Pubmed du 06/03/22
1. Donabedian PL, Walia JY, Agarwal-Sinha S. Partial CHARGE syndrome with bilateral retinochoroidal colobomas associated with 7q11.23 duplication syndrome: case report. BMC ophthalmology. 2022; 22(1): 100.
BACKGROUND: CHARGE syndrome is a relatively common cause of deafness and blindness resulting from failure to form the primordia of specific organs due to deficient contribution of neural crest cell derivatives. The majority of CHARGE syndrome cases are caused by heterozygous mutations in CHD7 on chromosome 8q21. Those with CHARGE syndrome without CHD7 mutation typically do not have an identified genetic defect. 7q11.23 duplication syndrome is associated with mild facial dysmorphism, heart defects, language delay, and autism spectrum disorder. In the current literature, 7q11.23 duplication has not been associated with CHARGE syndrome, retinochoroidal colobomas, or significant ear abnormalities. CASE PRESENTATION: We describe a patient with 7q11.23 duplication syndrome and clinical CHARGE syndrome with no variant in CHARGE-associated genes. CONCLUSIONS: This case highlights the still incomplete understanding of the pathogenesis of CHARGE syndrome and raises the possibility of a dose-sensitive effect of genes in the 7q11.23 critical region on neural crest differentiation and fate.
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2. Leonard H, Gold W, Samaco R, Sahin M, Benke T, Downs J. Improving clinical trial readiness to accelerate development of new therapeutics for Rett syndrome. Orphanet journal of rare diseases. 2022; 17(1): 108.
Rett syndrome is associated with severe functional impairments and many comorbidities, each in urgent need of treatments. Mutations in the MECP2 gene were identified as causing Rett syndrome in 1999. Over the past 20 years there has been an abundance of preclinical research with some studies leading to human clinical trials. Despite this, few viable therapeutic options have emerged from this investment of effort. Reasons for this lack of success as they relate both to preclinical research and the clinical trial landscape are discussed. Considering what needs to be done to promote further success in the field, we take a positive and constructive approach and introduce the concept of clinical trial readiness and its necessary ingredients for Rett syndrome. These include: listening to the needs of families; support from advocacy groups; optimising use of existing clinic infrastructures and available natural history data; and, finally, the validation of existing outcome measures and/or the development and validation of new measures. We conclude by reiterating the need for a collaborative and coordinated approach amongst the many different stakeholder groups and the need to engage in new types of trial design which could be much more efficient, less costly and much less burdensome on families.
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3. Meraj N, Yasin M, Rehman ZU, Tahir H, Jadoon H, Khan N, Shahid R, Zubair M, Zulfiqar I, Jabeen M, Neelam S, Hameed A, Saleha S. Fragile X premutation carrier screening in Pakistani preconception women in primary care consultation. BMC women’s health. 2022; 22(1): 57.
PURPOSE: Women of reproductive age who carry fragile X premutation (PM) alleles have 56 to 200 CGG repeats in the 5′-untranslated region of FMR1 gene are at increased risk for producing children with intellectual disabilities (ID) or autism spectrum disorders (ASD) due to expansion of PM alleles to full mutation alleles (> 200 repeats) during maternal transmission. METHODS: In present study fragile X PM carrier screening was performed in total 808 women who were consulting primary health care centers for preconception care in Khyber Pakhtunkhwa region of Pakistan between April, 2018 and December, 2020. Polymerase chain reaction (PCR) was performed for detection of PM carrier women and the CGG repeats number was confirmed by Southern blotting and capillary electrophoresis. RESULTS: The prevalence rate for PM carriers among preconception women was found to be 0.7% that was contributed by 0.5% women in risk group (RG1) with family history of ID and 0.2% in risk group 2 (RG2) with family history of ASD. PM carrier women had at least one affected child or sibling. In addition, the preconception women with FMR1 PM alleles were found to be at increased risk for primary ovary insufficiency (RG1: P = 0.0265, RG2: P = 0.0389), postpartum depression (RG1: P = 0.0240, RG2: P = 0.0501) and neuropsychiatric disorders (RG1: P = 0.0389, RG2: P = 0.0432). CONCLUSIONS: Current study provides first evidence of fragile X PM carrier screening in Pakistani preconception women in primary care consultation. Findings of current study may help to improve preconception care and to reduce burden of fragile X associated disorders in our population.
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4. Siafis S, Çıray O, Wu H, Schneider-Thoma J, Bighelli I, Krause M, Rodolico A, Ceraso A, Deste G, Huhn M, Fraguas D, San José Cáceres A, Mavridis D, Charman T, Murphy DG, Parellada M, Arango C, Leucht S. Pharmacological and dietary-supplement treatments for autism spectrum disorder: a systematic review and network meta-analysis. Molecular autism. 2022; 13(1): 10.
BACKGROUND: There is still no approved medication for the core symptoms of autism spectrum disorder (ASD). This network meta-analysis investigated pharmacological and dietary-supplement treatments for ASD. METHODS: We searched for randomized-controlled-trials (RCTs) with a minimum duration of seven days in ClinicalTrials.gov, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (from inception up to July 8, 2018), CENTRAL and PubMed (up to November 3, 2021). The co-primary outcomes were core symptoms (social-communication difficulties-SCD, repetitive behaviors-RB, overall core symptoms-OCS) measured by validated scales and standardized-mean-differences (SMDs). Associated symptoms, e.g., irritability/aggression and attention-deficit/hyperactivity disorder (ADHD) symptoms, dropouts and important side-effects, were investigated as secondary outcomes. Studies in children/adolescents and adults were analyzed separately in random-effects pairwise and network meta-analyses. RESULTS: We analyzed data for 41 drugs and 17 dietary-supplements, from 125 RCTs (n = 7450 participants) in children/adolescents and 18 RCTs (n = 1104) in adults. The following medications could improve at least one core symptom domain in comparison with placebo: aripiprazole (k = 6 studies in analysis, SCD: SMD = 0.27 95% CI [0.09, 0.44], RB: 0.48 [0.26, 0.70]), atomoxetine (k = 3, RB:0.49 [0.18, 0.80]), bumetanide (k = 4, RB: 0.35 [0.09, 0.62], OCS: 0.61 [0.31, 0.91]), and risperidone (k = 4, SCM: 0.31 [0.06, 0.55], RB: 0.60 [0.29, 0.90]; k = 3, OCS: 1.18 [0.75, 1.61]) in children/adolescents; fluoxetine (k = 1, RB: 1.20 [0.45, 1.96]), fluvoxamine (k = 1, RB: 1.04 [0.27, 1.81]), oxytocin (k = 6, RB:0.41 [0.16, 0.66]) and risperidone (k = 1, RB: 0.97 [0.21,1.74]) in adults. There were some indications of improvement by carnosine, haloperidol, folinic acid, guanfacine, omega-3-fatty-acids, probiotics, sulforaphane, tideglusib and valproate, yet imprecise and not robust. Confidence in these estimates was very low or low, except moderate for oxytocin. Medications differed substantially in improving associated symptoms, and in their side-effect profiles. LIMITATIONS: Most of the studies were inadequately powered (sample sizes of 20-80 participants), with short duration (8-13 weeks), and about a third focused on associated symptoms. Networks were mainly star-shaped, and there were indications of reporting bias. There was no optimal rating scale measuring change in core symptoms. CONCLUSIONS: Some medications could improve core symptoms, although this could be likely secondary to the improvement of associated symptoms. Evidence on their efficacy and safety is preliminary; therefore, routine prescription of medications for the core symptoms cannot be recommended. Trial registration PROSPERO-ID CRD42019125317.
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5. Taylor HL, Dove EJ, Elverum CL, Gunther WM. Sudden death caused by ruptured brain arteriovenous malformation in an adolescent with autism spectrum disorder. Journal of forensic sciences. 2022.
Brain arteriovenous malformations (bAVMs) are infrequent disorders in the pediatric population. The rupture of a bAVM is a clinical emergency often followed by death. Autism spectrum disorder shares a number of symptoms with AVM malformation; this may impede antemortem diagnosis. An 11-year-old boy with autism spectrum disorder (ASD) without other medical history died suddenly. Initially, choking on a peanut butter sandwich was suspected; autopsy did not demonstrate aspiration, but identified a ruptured right cerebellar AVM, with the characteristic tortuous vessels. The histology on the lesion confirmed the presence of arterialized veins and showed gliotic tissue and hemosiderin-laden macrophages, consistent with prior bleeding. BAVM pathogenesis is unknown; congenital disease may have several mechanisms including genetic predisposition and familial risk factors; development de novo may occur after hemorrhagic intracranial events such as surgical intervention and head trauma. ASD may present with overlapping symptoms of bAVM and may also interfere with expressing subtle neurologic symptoms to caretakers. ASD and AVM are rarely reported in association.
