Intellectual Developmental Delay Research Articles

Clinical characteristics and prognosis of five children with maturity onset of diabetes of the young 12 subtype

Objective: To analyze the genetic and clinical characteristics, treatment and prognosis of patients diagnosed with maturity onset of diabetes of the young (MODY) 12 subtype. Methods: This retrospective study collected and analyzed data from 5 children with MODY12 subtype caused by ABCC8 gene variants who underwent inpatient and outpatient genetic testing at Beijing Children's Hospital from January 2016 to December 2023. Their clinical and genetic features, treatment, and follow-up results were analyzed. Results: Among the 5 patients with MODY12 subtype, 4 were male and 1 was female, with an age of 13.4 (5.5, 14.6) years. Four of the patients were born large for gestational age, while one was born small for gestational age. Two patients were overweight or obese. Three patients exhibited typical symptoms of diabetes, while 2 were incidentally found to have elevated blood glucose level. One patient was found to have diabetic ketoacidosis at onset, who was diagnosed with congenital hyperinsulinism during the neonatal period and received diazoxide treatment, and experienced intellectual developmental delay. All 5 patients had autosomal dominant inherited diabetes within 3 generations. The fasting blood glucose at onset was 7.5 (6.5, 10.0) mmol/L, the haemoglobin, A1c (HbA1c) was 11.8% (7.5%, 13.5%), and the fasting C-peptide was 1.2 (1.1, 2.2)μg/L. The duration of follow-up was 15 (9, 32) months. One patient underwent lifestyle intervention, two received metformin orally, one received insulin therapy, and the other received subcutaneous injection of insulin combined with sulfonylurea orally. At the last follow-up, the median fasting blood glucose was 6.1 (5.1, 7.0) mmol/L, the HbA1c was 5.9% (5.7%, 7.1%), and the fasting C-peptide was 1.7 (0.9, 2.9)μg/L. One patient developed diabetic retinopathy. There were 4 missense variations in ABCC8 gene and one in-frame deletion, all of which were maternally inherited heterozygotes. Conclusions: MODY12 subtype is a heterogeneous disorder with the age of onset from infancy to adolescence. It can present as mild hyperglycemia or diabetic ketoacidosis, and has a high incidence of obesity. Definitive diagnosis can be achieved through genetic test, and individualized treatment is recommended based on glucose levels.

Nondisjunction in Trisomy 21: Origin and Mechanisms

Down’s Syndrome is a chromosomal abnormality with a gain of a third copy of chromosome 21, characterized by craniofacial abnormalities, intellectual developmental delay and growth retardation. In the present study, one-day-old neonate and a patient with an aborted fetus were presented to rule out genetic aberrations via CMA screening. DNA was extracted using from the case samples and evaluated by CMA Affymetrix platform. Chromosomal abnormalities in the fetus such as trisomy emerges due to several factors including maternal age, genetic mutational events, non-disjunction of chromosomes and epigenetic changes. Genetic Cause of trisomy 21 is chromosomal aneuploidy and gain of three copies of chromosome 21. The Trisomy 21 can occur due to Robertsonian translocation, Mosaicisms or duplication of critical region of chromosome 21. The trisomy 21 is the result of nondisjunction of homologous chromosomes 21 during gametogenesis at the time of embryo development. CMA is an effective molecular diagnostic tool for predicting and diagnosing chromosomal abnormalities which needs to be promoted in India for healthy pregnancy outcomes. We report two cases of confirmed post-natal Trisomy 21. The main aim of this study is to focus on genetic diagnosis and its awareness which is still lacking with 100% coverage, in developing countries to reduce the burden of genetic diseases and associated emotional and economic consequences.

The burden of psychiatric disorders associated with orofacial cleft pathology among children in Ontario, Canada

Individuals with orofacial cleft (OFC) may be at a higher risk of developing psychiatric disorders (PD) than the general population. We determined the risk of psychiatric diagnoses in children with OFC in Canada. This population-based retrospective cohort study used health administrative data from the province of Ontario, Canada. Children with OFC who were born between April 1, 1994, and March 31, 2017, in Ontario were matched to five non-OFC children based on sex, date of birth, and mother's age. We determined the rate of events and time-to-event for first diagnosis of PD in children aged ≥3 years (y), and for intellectual developmental delay (IDD) from birth. Risk factors for PD and IDD were assessed using 1-way ANOVA for means, Kruskal-Wallis for medians, and the χ2 test for categorical variables. There were 3051 children with OFC (matched to 15,255 controls), of whom 2515 patients with OFC (12,575 controls) had a complete follow-up to the third birthday. Children with OFC were more likely to have PD than controls (54.90 vs. 43.28 per 1000 patient-years, P<.001), with a mean age to first diagnosis of 8.6±4.2y. The cleft palate group had the highest risk (HR 1.33, 95% CI 1.18-1.49). Children with OFC also had a higher risk of IDD than non-OFC children (27.78 vs. 3.46 per 1000 patient-years, p<.001). Children born with OFC in Ontario had a higher risk of psychiatric diagnosis and IDD compared to controls. Further research is also required to better understand the predictors of variation in risk, including geographic location and the presence of congenital abnormalities, and identify potential areas for intervention. Level II.

The third patient of ACACA-related acetyl-CoA carboxylase deficiency with seizure and literature review

Pathogenic variants in ACACA are the cause of acetyl-CoA carboxylase deficiency with an autosomal recessive inheritance that is identified by hypotonia, motor, and intellectual developmental delay. In this article, we describe a seven-year-old boy who is the child of consanguineous parents with a homozygous variant in ACACA (NM_198834.3:c.6641C > A, p.P2214H) that was detected by Whole-Exome Sequencing and confirmed by Sanger sequencing. This is the first reported patient of acetyl-CoA carboxylase deficiency that results from a homozygous pathogenic variant in the ACACA gene in the Iranian family. The proband presents with motor and intellectual developmental delay, muscle weakness, language disorder, facial dysmorphism, and poor growth. The patient discussed here is similar to other patients that were previously published; however, we were able to identify seizure that has hitherto not been reported. This paper describes the third person with a novel variant in the ACACA gene in the world that accounts for acetyl-CoA carboxylase deficiency and implicates the clinical spectrum of the disease. Finally, we describe an individual-based review of the symptoms associated with acetyl-CoA carboxylase deficiency. So far, only two acetyl-CoA carboxylase deficiency patients have been reviewed in the literature.

Healthcare utilization by children with neurological impairments and disabilities in rural Kenya: a retrospective cohort study combined with secondary analysis of audit data

Background: There is a paucity of data on healthcare utilization by children with neurological impairments (NI) in sub-Saharan Africa. We determined the rate, risk factors, causes, and outcomes of hospital admission and utilization patterns for rehabilitative care among children with NI in a defined rural area in Kenya. Methods: We designed two sub-studies to address the primary objectives. Firstly, we retrospectively observed 251 children aged 6–9 years with NI and 2162 age-matched controls to determine the rate, causes and outcomes of hospitalization in a local referral hospital. The two cohorts were identified from an epidemiological survey conducted in 2015 in a defined geographical area. Secondly, we reviewed hospital records to characterize utilization patterns for rehabilitative care. Results: Thirty-four in-patient admissions occurred in 8503 person-years of observation (PYO), yielding a crude rate of 400 admissions per 100 000 PYO (95% confidence interval (Cl): 286–560). The risk of admission was similar between cases and controls (rate ratio=0.70, 95%CI: 0.10–2.30, p = 0.31). The presence of electricity in the household was associated with reduced odds of admission (odds ratio=0.32, 95% Cl: 0.10–0.90, p &lt; 0.01). Seizures and malaria were the main causes of admission. We confirmed six (0.3%) deaths during the follow-up period. Over 93% of outpatient paediatric visits for rehabilitative care were related to cerebral palsy and intellectual developmental delay. Health education (87%), rehabilitative exercises (79%) and assistive technology (64%) were the most common interventions. Conclusions: Surprisingly, the risk of hospitalization was not different between children with NI and those without, possibly because those with severe NI who died before this follow-up were under seclusion and restraint in the community. Evidence-based and tailored rehabilitative interventions are urgently required based on the existing secondary data.

Two infants with mild, atypical clinical features of Kagami-Ogata syndrome caused by epimutation

Kagami-Ogata syndrome (KOS) is an imprinting disorder characterized by polyhydramnios, bell-shaped thorax with coat-hanger appearance (curved ribs), respiratory distress, abdominal wall defects, and distinct facial features, together with intellectual developmental delay with special needs. Abnormal expression of the imprinted genes on chromosome 14q32.2 causes KOS. Epimutation with aberrant hypermethylation of the MEG3/DLK1: intergenic differentially methylated region (MEG3/DLK1:IG-DMR) and the MEG3:TSS-DMR is one of the etiologies of KOS. We report two infants with KOS caused by epimutation presenting with some characteristic clinical features, mild clinical course, and almost normal motor and intellectual development. Methylation analysis for ten DMRs related to major imprinting disorders using pyrosequencing with genomic DNA (gDNA) extracted from leukocytes showed abnormally increased methylation levels of the MEG3/DLK1:IG-DMR and MEG3:TSS-DMR in both patients, but lower than those in patients with paternal uniparental disomy chromosome 14 (upd(14)pat). The methylation levels in the DMRs other than both DMRs were within normal range. We also conducted methylation analysis for the MEG3/DLK1:IG-DMR and MEG3:TSS-DMR with gDNA extracted from nails and buccal cells of both patients. Methylation levels in the MEG3:TSS-DMR, particularly in buccal cells, were closer to normal range compared to those in leukocytes. Microsatellite analysis for chromosome 14 and array comparative hybridization analysis showed no upd(14)pat or microdeletion involving the 14q32.2 imprinted region in either patient. A differential mosaic ratio of cells with aberrant methylation of DMRs at the 14q32.2 imprinted region among tissues (connective tissue, lung, and brain) might have led to their atypical clinical features. Further studies of patients with epimutation should further expand the phenotypic spectrum of KOS.

Intellectual developmental delay and genetic disorders

智力发育落后是高度异质性疾病，具有复杂的遗传学病因。拷贝数变异和单基因疾病是导致智力发育落后发生的主要病理性遗传改变。而染色体微阵列技术和外显组测序技术的临床应用则显著提高了智力发育落后患儿的病因诊断率。.

The Burden of Psychiatric Disorders Associated With Orofacial Cleft Pathology Among Children in Ontario, Canada

Background: Individuals with orofacial cleft (OFC) may be at higher risk of developing psychiatric disorders(PD). We determined the risk of psychiatric diagnoses in children with OFC in Canada. Methods: This population-based retrospective cohort study used health administrative data from the province of Ontario, Canada. Children with OFC who were born from April 1, 1994 to March 31, 2017 in Ontario were each matched to five non-OFC children based on sex, date of birth and mother’s age. We determined rate of events and time-to-event for first diagnosis of PD in children aged ≥3 years(y), and for intellectual developmental delay (IDD) from birth. Risk factors for PD and IDD were assessed using 1-way ANOVA for means, Kruskal-Wallis for medians, χ 2 test for categorical variables. Outcomes: There were 3,051 children with OFC (matched to 15,255 controls), of whom 2,515 OFC patients had complete follow-up to the third birthday (matched to 12,575 controls). The mean age to first PD diagnosis was 8.6±4.2y for OFC patients; the cleft palate group had a higher risk (HR 1.33, 95% CI 1.18-1.49). The OFC patients had a higher risk of IDD diagnosis (HR 8.08, 95% CI 7.28-8.97, p<001), especially those with other congenital malformations (HR 4.57, 95% CI 3.95-5.28 p<0.001). Geography (place of living) was a significant risk factor for PD and IDD. Interpretation: Children born with OFC in Ontario had a higher risk of psychiatric diagnosis and IDD compared to controls. Further research is required to better understand the cause of geographical variation and identify potential areas for intervention. Funding: Claudia Malic was supported by the ICES Faculty Scholars Program. Eric Benchimol was supported by a New Investigator Award from the Canadian Institutes of Health Research, Canadian Association of Gastroenterology, and Crohn’s and Colitis Canada. He was also supported by the Career Enhancement Program of the Canadian Child Health Clinician Scientist Program. Conflict of Interest: Simone Vigod reports royalties from UpToDate Inc for authorship of chapters related to depression and pregnancy. The remaining authors have no conflicts of interest to disclose. Ethical Approval: The Research Ethics Board of the Children’s Hospital of Eastern Ontario approved this study and informed consent was not required as per Ontario privacy law.

Use of the method for the formation of the concepts of size and shape in preschool children for clinical research

The goal of the present study was to test the method of forming or actualizing preverbal concepts in the conditions of an independent search for a task solution in order to use the method in clinical practice. The conditions of the absence of researchers instructions allow: 1) to compare in ontogenetic and clinical aspects; 2) to develop the skills of an independent search for solutions in problem situations; 3) to improve the creative potential of a child; 4) to develop the ability to achieve a goal. The advantage of using the preverbal concepts of size and shape is that this method can be applied to children of primary preschool age and children with a delay in speech development. To test the method, 7 healthy children of the middle preschool age (4-5-year-old children) were selected. The first task was to form or actualize the concept of a bigger or smaller size in children during the simultaneous presentation of 4 flat or volume geometrical figures. The second task was to form or actualize the concept of a flat or volumetric object among simultaneously presented 4 figures of the same size (small, medium or big). To get reward children should have chosen the figure, which was different from the other 3 ones in a trial during the formation of both the concepts. In the both tasks, we calculated the quantity of trials, which were needed for the single attainment or excess of the 70% level of the correct task performance per each type of learning. The behavioral results showed that the learning speeds during the formation of the concepts of the bigger/smaller size and flat/volumetric shape did not significantly differ from each other. It could be suggested that those concepts were equally important for the 4-5-year-old children. The study showed that the concept formation model is a convenient psychological method for testing the level of the development of the higher cognitive functions in participants and its use is possible in clinical practice with the parallel recording of the brain activity (EEG, evoked potentials etc.) in children in the process of their performing cognitive tasks. The described model is promising for identifying intellectual developmental delays in preschool children and can be used to test children with various cognitive abnormalities.

A transient lesion occupying the entire corpus callosum associated with neonatal hypoglycemia

A one-year-old girl, the product of an uncomplicated vaginal delivery presented on day 3 of life with complaints of poor sucking. She was hypotonic on examination and ultimately developed seizures. Laboratory examination revealed marked hypoglycemia (2 mg/dL). Rest of the investigations including serum electrolytes was normal but serum osmolality was not done at that time. Her symptoms resolved with glucose loading. The etiology of her hypoglycemia was unclear. Computerized tomography of the brain demonstrated bilateral low-density lesions in the occipital lobes on the 4th postnatal day. On postnatal day 17, diffusion weighted magnetic resonance imaging (MRI) of the brain disclosed a high intensity lesion occupying the entire corpus callosum (Fig. 1), with an accompanying lesion in the occipital lobe present on a T2-weighted MRI (Fig. 2). The corpus callosum lesion resolved at three months of age. Presently the patient only has mild motor and intellectual developmental delay. Reversible lesions occupying the entire corpus callosum or the splenium, characterized by reduced diffu-

Short Communication Assessment of clinical scoring systems for the diagnosis of Williams-Beuren syndrome

Williams-Beuren syndrome (WBS) is a genetic disorder characterized by physical and intellectual developmental delay, associated with congenital heart disease and facial dysmorphism. WBS is caused by a microdeletion on chromosome 7 (7q11.23), which encompasses the elastin (ELN) gene and about 27 other genes. The gold standard for WBS laboratory diagnosis is FISH (fluorescence in situ hybridization), which is very costly. As a possible alternative, we investigated the accuracy of three clinical diagnostic scoring systems in 250 patients with WBS diagnosed by FISH. We concluded that all three systems could be used for the clinical diagnosis of WBS, but they all gave a low percentage of false-positive (6.0-9.2%) and false-negative (0.8-4.0%) results. Therefore, their use should be associated with FISH testing.