Severe Intellectual Impairment Research Articles

NGS-Based Identification of Two Novel PCDH19 Mutations in Female Patients with Early-Onset Epilepsy.

Developmental and epileptic encephalopathy-9 (DEE9) is characterized by seizure onset in infancy, mild to severe intellectual impairment, and psychiatric features and is caused by a mutation in the PCDH19 gene on chromosome Xq22. The rare, unusual X-linked type of disorder affects heterozygous females and mosaic males; transmitting males are unaffected. In our study, 165 patients with epilepsy were tested by Next Generation Sequencing (NGS)-based panel and exome sequencing using Illumina technology. PCDH19 screening identified three point mutations, one indel, and one 29 bp-long deletion in five unrelated female probands. Two novel mutations, c.1152_1180del (p.Gln385Serfs*6) and c.830_831delinsAA (p.Phe277*), were identified and found to be de novo pathogenic. Moreover, among the three inherited mutations, two originated from asymptomatic mothers and one from an affected father. The PCDH19 c.1682C>T and c.1711G>T mutations were present in the DNA samples of asymptomatic mothers. After targeted parental testing, X chromosome inactivation tests and Sanger sequencing were carried out for mosaicism examination on maternal saliva samples in the two asymptomatic PCDH19 mutation carrier subjects. Tissue mosaicism and X-inactivation tests were negative. Our results support the opportunity for reduced penetrance in DEE9 and contribute to expanding the genotype-phenotype spectrum of PCDH19-related epilepsy.

The Effect of O'clock Puzzle Playing Therapy on Cognitive Function in the Elderly in Nursing Home Area 3 Cirebon in 2023

Significant changes in the neurological system, which can lead to a decline in cognitive function, are shared among the aged. Giving puzzle play therapy to senior citizens is one way to enhance their cognitive abilities. This study aims to find out how O'clock Puzzle Play Therapy affects cognitive function in the elderly at Nursing Home Region 3 Cirebon in 2023. This study uses a pretest-posttest with a control group design and a proper experimental design. A total of 40 respondents make up the sample, which is obtained by complete sampling. They are employing the SPMSQ questionnaire to assess the cognitive abilities of the elderly. Univariate and bivariate data analysis was performed using the data normalcy test and the marginal homogeneity test. When older patients receiving o'clock puzzle play therapy were compared to those who did not get therapy, the results of the intellectual evaluation score using the SPMSQ showed a substantial rise. Four older adults from the intervention group (26.7%) who had severe cognitive impairment during the SPMSQ assessment prior to playing the o'clock puzzle therapy had severe intellectual impairment. In contrast, the number of older adults in the intervention group who had severe intellectual impairment decreased to zero. The study's findings, when combined with the Asymptotic value of the Marginal Homogeneity Test, indicate that o'clock puzzle play therapy impacts cognitive performance in the senior residents of the regional 3 Cirebon caring facility. 0.002 as the 2-tailed significance. Asymptotic value. Sig shows an Asymp in this study. The value difference is substantial when the sig value is less than 0.05.

Clinical features associated with epilepsy occurrence, resolution, and drug resistance in children with cerebral palsy: A population-based study.

To investigate clinicoradiological features associated with epilepsy, its resolution, and drug resistance in children with cerebral palsy (CP). Data were gathered from the New South Wales/Australian Capital Territory CP Register, encompassing children with CP born between 2003 and 2015 (n = 1916). Clinical features and the severity of impairments were compared among three groups: children with current epilepsy (n = 604), those with resolved epilepsy by age 5 years (n = 109), and those without epilepsy (n = 1203). Additionally, a subset of the registry cohort attending Children's Hospital Westmead (n = 256) was analysed to compare epilepsy and treatment characteristics between drug-responsive (n = 83) and drug-resistant groups (n = 147) using logistic regression and hierarchical cluster analysis. Manual Ability Classification System levels IV and V, intellectual impairment, and vision impairment were found to be associated with epilepsy in children with CP on multivariable analysis (p < 0.01). Moderate to severe intellectual impairment and bilateral spastic CP were independent positive and negative predictors of epilepsy persistence at the age of 5 years respectively (p < 0.05). Microcephaly and multiple seizure types were predictors of drug-resistant epilepsy (area under the receiver operating characteristic curve of 0.83; 95% confidence interval 0.77-0.9). Children with a known genetic cause (14%) and CP epilepsy surgery group (4.3%) formed specific clinical subgroups in CP epilepsy. Our study highlights important clinical associations of epilepsy, its resolution, and treatment response in children with CP, providing valuable knowledge to aid in counselling families and identifying distinct prognostic groups for effective medical surveillance and optimal treatment. Severe motor and non-motor impairments in cerebral palsy (CP) increase epilepsy risk. Epilepsy more likely resolves in bilateral spastic and milder CP impairments. Epilepsy in CP often manifests at an early age with multiple seizure types and high drug resistance. Children with a known genetic cause and CP epilepsy surgery group represent distinct clinical subgroups.

A single-center observational study on long-term neurodevelopmental outcomes in children with tuberous sclerosis complex

BackgroundTuberous sclerosis complex (TSC) is a rare multisystem disorder caused by mutations in the TSC1 or TSC2 gene. More than 90% of patients with TSC develop neurological and/or neuropsychiatric manifestations. The aim of the present study was to determine the developmental and cognitive long-term outcomes of pediatric TSC patients.MethodsThis cross-sectional, monocenter study included pediatric TSC patients who received multidisciplinary long-term care with a last visit between 2005 and 2019. Neurological manifestations and cognitive development (BSID, K-ABC) were analyzed in relation to age and type of mutation.ResultsThirty-five patients aged 13.5 ± 7.8 years were included in the study. Diagnosis was confirmed genetically in 65.7% of patients (TSC1, 26.1%; TSC2, 65.2%; NMI, 8.7%). Mean age at diagnosis was 1.3 ± 3.5 years; 74.3% of the patients had been diagnosed within the first year of life due to seizures (62.9%) or/and cardiac rhabdomyomas (28.6%). The most common TSC manifestations included structural brain lesions (cortical tubers, 91.4%; subependymal nodules, 82.9%), epilepsy (85.7%), and cardiac rhabdomyomas (62.9%). Mean age at seizure onset was 1.5 ± 2.3 years, with onset in 80.0% of patients within the first two years of life. Infantile spasms, which were the first seizure type in 23.3% of the patients, developed earlier (0.6 ± 0.4 years) than focal seizures (1.8 ± 2.5 years). Refractory epilepsy was present in 21 (70.0%) patients, mild or severe intellectual impairment in 66.6%, and autism spectrum disorders in 11.4%. Severe cognitive impairment (33.3%) was significantly associated with epilepsy type and age at seizure onset (p < 0.05).ConclusionsThe results emphasized the phenotypic variability of pediatric-onset TSC and the high rate of neurological and neuropsychiatric morbidity. Early-onset refractory epilepsy was associated with impaired cognitive development. Children of all ages with TSC require multidisciplinary long-term care and individual early-intervention programs.

Missing Narrative: Examining the Impact of Disability on Post-Operative Infectious Complications.

Background: More than 20% of the population in the United States suffers from a disability, yet the impact of disability on post-operative outcomes remains understudied. This analysis aims to characterize post-operative infectious complications in patients with disability. Patients and Methods: This was a retrospective review of the National Readmission Database (2019) among patients undergoing common general surgery procedures. As per the U.S. Centers for Disease Control and Prevention (CDC), disability was defined as severe hearing, visual, intellectual, or motor impairment/caregiver dependency. A propensity-matched analysis comparing patients with and without a disability was performed to compare outcomes, including post-operative septic shock, sepsis, bacteremia, pneumonia, catheter-associated urinary tract infection (CAUTI), urinary tract infection (UTI), catheter-associated blood stream infection, Clostridioides Difficile infection, and superficial, deep, and organ/space surgical site infections during index hospitalization. Patients were matched using age, gender, comorbidities, illness severity, income, neighborhood, insurance, elective procedure, and the hospital's bed size and type. Results: A total of 710,548 patients were analysed, of whom 9,451(1.3%) had at least one disability. Motor disability was the most common (3,762; 40.5%), followed by visual, intellectual, and hearing impairment. Patients with disability were older (64 vs. 57 years; p < 0.001), more often insured under Medicare (65.2% vs. 37.3% p < 0.001) and had more medical comorbidities (Elixhauser comorbidity score ≥3; 69.2% vs. 41.9%; p < 0.001). After matching, 9,292 pairs were formed. Patients with a disability had a higher incidence of pneumonia (10.1% vs. 6.5%; p < 0.001), aspiration pneumonia (5.2% vs. 1.4%; p < 0.001), CAUTI (1.0% vs. 0.4%; p < 0.001), UTI (10.4% vs. 6.2%; p < 0.001), and overall infectious complications (21.8% vs. 14.5%; p < 0.001). Conclusions: Severe intellectual, hearing, visual, or motor impairments were associated with a higher incidence of infectious complications. Further investigation is needed to develop interventions to reduce disparities among this high-risk population.

Cardiotocography, Hypoxia, and Feto-Neonatal Neurological Damage

Complications occurring at any level of fetal oxygen supply can result in hypoxemia, which may ultimately lead to hypoxia/acidosis and neurological damage. Hypoxic-ischemic encephalopathy (HIE) is the short-term neurological dysfunction caused by intrapartum hypoxia/acidosis. This diagnosis requires the presence of several findings, including confirmation of newborn metabolic acidosis, low Apgar scores, early imaging evidence of cerebral edema, and the appearance of clinical signs of neurological dysfunction in the first 48 hours of life. Cerebral palsy (CP) comprises a heterogeneous group of nonprogressive movement and posture disorders, often accompanied by cognitive and sensory impairments, epilepsy, nutritional deficiencies, and secondary musculoskeletal lesions. Although CP is the most common long-term neurological complication associated with intrapartum hypoxia/acidosis, over 80% of cases are caused by other factors. Data on minor long-term neurological deficits are limited, but they suggest that less severe intellectual and motor impairments may result from intrapartum hypoxia/acidosis. Birth asphyxia is a broad term referring to intrapartum asphyxia severe enough to cause neurological damage in some newborns and, rarely, intrapartum or neonatal death. Cerebral palsy and long-term neurological complications such as learning difficulties and motor impairments may have causes other than birth asphyxia. Several intrapartum events can lead to asphyxia (i.e., hypoxia and metabolic acidosis), increasing the likelihood of neurological injury. The cardiotocograph (CTG) is a screening tool used to assess fetal well-being during labor and to identify the possibility of asphyxia. An abnormal CTG, sometimes severe enough to be described as a pathological trace, is commonly referred to as “fetal distress”, although many fetuses with such traces may not have hypoxia and metabolic acidosis. In current practice, these events are appropriately termed “pathological CTG trace” or “acidotic pH” rather than “fetal distress”. Accurate interpretation of the CTG is essential, and it is important to recognize a fetus displaying a pathological CTG in labor, which may imply possible hypoxia and birth asphyxia. Considering the broader clinical context when interpreting the CTG and taking timely and appropriate action based on the findings may help prevent birth asphyxia.

A-312 Segregation in Two Families of the PCDH19Gene Deletion Associated With Infantile Epileptic Encephalopathy of X-Linked Inheritance and Expression in Female Carriers

Abstract Background Developmental and epileptic encephalopathy-9 (DEE9) is an X-linked disorder characterized by seizure onset in infancy and mild to severe intellectual impairment. Autistic and psychiatric features have been reported in some individuals. The disorder affects heterozygous females only; transmitting males are unaffected. We described the segregation in two unrelated families where the proband was clinically affected as a female and another family where the proband was clinically unaffected as a male. Methods Array-CGH analysis was performed by a CGXTM HD v1,1 4-plex array 180 k (PerkinElmer), with an average resolution of 40 kb in the backbone and 20 kb in the regions of interest. Results In the first family a deletion of 809.93 Kilobases was detected in the chromosomal region Xq22.1, which includes the PCDH19 gene, in a 1 year old patient with very early onset seizures, 8 months old, inherited from an asymptomatic father. In the second family, a deletion that includes the entire PCDH19 gene was detected in a 5-year-old male patient referred to genetics for autism spectrum disorder (ASD) and not symptomatic for epilepsy; this deletion was inherited from a mother who had episodes of epilepsy in childhood. Conclusion The aCGH technique is currently the technique of choice to determine the presence of deletions/duplications in genes of interest with high reliability in patients with neurodevelopmental disorders such as epilepsy or ASD. The probands of these two families have been studied for different clinical pathology and in both the deletion of the complete PCDH19 gene has been detected. The PCDH19 gene is expressed in developing human and mouse central nervous system, including the hippocampus and cortex, suggesting a role in cognitive function. Malfunction of the protocadherin19 protein is the cause of epileptic seizures in early childhood, the seizures are mostly focal and cause serial seizures (many seizures that cluster together over a few days). It is a type of epilepsy that usually begins in early childhood. Onset may occur spontaneously or in association with fever. Mutations/deletions of the PCDH19 gene are described to cause Early Childhood Epileptic Encephalopathy, with high but incomplete penetrance. DEE9 affects only females heterozygous for the deletion and is characterised by childhood onset of seizures/epilepsy, usually with mild/severe intellectual disability, with males being healthy carriers. Although the cause is not known specifically, it is thought to be related to X-chromosome silencing that occurs in females heterozygous for this mutation. It causes an autosomal dominant X-linked disorder. Some cases of males with a mosaic PCDH19 mutation/deletion have been found to be affected and it has been suggested that the presence of both the normal gene and the mutated/deleted gene is necessary to develop for this epileptic encephalopathy.

SLC4A10 mutation causes a neurological disorder associated with impaired GABAergic transmission.

SLC4A10 is a plasma-membrane bound transporter that utilizes the Na+ gradient to drive cellular HCO3- uptake, thus mediating acid extrusion. In the mammalian brain, SLC4A10 is expressed in principal neurons and interneurons, as well as in epithelial cells of the choroid plexus, the organ regulating the production of CSF. Using next generation sequencing on samples from five unrelated families encompassing nine affected individuals, we show that biallelic SLC4A10 loss-of-function variants cause a clinically recognizable neurodevelopmental disorder in humans. The cardinal clinical features of the condition include hypotonia in infancy, delayed psychomotor development across all domains and intellectual impairment. Affected individuals commonly display traits associated with autistic spectrum disorder including anxiety, hyperactivity and stereotyped movements. In two cases isolated episodes of seizures were reported in the first few years of life, and a further affected child displayed bitemporal epileptogenic discharges on EEG without overt clinical seizures. While occipitofrontal circumference was reported to be normal at birth, progressive postnatal microcephaly evolved in 7 out of 10 affected individuals. Neuroradiological features included a relative preservation of brain volume compared to occipitofrontal circumference, characteristic narrow sometimes 'slit-like' lateral ventricles and corpus callosum abnormalities. Slc4a10 -/- mice, deficient for SLC4A10, also display small lateral brain ventricles and mild behavioural abnormalities including delayed habituation and alterations in the two-object novel object recognition task. Collapsed brain ventricles in both Slc4a10-/- mice and affected individuals suggest an important role of SLC4A10 in the production of the CSF. However, it is notable that despite diverse roles of the CSF in the developing and adult brain, the cortex of Slc4a10-/- mice appears grossly intact. Co-staining with synaptic markers revealed that in neurons, SLC4A10 localizes to inhibitory, but not excitatory, presynapses. These findings are supported by our functional studies, which show the release of the inhibitory neurotransmitter GABA is compromised in Slc4a10-/- mice, while the release of the excitatory neurotransmitter glutamate is preserved. Manipulation of intracellular pH partially rescues GABA release. Together our studies define a novel neurodevelopmental disorder associated with biallelic pathogenic variants in SLC4A10 and highlight the importance of further analyses of the consequences of SLC4A10 loss-of-function for brain development, synaptic transmission and network properties.

Characterizing the physical and mental health profile of children, adolescents and adults with autism spectrum disorder in Spain.

Autistic men and women are more likely to experience health issues than the general population, although the available epidemiological studies addressing co-occurrence conditions are limited. This is the first Spanish epidemiologic study addressing the health profile and poor-health exacerbating factors in individuals of all ages with autism spectrum disorder (ASD). We analyzed 2,629 registries extracted from Autism Spain's sociodemographic registry (November 2017-May 2020). A descriptive health data analysis was conducted to assess the prevalence of other conditions associated to ASD in the Spanish population. Nervous system disorders (12.9%), mental health diagnoses (17.8%), and other comorbidities (25.4%) were reported. Men-to-women ratio was 4:1. Women, elder individuals and those with intellectual disability (ID) were at an increased risk of health comorbidities and psychopharmacological exposure. Women were also more prone to severe intellectual and functional impairment. Nearly all individuals had difficulties in their adaptative functioning, especially those with ID (50% of the population). Almost half of the sample received psychopharmacological treatments starting from infancy and early childhood, mostly antipsychotics and anticonvulsants. This study represents an important first approach to the health status of autistic people in Spain and can contribute to the development of public policies and innovative health strategies.

Expanding the phenotype of children presenting with hypoventilation with biallelic TBCK pathogenic variants and literature review

Individuals with biallelic TBCK pathogenic variants present in infancy with distinctive facial features, profound hypotonia, severe intellectual impairment and epilepsy. Although rare, it may mimic other neurogenetic disorders leading to extensive investigations. Improved understanding of the clinical phenotype can support early monitoring of complications due to respiratory insufficiency. We present six individuals who were found to have pathogenic biallelic TBCK variants. The clinico-radiological and diagnostic records were reviewed. Five individuals were diagnosed with hypoventilation, requiring respiratory support, highlighting the need for early respiratory surveillance. Characteristic brain imaging in our cohort included periventricular leukomalacia-like changes. We recommend screening for TBCK in hypotonic children with periventricular leukomalacia-like changes, particularly in the absence of prematurity.

Similarities and Differences in the Neurodevelopmental Outcome of Children with Congenital Heart Disease and Children Born Very Preterm at School Entry

To describe the similarities and differences in the neurodevelopmental outcome of children with congenital heart disease (CHD) undergoing cardiopulmonary bypass surgery compared with children born very preterm (VPT) at school entry. IQ, motor abilities, behavior, and therapy use were assessed in 155 children with CHD as part of a prospective, single-center, longitudinal study, and in 251 children born VPT as part of a national follow-up register at the same center. Group differences were tested using independent t-tests and χ2-tests. Equivalence testing was used to investigate similarities between the groups. Mild (ie, 70 ≤ IQ<85) and severe intellectual impairments (ie, IQ<70) occurred in 17.4% and 4.5% of children with CHD compared with 22.1% and 5.5% in children VPT, respectively. Motor and behavioral functions were impaired in 57.0% and 15.3% of children with CHD compared with 37.8% and 11.5% of children born VPT, respectively. Children with CHD had poorer global motor abilities (d=-0.26) and poorer dynamic balance (d=-0.62) than children born VPT, and children born VPT had poorer fine motor abilities than children with CHD (d=0.34; all P<.023). Peer problems were statistically similar between the groups (P=.020). Therapies were less frequent in children with CHD compared with children born VPT (23.4% vs 40.3%; P<.001). Children with CHD undergoing cardiopulmonary bypass surgery and children born VPT share an overall risk for neurodevelopmental impairments that manifest in different domains. Despite this, children with CHD receive fewer therapies, indicating a lack of awareness of the neurodevelopmental burden these children face.

The Challenges and Dilemmas of Interpreting Protein Labelling of Prepackaged Foods Encountered by the PKU Community.

Phenylketonuria (PKU) can lead to severe intellectual impairment unless a phenylalanine-restricted diet starts early in life. It requires expert user knowledge about the protein content of foods. The ability of adults or caregivers of children with PKU to calculate protein exchanges from food labels on manufactured foods and any difficulties they encounter in interpreting food labels has not been studied systematically. Individuals with PKU or their caregivers residing in the UK were invited to complete a cross-sectional online survey that collected both qualitative and quantitative data about their experience when calculating protein exchanges from the food labelling on prepackaged foods. Data was available from 246 questionnaire respondents (152 caregivers of patients with PKU aged <18 years, 57 patients with PKU aged ≥18 years or their caregivers (n = 28), and 9 teenagers with PKU). Thirty-one per cent (n = 76/246) found it difficult to interpret food protein exchanges from food labels. The respondents listed that the main issues with protein labelling were the non-specification of whether the protein content was for the cooked or uncooked weight (64%, n = 158/246); labels stating foods contained 0 g protein but then included protein sources in the list of ingredients (56%, n = 137/246); the protein content being given after a product was prepared with regular milk rather than the dry weight of the product (55%, n = 135/246); and the non-clarity of whether the protein content was for the weight of prepared or unprepared food (in addition to non-specification of cooked or uncooked weights on food labelling) (54%, n = 133/246). Over 90% (n = 222/246) of respondents had experienced problems with food labelling in the previous six months. Misleading or confusing protein labelling of manufactured foods was common. The food industry and legislators have a duty to provide accurate and clear protein food labelling to protect populations requiring low protein diets.

Phonological Process in Arabic-Speaking Children with Down Syndrome: A Psycholinguistic Investigation

No prevalence statistics for articulation and phonological problems in Arabic children with Down syndrome (DS) have been published. The goal of this study was to see how common consonant production errors and phonological processes are in Emirati Arabic-speaking children with DS, and how they relate to their intellectual level and hearing status. Thirty Emirati children with DS, aged 9–12 years, and a control group of the same age, participated. An informal linguistic assessment was used to diagnose all the participants. All the participants were found to have phonological and articulation problems. On total words in mistake and typical segmental errors, there were significant disparities between the normal hearing group and the mild conductive hearing loss group. On the total number of wrong words and normal and atypical segmental errors, there were similar significant disparities between mild and severe intellectual impairments. Furthermore, as the age of the participants increased, the percentage of errors reduced.

Monitoring system for assessing children’s with severe intellectual impairments life competencies (Part 1)

Monitoring system for assessing children’s with severe intellectual impairments life competencies (Part 1)

16.5 CARVING CLINICAL HETEROGENEITY AT ITS JOINTS: THE POTENTIAL ROLE OF COPY NUMBER VARIATION IN UNDERSTANDING AUTISM SPECTRUM DISORDER

Autism spectrum disorder (ASD) is characterized by marked clinical heterogeneity. Copy number variation (CNV), a type of structural genetic variation involving the deletion or duplication of a DNA segment, may help parse this heterogeneity by defining ASD subtypes. Several CNV-associated ASD syndromes have been described with characteristic phenotypes. This presentation will focus on 1 such syndrome, 16p11.2 CNV, and will include a discussion of recent unpublished work that we have conducted with this population. We will discuss what is known about the 16p11.2 CNV. We will then describe the results and implications of the recent work we conducted with a small (n = 19) pilot sample of 16p11.2 CNV carriers. 16p11.2 duplication and 16p11.2 deletion are both associated with ASD, but their clinical phenotypes otherwise diverge in notable ways. 16p11.2 duplication is associated with microcephaly, thinness, and a variable degree of intellectual impairment (from mild to severe). 16p11.2 deletion is associated with macrocephaly, obesity, and consistently severe intellectual impairment. Notably, 16p11.2 duplication, but not the deletion, is also associated with schizophrenia. In a small pilot study, we conducted in-depth interviews with 16p11.2 duplication and deletion carriers and assessed them for formal thought disorder. We found a suggestion of quantitative differences in thought process between the 2 groups. Given the small size of our pilot sample, our findings are not definitive. However, they represent a proof of concept that CNVs represent a way to identify subtle, detectable differences between people with ASD that would otherwise be obscured by the disorder’s overall heterogeneity and that may have clinical meaning.

A comparison of formal and informal methods for assessing language and cognition in children with Rett syndrome

BackgroundOpinions about the cognitive and receptive language skills of people with Rett syndrome (RTT) range from severe intellectual impairment to near-normal development. Assessment is challenging because most are non-verbal, with no purposeful hand use. Clarkson et al. (2017) adapted the Mullen Scales of Early Learning for use with eye gaze technology (MSEL-A/ET) for people with RTT. AimsTo investigate and compare the performance of children with RTT on formal and newly-designed informal assessments of language and cognition using eye gaze/tracking technology. Methods and proceduresTen children with RTT aged 4:0–6:8 were assessed on the MSEL-A/ET for Visual Reception (VR) and Receptive Language (RL), and standard MSEL for Expressive Language (EL). Informal assessments of the same skills were embedded in activities such as reading and cake-decorating. Outcomes and resultsStandard scores on MSEL-A/ET VR and RL subtests ranged from ‘very low’ to ‘above average’. All children scored ‘very low’ on standard EL assessment. Informal assessments added information about EL, with children producing 1–3 word utterances and a range of communicative functions through an eye gaze device. Conclusions and implicationsCombining low-tech augmentative and alternative communication, eye gaze technology, informal activities and formal assessment, yields greater insight into children’s abilities. This is important in informing suitable support and education for the individual.

FBXO28 causes developmental and epileptic encephalopathy with profound intellectual disability.

Chromosome 1q41-q42 deletion syndrome is a rare cause of intellectual disability, seizures, dysmorphology, and multiple anomalies. Two genes in the 1q41-q42 microdeletion, WDR26 and FBXO28, have been implicated in monogenic disease. Patients with WDR26 encephalopathy overlap clinically with those with 1q41-q42 deletion syndrome, whereas only one patient with FBXO28 encephalopathy has been described. Seizures are a prominent feature of 1q41-q42 deletion syndrome; therefore, we hypothesized that pathogenic FBXO28 variants cause developmental and epileptic encephalopathies (DEEs). We describe nine new patients with FBXO28 pathogenic variants (four missense, including one recurrent, three nonsense, and one frameshift) and analyze all 10 known cases to delineate the phenotypic spectrum. All patients had epilepsy and 9 of 10 had DEE, including infantile spasms (3) and a progressive myoclonic epilepsy (1). Median age at seizure onset was 22.5months (range 8months to 5years). Nine of 10 patients had intellectual disability, which was profound in six of nine and severe in three of nine. Movement disorders occurred in eight of 10 patients, six of 10 had hypotonia, four of 10 had acquired microcephaly, and five of 10 had dysmorphic features, albeit different to those typically seen in 1q41-q42 deletion syndrome and WDR26 encephalopathy. We distinguish FBXO28 encephalopathy from both of these disorders with more severe intellectual impairment, drug-resistant epilepsy, and hyperkinetic movement disorders.

Case report: Pitt-Hopkins like syndrome with CNTNAP2 mutation

BackgroundPitt-Hopkins syndrome (PHS) is a rare cause of severe intellectual disability, seizures, language impairment, and peculiar facial dysmorphism. It is caused by a mutation in transcription factor 4 (TCF4). Through molecular karyotyping and mutational analysis, a study identified recessive defects in two genes, contactin associated protein like 2 (CNTNAP2) and Neurexin I (NRXN1), in patients with similar presentations of Pitt-Hopkins syndrome and called Pitt-Hopkins-like syndrome (Zweier et al., J Med Genet 80: 994-1001, 2007).We present the first case report of a child in Iraq with Pitt-Hopkins-like syndrome that was referred to the Welfare Children’s Hospital/Medical City of Baghdad because of her intellectual disability.Case presentationThe patient was 4-year-old female child who presented with psychomotor delay and language impairment. She had frequent attacks of the respiratory tract and eye infections. Ophthalmologic examination revealed left-sided esotropia and severe myopia. Routine hematologic, serologic, and chemistry tests were within normal ranges. EEG revealed diffuse theta slowing and diffuse beta activity. The audiological test was normal. NCS and EMG showed normal results. Echo study, chest X-ray, and abdominal/pelvic ultrasound revealed normal findings. Brain MRI showed mild bilateral frontal-temporal atrophy. Whole-exome sequencing (WES) revealed a homozygous stop mutation in CNTNAP2 with a heterozygous state in both parents.ConclusionIntellectual disability may result from different types of abnormal cellular processes and with widening the use of molecular gene analysis in cases of intellectual disability, underdiagnosed cases of Pitt-Hopkins and Pitt-Hopkins-like syndromes may be uncovered.

Did previous involvement in research affect recruitment of young people with cerebral palsy to a longitudinal study of transitional health care?

ObjectiveTo assess whether being contacted about or participating in previous research and method of approaching potential participants affected recruitment to a transition study from child to adult healthcare services of...

Cancer treatment in disabled children.

The incidence of cancer in children with intellectual disability has been poorly documented. We report our experience of treating children and adolescents with cancer and intellectual disability (40 patients), from 2004 to 2018. A treatment-sparing approach was adopted for 6 patients with severe intellectual impairment to minimize toxicity: a child with postpartum asphyxia and medulloblastoma did not receive radiotherapy; 1 patient with mitochondrial encephalopathy and a testicular germ cell tumor did not receive bleomycin and lung metastasectomy; 2 patients (1 with Down + West syndrome + Wilms tumor (WT) and 1 with Denys-Drash syndrome + WT) did not receive vincristine; 1 child with corpus callosum agenesis and anaplastic ependymoma did not receive chemotherapy; 1 child with structural chromosomal aberrations and a primitive neuro-ectodermal tumor received personalized chemotherapy. Heminephrectomy was performed in 4 patients with WT to preserve their kidney function. We found no statistically significant correlation between relapse or mortality rates and the use of a treatment-sparing approach. The 5-year overall survival (OS) and event-free survival (EFS) rates were 84.5% and 66.1% as opposed to 82.5% and 46.9%, respectively, for patients in our usual-treatment and treatment-sparing groups.Conclusion: We only opted for a treatment-sparing approach for patients with severe disabilities, and their OS was in line with that of children without intellectual disability. What is Known: • There are few reports on children/adolescents with cancer and intellectual disability (ID). • It is not clear how to manage them and whether a treatment sparing should be considered, especially in the case of severe disability. What is New: • Most patients received the standard cancer treatment and only in the case of severe disability, a therapeutic saving approach was applied. • No statistically significant correlations between relapse/mortality rates and the use of a treatment-sparing approach were found.