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1.
Neonatal hyperglycaemia is associated with worse neurodevelopmental outcomes in extremely preterm infants.
Zamir, I, Stoltz Sjöström, E, Ahlsson, F, Hansen-Pupp, I, Serenius, F, Domellöf, M
Archives of disease in childhood. Fetal and neonatal edition. 2021;(5):460-466
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Abstract
OBJECTIVE To assess the associations between neonatal hyperglycaemia and insulin treatment, versus long-term neurodevelopmental outcomes in children born extremely preterm. DESIGN AND SETTING Observational national cohort study (Extremely Preterm Infants in Sweden Study) using prospectively and retrospectively collected data. Neurodevelopmental assessment was performed at 6.5 years of age. PATIENTS 533 infants born <27 gestational weeks during 2004-2007; 436 survivors were assessed at 6.5 years. OUTCOME MEASURES Neurodevelopmental disability (NDD), survival without moderate to severe NDD, Wechsler Intelligence Scale for Children IV Full scale intelligence quotient (WISC-IV FSIQ) and Movement Assessment Battery for Children 2 (MABC-2) total score. RESULTS Duration of neonatal hyperglycaemia >8 mmol/L was associated with WISC-IV scores-for each day with hyperglycaemia there was a decrease of 0.33 points (95% CI 0.03 to 0.62) in FSIQ. Neonatal hyperglycaemia >8 mmol/L occurring on 3 consecutive days was associated with lower MABC-2 scores (adjusted mean difference: -4.90; 95% CI -8.90 to -0.89). For each day with hyperglycaemia >8 mmol/L, there was a decrease of 0.55 points (95% CI 0.17 to 0.93) in MABC-2 total score. Insulin treatment was not associated with any of the outcome measures. CONCLUSION Neonatal hyperglycaemia >8 mmol/L was associated with lower intelligence scores and worse motor outcomes at 6.5 years of age. Insulin treatment was not associated with either worsened or improved neurodevelopmental outcomes. Randomised controlled trials are needed to clarify the role of insulin in treating hyperglycaemia in extremely preterm infants.
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Tissue-specific DNase I footprint analysis confirms the association of GATAD2B Q470* variant with intellectual disability.
Nikam, V, Shaik Mohammad, N
Journal of genetics. 2021
Abstract
Intellectual disability (ID) is a neurodevelopmental disorder in which genetics play a key aetiological role. GATA zinc finger domain-containing 2B (GATAD2B) gene encodes a zinc-finger protein transcriptional repressor which is a part of the methyl-CpG binding protein-1 complex. Pathogenic variants in this gene are linked to ID, dysmorphic features, and cognitive disability. To date, only 18 cases are reported worldwide and only one case is reported from India. A 12-year-old girl presented with a heterozygous nonsense variation in exon 8 of the GATAD2B gene (chr1:153785737G>A). She has severe ID and significant delayed developmental milestones along with clinical features including broad arched eyebrows, low-set ears, a bulbous nose tip, thin upper lip, and wide mouth with downturned corners. This is the second report of a heterozygous mutation in the GATAD2B gene from India with a novel phenotype. To substantiate the association of GATAD2B mutation with ID, we performed DNase I footprint analysis of wild and mutant DNA sequences to establish k-mer binding profile and deduced GATA binding affinity using human ENCODE experimental data of foetal brain. We observed that in the presence of variation, GATA zinc finger domain was altered thus contributing to ID. Our findings support the importance of the GATAD2B gene in the study of neurodevelopmental disorders.
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Intellectual disability in paediatric patients with genetic muscle diseases.
Specht, S, Straub, V
Neuromuscular disorders : NMD. 2021;(10):988-997
Abstract
The differential diagnosis of genetic muscle disease has become increasingly difficult due to the rapid progress in genetic medicine in recent years. Where classifications based on the clinical picture were attributed to one gene only a few years ago, today we know that a variety of clinical presentations can result from the same mutation and, conversely, various genes are associated with a similar phenotype. A significant consideration in assessing a patient with muscle weakness is the presence or absence of intellectual disability, thus narrowing the differential diagnostic approach in any child with an as yet undiagnosed muscle disease. Intellectual disability in neuromuscular diseases is often associated with behavioural disorders and may be correlated with abnormal brain imaging. Conversely, brain involvement can sometimes be seen without intellectual disability, but may be associated with an epilepsy risk and is helpful for the differential diagnosis. This review focuses on the three most common causes of paediatric muscle diseases with intellectual disability, dystrophinopathies, myotonic dystrophy type 1 and dystroglycanopathies. It also summarises differential diagnostic considerations when assessing a child with a genetic muscle disease and intellectual disability. The recent scientific literature on this topic is reviewed, the frequency of intellectual disability assessed, and specific clinical features are described. Where available, data on disease onset, progression and serum creatine kinase levels are presented and the pattern of muscle involvement described in an algorithm. Central nervous involvement and brain imaging analysis was reviewed and included.
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A Novel Missense Variant in the Gene PPP2R5D Causes a Rare Neurodevelopmental Disorder with Increased Phenotype.
Yan, L, Shen, R, Cao, Z, Han, C, Zhang, Y, Liu, Y, Yang, X, Xie, M, Li, H
BioMed research international. 2021;:6661860
Abstract
PPP2R5D-related neurodevelopmental disorder, which is mainly caused by de novo missense variants in the PPP2R5D gene, is a rare autosomal dominant genetic disorder with about 100 patients and a total of thirteen pathogenic variants known to exist globally so far. Here, we present a 24-month-old Chinese boy with developmental delay and other common clinical characteristics of PPP2R5D-related neurodevelopmental disorder including hypotonia, macrocephaly, intellectual disability, speech impairment, and behavioral abnormality. Trio-whole exome sequencing (WES) and Sanger sequencing were performed to identify the causal gene variant. The pathogenicity of the variant was evaluated using bioinformatics tools. We identified a novel pathogenic variant in the PPP2R5D gene (c.620G>T, p.Trp207Leu). The variant is located in the variant hotspot region of this gene and is predicted to cause PPP2R5D protein dysfunction due to an increase in local hydrophobicity and unstable three-dimensional structure. We report a novel pathogenic variant of PPP2R5D associated with PPP2R5D-related neurodevelopmental disorder from a Chinese family. Our findings expanded the phenotypic and mutational spectrum of PPP2R5D-related neurodevelopmental disorder.
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Increased creatine demand during pregnancy in Arginine: Glycine Amidino-Transferase deficiency: a case report.
Alessandrì, MG, Strigini, F, Cioni, G, Battini, R
BMC pregnancy and childbirth. 2020;(1):506
Abstract
BACKGROUND Creatine (Cr), an amino acid derivative, is one of the most important sources of energy acting as both a spatial and temporal energy buffer through its phosphorylated analogue phosphocreatine (PCr) and creatine kinase (CK). Maternal Cr biosynthesis and metabolism seem to play an important role in pregnancy, as shown in preclinical and in healthy human pregnancy studies. Patients with Arginine:Glycine Amidino-Transferase deficiency (AGAT-d), due to the deficit of the first enzyme involved in Cr synthesis, are at a disadvantage due to their failure to synthesize Cr and their dependence on external intake, in contrast to normal subjects, where changes in Cr biosynthesis supply their needs. We report the outcomes of a pregnancy in an AGAT-d woman, and the challenge we faced in managing her treatment with oral Cr to ensure optimal conditions for her fetus. CASE PRESENTATION A 22-year-old AGAT-d woman referred to our Institute for the management of her first conception at 11 weeks of fetal gestational age. Sonographic monitoring at 20 w GA indicated a reduction of fetal growth, in particular of the head circumference that was below the 3rd centile. Biochemical monitoring of Cr in biological fluids of the mother revealed a decline of the Cr concentrations, in particular in the urine sample, requiring prompt correction of the Cr dose. At 35 weeks of gestation the patient delivered a male infant, heterozygous for GATM mutation, with normal brain Cr levels; at one year the baby achieved typical developmental milestones. CONCLUSIONS This rare pregnancy demonstrates that Cr levels in the blood and urine of the mother with AGAT-d decreased since the first months of gestation. The increase of the Cr daily dose administered to the mother seems to have produced beneficial effects also on the fetus.
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Bosch-Boonstra-Schaaf Optic Atrophy Syndrome Presenting as New-Onset Psychosis in a 32-Year-Old Man: A Case Report and Literature Review.
Hobbs, MM, Wolters, WC, Rayapati, AO
Journal of psychiatric practice. 2020;(1):58-62
Abstract
Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a recently described autosomal dominant disorder caused by mutations in the nuclear receptor subfamily 2 group F member 1 (NR2F1) gene. Its common features include optic atrophy and/or hypoplasia, developmental delay, intellectual disability, attention deficit disorder, autism spectrum disorder, seizures, hearing defects, spasticity, hypotonia, and thinning of the corpus callosum. Mitochondrial involvement has also been described with BBSOAS. Currently, 31 cases of BBSOAS have been described in the literature. Here we report a case of undiagnosed BBSOAS presenting as psychosis in a 32-year-old man with a history of bilateral optic nerve atrophy, intellectual disability, epilepsy, and mitochondrial complex I abnormality on muscle biopsy. Whole-genome sequencing identified a heterozygous de novo nonsense mutation in the NR2F1 gene [c.253 G>T (guanine to thymine mutation in coding position 253) in exon 1, p.E85X variant (GAG>TAG) (glutamic acid to stop codon mutation; protein truncated to 85 amino acids)]. A pathogenic nonsense mutation has not previously been reported in the literature in association with BBSOAS and represents an expansion of clinically relevant variants. Psychosis has also not been previously reported in this syndrome and may represent a phenotypic expansion of BBSOAS, a manifestation of prolonged disease, or a result of disease management.
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Constraint and conservation of paired-type homeodomains predicts the clinical outcome of missense variants of uncertain significance.
Thai, MHN, Gardner, A, Redpath, L, Mattiske, T, Dearsley, O, Shaw, M, Vulto-van Silfhout, AT, Pfundt, R, Dixon, J, McGaughran, J, et al
Human mutation. 2020;(8):1407-1424
Abstract
The need to interpret the pathogenicity of novel missense variants of unknown significance identified in the homeodomain of X-chromosome aristaless-related homeobox (ARX) gene prompted us to assess the utility of conservation and constraint across these domains in multiple genes compared to conventional in vitro functional analysis. Pathogenic missense variants clustered in the homeodomain of ARX contribute to intellectual disability (ID) and epilepsy, with and without brain malformation in affected males. Here we report novel c.1112G>A, p.Arg371Gln and c.1150C>T, p.Arg384Cys variants in male patients with ID and severe seizures. The third case of a male patient with a c.1109C>T, p.Ala370Val variant is perhaps the first example of ID and autism spectrum disorder (ASD), without seizures or brain malformation. We compiled data sets of pathogenic variants from ClinVar and presumed benign variation from gnomAD and demonstrated that the high levels of sequence conservation and constraint of benign variation within the homeodomain impacts upon the ability of publicly available in silico prediction tools to accurately discern likely benign from likely pathogenic variants in these data sets. Despite this, considering the inheritance patterns of the genes and disease variants with the conservation and constraint of disease variants affecting the homeodomain in conjunction with current clinical assessments may assist in predicting the pathogenicity of missense variants, particularly for genes with autosomal recessive and X-linked patterns of disease inheritance, such as ARX. In vitro functional analysis demonstrates that the transcriptional activity of all three variants was diminished compared to ARX-Wt. We review the associated phenotypes of the published cases of patients with ARX homeodomain variants and propose expansion of the ARX-related phenotype to include severe ID and ASD without brain malformations or seizures. We propose that the use of the constraint and conservation data in conjunction with consideration of the patient phenotype and inheritance pattern may negate the need for the experimental functional validation currently required to achieve a diagnosis.
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Feedback and Strategies From People With Intellectual Disability Completing a Personalized Online Weight Loss Intervention: A Qualitative Analysis.
Guerra, N, Neumeier, WH, Breslin, L, Geer, B, Thirumalai, M, Ervin, DA, Rimmer, JH
Intellectual and developmental disabilities. 2019;(6):527-544
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Abstract
Coaching log notes for 15 participants from a 24-week blended online and telehealth randomized controlled trial were analyzed using thematic analysis and analyst triangulation to determine the factors that facilitated participant adherence to weight loss strategies, use of technology, and motivational interviewing. Several participants reported that restricting processed carbohydrates, limiting portion size, and maintaining healthy substitutions were effective nutritional strategies. Participants were less successful with adherence to their exercise goals, often due to time constraints and a lack of support. Results suggested consistent caregiver support improved participants' adherence to weight loss strategies and use of technology. Future programs should address obesity among people with intellectual and developmental disabilities by offering a range of interventions that are customized to their specific weight loss needs.
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One-month-old girl presenting with pseudohypoaldosteronism leading to the diagnosis of CDK13-related disorder: a case report and review of the literature.
Yakubov, R, Ayman, A, Kremer, AK, van den Akker, M
Journal of medical case reports. 2019;(1):386
Abstract
BACKGROUND It is not uncommon that an infant with a disease of unknown etiology is presented to a physician. Facial dysmorphic features lead to a different diagnosis. It is a challenge to link the presentation to the newfound diagnosis. CASE PRESENTATION A 37-day-old Yemenite Jewish girl was presented to our institution with a clinical picture of pseudohypoaldosteronism due to abnormal facial features and a psychomotor developmental delay. Further investigation led to the diagnosis of CDK13-related disorder. According to the literature, CDK13 has a key role in the cell cycle, but no interference with the aldosterone signaling pathway or electrolyte balance was described. No mutations in the previously described gene NR3C2 (cytogenetic location 4q31.23), encoding the mineralocorticoid receptor, were found. Although the clinical presentation corresponded to pseudohypoaldosteronism type 1, we could not genetically confirm this. CONCLUSIONS Probably pseudohypoaldosteronism was a coincidental finding in this girl with a CDK13 mutation, but because only limited information is known about CDK13-related disorders, further investigation could be more informative to clarify this presentation.
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Oral health of adults with intellectual disabilities: a systematic review.
Ward, LM, Cooper, SA, Hughes-McCormack, L, Macpherson, L, Kinnear, D
Journal of intellectual disability research : JIDR. 2019;(11):1359-1378
Abstract
BACKGROUND There have been several past reports that adults with intellectual disabilities experience poor oral health (tooth loss, periodontal health and untreated dental caries). Loss of a functional dentition has serious consequences, including problems with chewing, swallowing, nutrition, speech, temporomandibular joint osteoarthritis and pain and systemic health conditions. Poor oral health is largely preventable through proactive oral care support. In recent years, social care provision for adults has changed, with deinstitutionalisation and home-based personalised care now being the typical provision in high income countries. Hence, oral health inequalities might be reducing. However, there is limited recent evidence-synthesis on the topic. We aimed to address this. METHOD PROSPERO registration number: CRD42018089880. We conducted a preferred reporting items for systematic reviews and meta-analyses systematic review of publications since 2008. Four databases were searched with a clear search strategy, strict inclusion criteria for selection of papers, double scoring (two raters), systematic data extraction and quality appraisal of included papers. RESULTS A total of 33/3958 retrieved articles were included, of which 14 were drawn from dental service users and 10 from Special Olympic athletes, therefore not necessarily being representative of the wider population with intellectual disabilities. Despite this limitation, adults with intellectual disabilities were still shown to experience poor oral health. High levels of poor oral hygiene and gingivitis were found, with many also affected by periodontitis and untreated dental decay. There is clear unmet need relating to both periodontal (gum) and tooth health, leading to tooth loss. CONCLUSIONS Despite reports in the past of poor oral health amongst adults with intellectual disabilities, and despite it being preventable, there remains a high burden of poor oral health. This highlights the need to raise awareness, and for polices on effective daily oral care, and appropriate service provision. The importance of oral health and its possible negative sequelae needs to be elevated amongst carers and professionals.