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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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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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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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Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment.
Salpietro, V, Malintan, NT, Llano-Rivas, I, Spaeth, CG, Efthymiou, S, Striano, P, Vandrovcova, J, Cutrupi, MC, Chimenz, R, David, E, et al
American journal of human genetics. 2019;(4):721-730
Abstract
VAMP2 encodes the vesicular SNARE protein VAMP2 (also called synaptobrevin-2). Together with its partners syntaxin-1A and synaptosomal-associated protein 25 (SNAP25), VAMP2 mediates fusion of synaptic vesicles to release neurotransmitters. VAMP2 is essential for vesicular exocytosis and activity-dependent neurotransmitter release. Here, we report five heterozygous de novo mutations in VAMP2 in unrelated individuals presenting with a neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features. In total, we identified two single-amino-acid deletions and three non-synonymous variants affecting conserved residues within the C terminus of the VAMP2 SNARE motif. Affected individuals carrying de novo non-synonymous variants involving the C-terminal region presented a more severe phenotype with additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities. Reconstituted fusion involving a lipid-mixing assay indicated impairment in vesicle fusion as one of the possible associated disease mechanisms. The genetic synaptopathy caused by VAMP2 de novo mutations highlights the key roles of this gene in human brain development and function.
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Characterizing adults with Type 2 diabetes mellitus and intellectual disability: outcomes of a case-finding study.
Bryant, LD, Russell, AM, Walwyn, REA, Farrin, AJ, Wright-Hughes, A, Graham, EH, Nagi, D, Stansfield, A, Birtwistle, J, Meer, S, et al
Diabetic medicine : a journal of the British Diabetic Association. 2018;(3):352-359
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Abstract
AIMS: To report the results of a case-finding study conducted during a feasibility trial of a supported self-management intervention for adults with mild to moderate intellectual disability and Type 2 diabetes mellitus, and to characterize the study sample in terms of diabetes control, health, and access to diabetes management services and support. METHODS We conducted a cross-sectional case-finding study in the UK (March 2013 to June 2015), which recruited participants mainly through primary care settings. Data were obtained from medical records and during home visits. RESULTS Of the 325 referrals, 147 eligible individuals participated. The participants' mean (sd) HbA1c concentration was 55 (15) mmol/mol [7.1 (1.4)%] and the mean (sd) BMI was 32.9 (7.9) kg/m2 , with 20% of participants having a BMI >40 kg/m2 . Self-reported frequency of physical activity was low and 79% of participants reported comorbidity, for example, cardiovascular disease, in addition to Type 2 diabetes. The majority of participants (88%) had a formal or informal supporter involved in their diabetes care, but level and consistency of support varied greatly. Post hoc exploratory analyses showed a significant association between BMI and self-reported mood, satisfaction with diet and weight. CONCLUSIONS We found high obesity and low physical activity levels in people with intellectual disability and Type 2 diabetes. Glycaemic control was no worse than in the general Type 2 diabetes population. Increased risk of morbidity in this population is less likely to be attributable to poor glycaemic control and is probably related, at least in part, to greater prevalence of obesity and inactivity. More research, focused on weight management and increasing activity in this population, is warranted.
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Correlates of Sedentary Behaviour in Adults with Intellectual Disabilities-A Systematic Review.
Oppewal, A, Hilgenkamp, TIM, Schäfer Elinder, L, Freiberger, E, Rintala, P, Guerra-Balic, M, Giné-Garriga, M, Cuesta-Vargas, A, Oviedo, GR, Sansano-Nadal, O, et al
International journal of environmental research and public health. 2018;(10)
Abstract
Individuals with intellectual disabilities (ID) are at high risk for high levels of sedentary behaviour. To inform the development of programmes to reduce sedentary behaviour, insight into the correlates is needed. Therefore, the aim of this study is to review the evidence on correlates of sedentary behaviour in adults with ID. We performed a systematic literature search in Ovid Medline, Ovid Embase, Web of Science and Google Scholar up to 19 January 2018, resulting in nine included studies that were published from 2011 to 2018. Correlates were categorized according to the ecological model. Studies predominantly focused on individual level correlates. Of those correlates studied in more than one study, having epilepsy was associated with less sedentary behaviour and inconsistent results were found for sex, genetic syndromes, weight status, physical health, mobility, level of ID, and mental health. Of the few interpersonal and environmental factors studied, only living arrangements were studied in more than one study, with inconsistent results. To date, we have limited and inconclusive evidence about correlates of sedentary behaviour in adults with ID. Only when future studies unravel correlates and determinants, across all domains of the ecological model, will the potential opportunities to improve health by reducing sedentary behaviour come within reach.
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Phenotypic heterogeneity of intellectual disability in patients with congenital insensitivity to pain with anhidrosis: A case report and literature review.
Liu, Z, Liu, J, Liu, G, Cao, W, Liu, S, Chen, Y, Zuo, Y, Chen, W, Chen, J, Zhang, Y, et al
The Journal of international medical research. 2018;(6):2445-2457
Abstract
Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive heterogeneous disorder mainly caused by mutations in the neurotrophic tyrosine receptor kinase 1 gene ( NTRK1) and characterized by insensitivity to noxious stimuli, anhidrosis, and intellectual disability. We herein report the first north Han Chinese patient with CIPA who exhibited classic phenotypic features and severe intellectual disability caused by a homozygous c.851-33T>A mutation of NTRK1, resulting in aberrant splicing and an open reading frame shift. We reviewed the literature and performed in silico analysis to determine the association between mutations and intellectual disability in patients with CIPA. We found that intellectual disability was correlated with the specific Ntrk1 protein domain that a mutation jeopardized. Mutations located peripheral to the Ntrk1 protein do not influence important functional domains and tend to cause milder symptoms without intellectual disability. Mutations that involve critical amino acids in the protein are prone to cause severe symptoms, including intellectual disability.