management for this vulnerable patient population.
Assuntos
Analgésicos Opioides/uso terapêutico , Deficiências do Desenvolvimento/complicações , Dor Pós-Operatória/tratamento farmacológico , Síndrome de Rett/complicações , Síndrome de Rett/cirurgia , Fusão Vertebral , Adolescente , Analgesia Controlada pelo Paciente/estatística & dados numéricos , Estudos de Casos e Controles , Relação Dose-Resposta a Droga , Feminino , HumanosRESUMO
Background and purpose - Studies have indicated that one-third of children with cerebral palsy (CP) develop dislocation of the hip that needs surgical intervention. When hip dislocation occurs during childhood surgical treatment consists of tenotomies, femoral varus derotation osteotomy (VDRO), and acetabuloplasty. Relapse is observed in one-fifth of cases during adolescence. In this prospective cohort study, we performed a descriptive evaluation of translation and rotation across VDROs in children with neuromuscular disorders and syndromes by radiostereometric analysis (RSA). We assessed "RSA stability" and migration across the VDROs. Patients and methods - Children with a neuromuscular disorder were set up for skeletal corrective surgery of the hip. RSA follow-ups were performed postoperatively, at 5 weeks, and 3, 6, and 12 months after surgery. Results - 27 femoral VDROs were included; 2 patients were excluded during the study period. RSA data showed stability across the VDRO in the majority of cases within the first 5 weeks. At the 1-year follow-up, the mean translations (SD) of the femoral shaft distal to the VDRO were 0.51 (1.12) mm medial, 0.69 (1.61) mm superior, and 0.21 (1.28) mm posterior. The mean rotations were 0.39° (2.90) anterior tilt, 0.02° (3.07) internal rotation, and 2.17° (2.29) varus angulation. Interpretation - The migration stagnates within the first 5 weeks, indicating stability across the VDRO in most patients.
Assuntos
Acetábulo/cirurgia , Paralisia Cerebral/complicações , Fêmur/cirurgia , Luxação do Quadril/cirurgia , Osteotomia/métodos , Tenotomia/métodos , Adolescente , Síndrome de Angelman/complicações , Criança , Pré-Escolar , Estudos de Coortes , Craniossinostoses/complicações , Feminino , Luxação do Quadril/etiologia , Humanos , Deficiência Intelectual/complicações , Instabilidade Articular , Masculino , Estudos Prospectivos , Procedimentos de Cirurgia Plástica/métodos , Síndrome de Rett/complicações , Rotação , Resultado do TratamentoRESUMO
Mutations in the X-linked MECP2 gene cause Rett syndrome (RTT), an autism spectrum disorder characterized by impaired social interactions, motor abnormalities, cognitive defects and a high risk of epilepsy. Here, we showed that conditional deletion of Mecp2 in cholinergic neurons caused part of RTT-like phenotypes, which could be rescued by re-expressing Mecp2 in the basal forebrain (BF) cholinergic neurons rather than in the caudate putamen of conditional knockout (Chat-Mecp2(-/y)) mice. We found that choline acetyltransferase expression was decreased in the BF and that α7 nicotine acetylcholine receptor signaling was strongly impaired in the hippocampus of Chat-Mecp2(-/y) mice, which is sufficient to produce neuronal hyperexcitation and increase seizure susceptibility. Application of PNU282987 or nicotine in the hippocampus rescued these phenotypes in Chat-Mecp2(-/y) mice. Taken together, our findings suggest that MeCP2 is critical for normal function of cholinergic neurons and dysfunction of cholinergic neurons can contribute to numerous neuropsychiatric phenotypes.