Rett syndrome (RTT) was first recognized in the late 1950s by Andreas Rett in Vienna and Bengt Hagberg in Uppsala. Hagberg, following a meeting with Rett, decided to call the disorder Rett syndrome in the landmark paper which appeared in the Annals of Neurology in 1983. That report led to the worldwide recognition of this relatively young and unique neurodevelopmental disorder, the concerted effort to establish its epidemiology, etiology, and natural history, and the establishment of clinical criteria for its diagnosis. Our understanding of RTT progressed rapidly, in part due to the remarkable diagnostic advances in genetics linking RTT with variations in the methyl-CpG-binding protein 2 (MECP2) gene at Xq28. In 2003, the NIH funded a Natural History study of RTT and related disorders which provided critical cross-sectional and longitudinal data that resulted in the increased understanding of RTT, the development of better management strategies, and an increase in pharmaceutical and gene-based products designed to provide specific therapies. The FDA-approved oral agent trofinetide has been shown to provide incremental improvements in the core features of RTT. Two gene-based therapies are currently being assessed in clinical trials in Canada and the US. Additional treatment strategies are being assessed at the clinical and translational levels.

BACKGROUND: Circulating β-casomorphins (BCM) and gluten exorphins (GE), which are exogenous opioid peptides originating from bovine milk protein casein and cereal protein gluten, respectively, have been proposed as potential trigger factor to symptoms observed in children with autism. OBJECTIVE: Given the debate surrounding the detectability of these opioid peptides in body fluids, particularly using highly sensitive and specific mass spectrometry (HPLC-MS) techniques, we aimed to investigate their presence in urine samples of autistic subjects. METHODS: We employed an HPLC-MS method for peptide detection. RESULTS: The presence of several BCMs and GEs in the urine of both autistic children (ASD) and healthy controls (HC) was documented. The detection of dietary opioid peptides even at very low concentrations underscores the sensitivity of this novel HPLC-MS method. BCM-8 was more often detected in the ASD group compared to the HC group. A higher prevalence of gastrointestinal (GI) symptoms were also observed in the ASD group. CONCLUSIONS: This pilot study supports the presence of BCMs and GEs in urine samples in subjects with autism as well as healthy controls which was the main goal of this pilot study. Prolonged exposure to bovine BCMs and GEs may play a role in the manifestation of core and GI symptoms in subgroups of autism. Further research is warranted to investigate this phenomenon thoroughly.

BACKGROUND: Multiple sclerosis (MS) is a long-term condition characterized by chronic inflammation, damage to the myelin sheath, and progressive nerve cell degeneration. It is a heterogeneous and multifactorial disease. The aim of the present investigation was to analyze the connection between variations in the vitamin D receptor gene. (APAI rs7975232) and vitamin D serum levels among MS patients. METHODS: Blood samples were collected from 75 Iraqi patients with MS (33 male, 42 female), and 75 control group volunteers who appeared to be in good health with an age range of 20–50 years. Vitamin D receptor (VDR) gene polymorphism was detected by HRM RT-PCR and vitamin D serum levels were assessed by ELISA. RESULTS: Detection of VDR gene polymorphism in MS patients discovered that the wild genotype was C/C 15 (20%), the heterozygous genotype CA was 27(36%), and the homozygous genotype AA was 33(44%), whilst allele C occurrence was 57(38%) and allele A was 93(62%), compared per control genotype C/C was 40(53.3%), CA genotype was 20(26.6%), AA genotype was 15(20%), C allele frequency was 100(66.6%) and A allele was 50(33.3%) with highly significant difference (P≤0.001). Analysis of vitamin D serum levels showed much higher levels in the control group (43.40±0.85 pg/ml) than in the MS patients group (15.46±0.93 pg/ml; P≤0.001). Result of relationship between Vitamin D serum level with genotype of VDR among individuals with MS was found to be significant decrease (5.3±0.52) at AA genotype of MS patients, followed by (11.79±0.68) in CA genotype and finally (15.52±0.93) in CC genotype, all highly significant (P≤0.01). CONCLUSION: There was a notable correlation observed with VDR (APAI rs7975232) genotypes and Vitamin D serum level in MS Iraqi patients.

BACKGROUND: Wiedemann-Rautenstrauch Syndrome (WRS) is a neonatal progeroid syndrome for which biallelic pathogenic variants in RNA polymerase III subunit A (POLR3A) have recently been described. POLR3 is a 17 subunits protein complex responsible for the transcription of short RNAs including all the transfer RNAs (tRNAs), the 5 S subunit of ribosomal RNA, the short nuclear RNA U6, among other regulatory RNAs. OBJECTIVE: We aim to evaluate the impact of POLR3A pathogenic variants on the relative expression of the short nuclear RNA U6 and on the differential profile of intron retention RNA U6, p53 isoforms and in fibroblasts derived from patients with WRS and control fibroblasts. METHODS: RNA was extracted by the TRIzol method; intron retention analysis was performed by using IRFinder from an mRNA sequencing (RNA-Seq) platform; P53 isoforms, short nuclear RNA U6 and additional genes related to cell senescence were measured by RT-PCR. RESULTS: No significant differences were found in the percentage of intron retention (control: 7.8%, WRS1 : 6.3%and WRS2 : 8.14%). Genes showing higher intron retention profile in both groups were mainly related to RNA binding pathways, cell cycle regulation, positive regulation of transcription, positive regulation of inflammatory pathways, negative regulation of apoptosis, RNA transcription, mitochondria, and regulation of translation initiation. However, in WRS fibroblasts the genes with more intron retention were those related to the immune response and mitochondrial function; while in control those related to the response to oxidative stress had the most introns retained. WRS1 showed higher expression of short nuclear RNA U6 compared to control and WRS2; while both WRS cells showed higher expression of p53β and lower percentage of Δ133p63α, consistent with a higher expression of the cellular senescence markers p16 and p21. CONCLUSIONS: These results demonstrated the important role of POLR3A in the maintenance of cellular homeostasis and highlight its potential role in cell senescence in WRS.

Duchenne Muscular Dystrophy (DMD) is a rare genetic disease, characterized by a severe, progressive muscle-weakening. Due to the localisation of the dystrophin gene in the X chromosome, DMD primarily affects males, but similar dystrophinopathies, that mimic DMD, can occur in females. The aim of this article is to present the main findings described in literature about these unusual dystrophinopathies clinical manifestations in females, in order to ease the practical approach to these conditions This article is a non-systematic review, with a view to presenting a critical review –all articles were researched in public databases PubMed, Medline, ScienceDirect, SciELO and Cochrane. Clinical presentation in female carriers shall vary from the traditional form in regards to the degrees and patterns of dysfunction, justified by the presence of a normal allele, as well as distinctive mutational mechanisms. Usually present with asymmetric bilateral leg weakness, myalgia, cramps, fatigue, calf muscles pseudohypertrophy, and dilated cardiomyopathy. Pathogenic variants in the DMD gene must be considered in the differential diagnosis of myopathic-suggestive clinical conditions, even in unusual presentations, such as female patients with muscular weakness or asymptomatic elevation of creatine kinase.

BACKGROUND: Patients with Rare Diseases (RDs) present with chronic and debilitating symptoms such as pain, anxiety and epileptic seizures. Symptoms can be unresponsive to conventional treatment and may lead to a decreased Quality of Life for patients. Cannabinoids have been reported to be efficacious against chronic pain refractory to conventional analgesics, anxiety and seizures. OBJECTIVE: Identification of RDs for which Medicinal Cannabis (MC) can be used and identification of issues related to RDs and perceptions on the use of MC in patients with RDs. METHODS: Study was divided into 2 phases. Phase 1: Literature Review to identify RDs in which cannabis or cannabinoids are used Phase 2: Development, validation and dissemination of 2 questionnaires for: (i) Health Care Professionals (HCPs) and (ii) RD patients. RESULTS: Cannabinoids were described as possible therapeutic agents in 20 RDs. The questionnaires were completed by 101 HCPs and 38 RD patients. Thirty-three HCPs had no experience on use of MC but would consider using it in their practice for management of RDs. Most patients (n = 29) did not have experience with use of MC and 20 patients would consider using MC to treat their condition or relieve symptoms of their disease. CONCLUSION: The study helps identify the potential of MC use in RDs associated with chronic symptoms such as pain, muscle spasticity, seizures and anxiety.

Autism is a group of neurodevelopmental disorders that involve definite impairments in social interactions, disturbance in language, and a stereotyped pattern of behaviour. These clinical features are described as the core symptoms. The condition represents a very large number of diseases and syndromes that are individually rare. Therefore, most people will refer to autism in the plural – autisms. The prevalence of autism has increased incredibly in the last three decades. However, although the number of people diagnosed with autism has increased, this is not the same as saying that there is an increase in the number of cases of autism. Most likely, many children and adults 40–50 years ago had autistic behaviour that went under other diagnoses. The cause of the autistic features has been thoroughly discussed for many years and has been the subject of many research activities. The dominant view today is that genetic and environmental factors mainly cause autism. In this article we want to give a brief status quo of the clinic, epidemiology and causes of autism.

BACKGROUND: Research has shown that some people with neuromuscular diseases may have a lower level of education due to lower socioeconomic status and possibly compromised health literacy. In view of these data, it appears important to document their decision-making needs to ensure better support when faced with the decision to participate or not in research projects. OBJECTIVES: 1) To document the decision-making needs of individuals with neuromuscular diseases to participate in research; 2) To explore their preferences regarding the format of knowledge translation tools related to research participation. METHODS: This qualitative study is based on the Ottawa Decision Support Framework. A two-step descriptive study was conducted to capture the decision-making needs of people with neuromuscular diseases related to research participation: 1) Individual semi-directed interviews (with people with neuromuscular diseases) and focus groups (with healthcare professionals); 2) Synthesis of the literature. RESULTS: The semi-directed interviews (n = 11), the two focus groups (n = 11) and the literature synthesis (n = 50 articles) identified information needs such as learning about ongoing research projects, scientific advances and research results, the potential benefits and risks associated with different types of research projects, and identified values surrounding research participation: helping other generations, trust, obtaining better clinical follow-up, and socialization. CONCLUSION: This paper provides useful recommendations to support researchers and clinicians in developing material to inform individuals with neuromuscular diseases about research participation.