Severe Intellectual Disability Research Articles

Endovascular treatment in Danon disease: a case report

BackgroundDanon disease is a lysosomal storage disorder with X-linked inheritance. The classic triad is severe hypertrophic cardiomyopathy, myopathy, and intellectual disability, with different phenotypes between both genders. Ischemic stroke is an uncommon complication, mostly cardioembolic, related to intraventricular thrombus or atrial fibrillation, among others.Case reportWe report the case of a 14-year-old Caucasian male patient with Danon disease who suffered from an acute ischemic stroke due to occlusion in the M1 segment of the middle cerebral artery. He underwent mechanical thrombectomy, resulting in successful revascularization with satisfactory clinical outcome. We objectified the intraventricular thrombus in the absence of arrhythmic events.ConclusionTo our knowledge, we report the first case of ischemic stroke related to Danon disease treated with endovascular treatment.

Clinical and genetic analyses of APMR4 syndrome caused by novel biallelic LSS variants

Alopecia intellectual disability syndromes 4 (APMR4) caused by Lanosterol synthase (LSS) gene variants is a very rare autosomal recessive neuroectodermal syndrome. It is characterized by congenital alopecia and variable degrees of intellectual disability (ID), frequently associated with developmental delay (DD) and epilepsy. Currently, only three studies regarding LSS-related APMR4 have been reported, the pathogenesis of APMR4 is poorly understood. We studied one patient with LSS-related APMR4 who presented with severe intellectual disability, alopecia, early-onset epilepsy and developmental delay. She is absence of hair on the eyebrows, eyelashes, and scalp. Two novel LSS variants (c.401 T > G and c.369C > G) were detected with whole-exome sequencing (WES). Analysis via WB experiment indicated that c.369 > G reduced the protein expression level of LSS. Analysis of protein stability prediction showed a destabilizing for LSS caused by the variant c.401 T > G. This study is the first study in Asia to date. These findings expanded the variantal spectrum of LSS-related APMR4 and revealed the potential pathogenic mechanism of LSS gene variants.

Identification of Iodotyrosines as Novel Substrates for the Thyroid Hormone Transporter MCT8.

Background: Monocarboxylate transporter 8 (MCT8) is the most specific thyroid hormone transporter identified to date, deficiency of which has been associated with severe intellectual and motor disability and abnormal serum thyroid function tests. However, it is presently unknown if MCT8, similar to other thyroid hormone transporters, also accepts additional substrates, and if disruption of their transport may contribute to the observed phenotype. Methods: In this study, we aimed to identify such substrates by applying liquid chromatography-mass spectrometry-based metabolome analysis in lysates of control and MCT8-overexpressing Xenopus oocytes. A subset of identified candidate substrates were validated by direct transport studies in transiently transfected COS-1 cells and human fibroblasts, which endogenously express MCT8. Moreover, transport characteristics were determined, including transport saturation and cis-inhibition potency of thyroid hormone transport. Results: Metabolome analysis identified 21 m/z ratios, corresponding to 87 candidate metabolites, with a 2.0-times differential abundance in MCT8-injected oocytes compared with controls. These metabolites included 3,5-diiodotyrosine (DIT) and several amino acids, including glutamate and glutamine. In accordance, MCT8-expressing COS-1 cells had 2.2-times lower intracellular accumulation of [125I]-DIT compared with control cells. This effect was largely blocked in the presence of 3,3',5-triiodothyronine (T3) (IC50: 2.5 ± 1.5 µM) or thyroxine (T4) (IC50: 5.8 ± 1.3 µM). Conversely, increasing concentrations of DIT enhanced the accumulation of T3 and T4. The MCT8-specific inhibitor silychristin increased the intracellular accumulation of DIT in human fibroblasts. COS-1 cells expressing MCT8 also exhibited a 50% reduction in intracellular accumulation of [125I]-3-monoiodotyrosine (MIT). In contrast, COS-1 cells expressing MCT8 did not alter the intracellular accumulation of [3H]-glutamate or [3H]-glutamine. However, studies in human fibroblasts showed a 1.5-1.9 times higher glutamate uptake in control fibroblasts compared with fibroblasts derived from patients with MCT8 deficiency, which was not affected in the presence of silychristin. Conclusions: Taken together, our results suggest that the iodotyrosines DIT and MIT can be exported by MCT8. MIT and DIT interfere with MCT8-mediated transport of thyroid hormone in vitro and vice versa. Future studies should elucidate if MCT8, being highly expressed in thyroidal follicular cells, also transports iodotyrosines invivo.

An Observation Study of Caries Experience and Potential Risk Assessments among Disabled Individuals Living in an Institutional Rehabilitation Centre

The aim of this study was to conduct salivary, microbiological, and caries risk assessments in relation to caries experience among individuals with intellectual disability in an institutional center in the Al-Baha region, Saudi Arabia. A cross-sectional study was conducted among 89 patients residing in special care homes in the Al-Baha region, Saudi Arabia, from October 2023 to February 2024. The demographic details of all participants were recorded. Clinical oral examinations were performed for the decayed, missing, or filled teeth (DMFT) and plaque indices. Salivary and microbiological assessments were also carried out. The mean age of the study sample was 30.11 ± 4.39 years, and the mean duration of years spent residing in the facility was 26.49 ± 4.66. There was no significant difference observed across plaque scores, S. mutans colony count, salivary rate, pH, DFMT, and caries experience when they were compared across the levels of severity of intellectual disability. Statistically significant differences were observed across diet score, circumstance score, and chances to avoid caries and were found to be correlated with the severity of intellectual disability (p = 0.001, p = 0.001, and p = 0.002), respectively. The cariogram revealed that participants in this study had poor oral health status, with participants with severe intellectual disability having higher diet scores, frequency scores, and susceptibility scores; hence lesser chances to avoid dental caries. Regular dental check-ups, including cleanings and other treatments if necessary, seem to be fundamental to prevent dental issues and maintain healthy teeth and gums for this group of people. Developing interventions that focus on improving oral health status among intellectually disabled individuals may be recommended to ensure the optimum level of support and reduce the burden of dental decay among those individuals.

The relationship between clinical presentation and the nature of care in adults with intellectual disability and epilepsy - national comparative cohort study.

A quarter of People with Intellectual Disabilities (PwID) have epilepsy compared with 1% of the general population. Epilepsy in PwID is a bellwether for premature mortality, multimorbidity and polypharmacy. This group depends on their care provider to give relevant information for management, especially epilepsy. There is no research on care status relationship and clinical characteristics of PwID and epilepsy. Explore and compare the clinical characteristics of PwID with epilepsy across different care settings. A retrospective multicentre cohort study across England and Wales collected information on seizure characteristics, intellectual disability severity, neurodevelopmental/biological/psychiatric comorbidities, medication including psychotropics/anti-seizure medication, and care status. Clinical characteristics were compared across different care settings, and those aged over and younger than 40 years. Of 618 adult PwID across six centres (male:female = 61%:39%), 338 (55%) received professional care whereas 258 (42%) lived with family. Significant differences between the care groups existed in intellectual disability severity (P = 0.01), autism presence (P < 0.001), challenging behaviour (P < 0.001) and comorbid physical conditions (P = 0.008). The two groups did not vary in intellectual disability severity/genetic conditions/seizure type and frequency/psychiatric disorders. The professional care cohort experienced increased polypharmacy (P < 0.001) and antipsychotic/psychotropic use (P < 0.001/P = 0.008).The over-40s cohort had lower autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD) comorbidity (P < 0.001/P = 0.007), increased psychiatric comorbidity and challenging behaviour (P < 0.05), physical multimorbidity (P < 0.001), polypharmacy (P < 0.001) and antipsychotic use (P < 0.001) but reduced numbers of seizures (P = 0.007). PwID and epilepsy over 40 years in professional care have more complex clinical characteristics, increased polypharmacy and antipsychotic prescribing but fewer seizures.

Changes in Psychiatric Medication Use During the COVID-19 Pandemic in a Pediatric Long-Term Care Facility.

Background: Coronavirus disease 2019 (COVID-19) caused a global pandemic that dramatically altered infection control procedures in long-term care facilities. Mental health decline among residents of geriatric facilities during the pandemic has been described (Ferro Uriguen et al., 2022). Our study aims to evaluate psychological effects of the pandemic on residents of a pediatric long-term care facility, a population comprised of medically complex children. To characterize this, we compared patterns of psychotropic medication use during the COVID-19 pandemic to those of the prepandemic period among residents of a 76-bed pediatric long-term care facility. Methods: We conducted a retrospective study of psychotropic medication use from January 2019 to August 2022 using de-identified monthly facility medication refill data. Linear multivariable regression models were used to estimate the level and trends in the monthly rates of medication refills per 10,000 bed days among resident children before and after the pandemic onset. Six classes of psychotropic medications were analyzed including antipsychotics, antidepressants and anxiety medications, trazodone, clonidine, mood stabilizers, and gabapentin. Results: The pandemic onset was associated with a significant increase in the monthly prescribing rates of antidepressant and anxiety medications (20.83; 95% CI, 3.96-37.71; p = 0.017), mood stabilizers (10.44; 95% CI, 5.79-15.09; p < 0.001), and trazodone (-27.66; 95% CI, -40.44 to 14.88; p < 0.001) above those expected by prepandemic trends. The trend in trazodone use changed significantly during the pandemic from decreasing prepandemic to increasing (2.21; 95% CI, 1.28-3.14; p < 0.001). Antidepressant, anxiety medication, and gabapentin use increased throughout the study. Antidepressant and anxiety medication use surged early in the pandemic, but then continued growth at their prior rates of use. Discussion: Increased use of antidepressant and anxiety medications and trazodone suggests a possible impact of the COVID-19 pandemic on rates of anxiety, depression, sleep disturbance, and agitation among children with severe intellectual and developmental disabilities living in long-term care.

Особенности интеллектуального развития при расстройстве аутистического спектра (РАС)

&lt;p style="text-align: justify;"&gt;The article presents an overview of the current understanding of the intellectual development of children and adults with autism spectrum disorder (ASD). A review of research indicates a wide heterogeneity in the levels of intellectual development in autism (from severe intellectual disability to giftedness) and demonstrates a lack of specific cognitive and intellectual profiles. The assessment of "strengths" and "weaknesses" of individual cognitive abilities and/or subtests of the measures comes to the fore. At the same time, the incidence of ASD and intellectual disability is higher than in the general population (33% to 70% in the studies reported in this article), indicating that these conditions are comorbid. These rates vary according to the methodological design of the studies, especially the type of data used (administrative, medical, educational, etc.) and the instruments used to assess intellectual ability. For example, Wechsler tests may underestimate scores in children and adults with ASD because of the large number of verbal instructions that are difficult for people with severe communication difficulties. Comprehensive nonverbal intelligence tests (e.g., Leiter-3 or UNIT-2) are the most appropriate methods. Assessing the level of intellectual ability in people with autism spectrum disorders in Russia is complicated by the existing deficit of methods, the elimination of which is an important task that researchers face.&lt;/p&gt;

Autism and attention-deficit/hyperactivity disorder in children with Dravet syndrome: A population-based study.

To identify on a population basis the prevalence of autism and attention-deficit/hyperactivity disorder (ADHD) in children with Dravet syndrome and factors associated with symptoms of autism and ADHD. Forty-one of 48 children with Dravet syndrome living in Sweden, born between 1st January 2000 and 31st December 2018 underwent assessment including measures of autism and ADHD. Diagnoses of autism and ADHD were made with respect to DSM-5 criteria. Factors associated with features of autism and ADHD were analysed via regression. Twenty-five of the 41 children fulfilled DSM-5 criteria for autism spectrum disorder and 12 of 37 children considered for an ADHD diagnosis fulfilled DSM-5 criteria for ADHD. Severe intellectual disability was significantly associated with a greater degree of autistic features (p < 0.001) and a DSM-5 diagnosis of autism spectrum disorder (p = 0.029). Younger children had significantly more features of ADHD (p = 0.004) and features of inattention were significantly more common than features of hyperactivity/impulsivity (p < 0.001). Children with Dravet syndrome often have significant features of autism and ADHD, primarily inattentive type. Screening for autism and ADHD should be routine in children with Dravet syndrome.

Periodontal Health among Individuals with Intellectual Disabilities Living in a Saudi Institutional Rehabilitation Centre.

The aim of this study was to explore periodontal health among intellectually disabled individuals living in an institutional rehabilitation centre in the Al-Baha Region of Saudi Arabia. A cross-sectional study was conducted from November 2023 to January 2024. Clinical oral examinations were carried out using the World Health Organization criteria for bleeding sites and the presence of periodontal pockets. Simplified oral hygiene and community periodontal indices were employed to evaluate participants' oral health. A total of 89 participants, comprising both males and females with intellectual disabilities, were included in this study. Gender, severity of intellectual disability, type of additional physical disability, tooth brushing habits and oral hygiene status were significantly associated with the presence of periodontal disease. Additionally, poor oral hygiene, not brushing teeth and periodontal pockets of 4-5 mm and 6 mm or more were significantly more prevalent among individuals with severe and moderate intellectual disabilities (p = 0.001, p = 0.001, p = 0.001 and p = 0.001, respectively). The prevalence of periodontal disease among the studied population was 54%. The odds of having periodontal disease were significantly higher in the severe intellectual disability group compared to the mild intellectual disability group (OR = 2.328, 95% CI = 1.430-3.631, p = 0.03). It was also found that intellectually disabled participants with additional physical disabilities suffered more from periodontal disease than those without additional physical disabilities (OR = 0.971, 95% CI = 0.235-4.023, p = 0.025). Overall, individuals with intellectual disabilities had a significant demand for periodontal care. This study highlighted the need for more organised preventive programmes for individuals with intellectual disabilities. Dentists should be vigilant about improving periodontal health, focus on preventive programmes and provide comprehensive dental care with an emphasis on periodic recall and monitoring.

Cannabidiol attenuates seizure susceptibility and behavioural deficits in adult CDKL5R59X knock-in mice.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is caused by a loss-of-function mutation in CDKL5 gene, encoding a serine-threonine kinase highly expressed in the brain. CDD manifests with early-onset epilepsy, autism, motor impairment and severe intellectual disability. While there are no known treatments for CDD, the use of cannabidiol has recently been introduced into clinical practice for neurodevelopmental disorders. Given the increased clinical utilization of cannabidiol, we examined its efficacy in the CDKL5R59X knock-in (R59X) mice, a CDD model based on a human mutation that exhibits both lifelong seizure susceptibility and behavioural deficits. We found that cannabidiol pre-treatment rescued the increased seizure susceptibility in response to the chemoconvulsant pentylenetetrazol (PTZ), attenuated working memory and long-term memory impairments, and rescued social deficits in adult R59X mice. To elucidate a potential mechanism, we compared the developmental hippocampal and cortical expression of common endocannabinoid (eCB) targets in R59X mice and their wild-type littermates, including cannabinoid type 1 receptor (CB1R), transient receptor potential vanilloid type 1 (TRPV1) and 2 (TRPV2), G-coupled protein receptor 55 (GPR55) and adenosine receptor 1 (A1R). Many of these eCB targets were developmentally regulated in both R59X and wild-type mice. In addition, adult R59X mice demonstrated significantly decreased expression of CB1R and TRPV1 in the hippocampus, and TRPV2 in the cortex, while TRPV1 was increased in the cortex. These findings support the potential for dysregulation of eCB signalling as a plausible mechanism and therapeutic target in CDD, given the efficacy of cannabidiol to attenuate hyperexcitability and behavioural deficits in this disorder.

‘To have a plan’: teachers’ perceptions of working with a literacy instruction combining phonics and comprehension applications for students with intellectual disability and communication difficulties

Purpose Students with intellectual disabilities (ID) typically have difficulties with literacy learning, often not acquiring basic literacy skills. Research and practical experience indicate that when these students are provided with evidence-based instruction, including comprehension as well as phonemic strategies, literacy may develop. Methods In this study, four pairs of teachers were interviewed regarding their perceptions of a 12-week digital literacy intervention that focused on both phonics and comprehension strategies. The intervention aimed to enhance literacy and communication development in students aged 7–21, who had mild to severe ID. Results and conclusion Four themes were identified in the analysis. It was seen that the teachers found it valuable to have access to two apps accessing and facilitating the use of different literacy strategies in meeting the needs of individual students. This digital format was also perceived as positive, contributing to creating a supportive and systematic learning environment that enhanced and increased literacy learning. The teachers recurringly also talked about the positive influence of participating in research, lifting the strong focus, and positive attention as very important for both teachers and students.

Enhancing Executive Functions in Pediatric Epilepsy: Feasibility and Efficacy of a Computerized Cognitive Training Program.

Epilepsy, a prevalent neurological disorder characterized by recurrent seizures, significantly impacts individuals' neurobiological, cognitive, and social lives. This report presents a feasibility study investigating the effects of a computerized cognitive training program on enhancing executive functions, particularly inhibitory control, in children and adolescents with epilepsy. Employing a pre-test-intervention-post-test design, the study involved 26 participants with diverse epileptic syndromes, focusing on those without severe intellectual disabilities. The intervention, based on the CogniFit Inc. platform, consisted of personalized tasks aiming to improve participants' inhibitory skills over 16 weeks, with an average of 40 sessions completed per participant. Results indicated significant improvements in reaction times and error rates in an anti-saccade task, demonstrating enhanced inhibitory control and general performance post-intervention. These findings suggest that targeted cognitive training is a feasible approach to bolster executive functions in young individuals with epilepsy, potentially improving their academic performance, employability, and social interactions. The study underscores the importance of early cognitive interventions in epilepsy management, highlighting the potential for computerized programs to aid in mitigating cognitive deficits associated with the condition.

Wybutosine hypomodification of tRNAphe activates HERVK and impairs neuronal differentiation

We previously reported that loss of function of TYW1 led to cerebral palsy with severe intellectual disability through reduced neural proliferation. However, whether TYW1 loss affects neural differentiation is unknown. In this study, we first demonstrated that TYW1 loss blocked the formation of OHyW in tRNAphe and therefore affected the translation efficiency of UUU codon. Using the brain organoid model, we showed impaired neuron differentiation when TYW1 was depleted. Interestingly, retrotransposons were differentially regulated in TYW1-/- hESCs (human embryonic stem cells). In particular, one kind of human-specific endogenous retrovirus-K (HERVK/HML2), whose reactivation impaired human neurodevelopment, was significantly up-regulated in TYW1-/- hESCs. Consistently, a UUU codon-enriched protein, SMARCAD1, which was a key factor in controlling endogenous retroviruses, was reduced. Taken together, TYW1 loss leads to up-regulation of HERVK in hESCs by down-regulated SMARCAD1, thus impairing neuron differentiation.

Examining the Changes in Problem Behaviours and Communication of Persons with Intellectual and Developmental Disabilities after Transitioning from an Institutional Setting to the Community

Worldwide, the community transition process away from institutions has increased in the past 30–50 years among persons with severe intellectual and developmental disabilities. This process, also known as “deinstitutionalization”, could potentially impact problem behaviors and communication. This study examined the impacts of community transitions on behavioural and communication outcomes in Canadians with intellectual and developmental disabilities. Data were collected using the Comprehensive Health Assessment Program and medical chart reviews. Descriptive, aggregate-level, and individual-level analyses were conducted for 32 adults who transitioned to community living. Descriptive analyses and the McNemar Chi-Square Test were conducted. Following community transitions, the study group experienced a significant decrease in problem behaviours and changes in communication. The study findings suggest that deinstitutionalization could provide effective strategies for addressing problem behaviors and fostering improvements in communication, promoting the well-being and quality of life of persons with intellectual and developmental disabilities.

Further evidence supporting the role of GTDC1 in glycine metabolism and neurodevelopmental disorders.

Copy number variants (CNVs) represent the genetic cause of about 15-20% of neurodevelopmental disorders (NDDs). We identified a ~67 kb de novo intragenic deletion on chromosome 2q22.3 in a female individual showing a developmental encephalopathy characterised by epilepsy, severe intellectual disability, speech delay, microcephaly, and thin corpus callosum with facial dysmorphisms. The microdeletion involved exons 5-6 of GTDC1, encoding a putative glycosyltransferase, whose expression is particularly enriched in the nervous system. In a previous study, a balanced de novo translocation encompassing GTDC1 was reported in a male child with global developmental delay and delayed speech and language development. Based on these premises, we explored the transcriptomic profile of our proband to evaluate the functional consequences of the novel GTDC1 de novo intragenic deletion in relation to the observed neurodevelopmental phenotype. RNA-seq on the proband's lymphoblastoid cell line (LCL) showed expression changes of glycine/serine and cytokine/chemokine signalling pathways, which are related to neurodevelopment and epileptogenesis. Subsequent analysis by ELISA (enzyme-linked immunosorbent assay) and HPLC (high-performance liquid chromatography) revealed increased levels of glycine in the proband's LCL and serum compared to matched controls. Given that an increased level of glycine has been observed in the plasma samples of individuals with Rett syndrome, a condition sharing epilepsy, microcephaly, and intellectual disability with our proband, we proposed that the GTDC1 downregulation is implicated in neurodevelopmental impairment by altering glycine metabolism. Furthermore, our findings expanded the phenotypic spectrum of the novel GTDC1-related condition, including microcephaly and epilepsy among relevant clinical features.

The behavioral phenotype of children and adolescents with attenuated non-ketotic hyperglycinemia, intermediate to good subtype.

We aim to describe the behavioral phenotype of children and adolescents with the good to intermediate attenuated form of non-ketotic hyperglycinemia (NKH) and to explore associations between the behavioral phenotype and age, sex, plasma glycine levels and drug treatment. Parents of children with attenuated NKH completed questionnaires assessing maladaptive behavior, adaptive behavior, social communication, speech/language development and motor development in addition to demographic and medical questions. Twelve children, age 6 to 21y, functioned at mild to severe intellectual disability levels. Their speech/language development was in line with their developmental quotient. Relative to their intellectual functioning, their motor development and communication were weaker in comparison to their general development. Their adaptive behavior, however, appeared a relative strength. There was no evidence for autism spectrum disorder occurring more frequently than expected, rather social skills, except for communication, were rated as a relative strength. Maladaptive behaviors with ADHD-like characteristics were present in more than two thirds of children. Maladaptive behaviors were significantly related to female sex and to taking dextromethorphan, but no significant relation between plasma glycine levels and behavior was found. Future studies will need to evaluate causality in the observed relation between dextromethorphan use and maladaptive behaviors. Clinicians should reconsider the benefit of dextromethorphan when presented with disruptive behaviors in children with attenuated NKH.

Ultrasonography is an effective tool for breast cancer screening in individuals with severe motor and intellectual disabilities.

Individuals with severe motor and intellectual disabilities have become an aging population, and high cancer morbidity and mortality are critical issues affecting their survival. Cancer screening is a crucial method of resolving this issue; however, a suitable screening method for them has not been established. We used ultrasonography alone and performed breast cancer screening for women over 30 years old in our facility from 2016 to 2023. We observed the outcomes and calculated the recall/detection rate in this screening. Three cases among 379 tested positive in this screening, all of which underwent radical surgery. They are alive and well without relapse present. We detected these breast cancer cases with a low recall rate. We were able to successfully detect breast cancer cases using ultrasonography alone. Ultrasonography is an effective and feasible tool for breast cancer screening in individuals with severe motor and intellectual disabilities.

A quantitative cross-sectional study of the burden of caring for patients with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex-associated epilepsy in Japan

IntroductionLennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC)-associated epilepsy are rare conditions associated with severe childhood-onset epilepsy. Caregivers play a critical role in the patients’ care and may experience significant psychosocial and socioeconomic burden. This cross-sectional study determined the burden of caring for patients with these rare epilepsy conditions in Japan. MethodsA quantitative online survey was used to assess patients’ and caregivers’ characteristics and the caregivers’ emotional state, among others. Several validated questionnaires were used: the Hospital Anxiety and Depression Scale (HADS; 0–21 score) assessed the caregivers’ emotional wellbeing, the Pediatric Quality of Life Inventory Family Impact Module (PedsQL FIM; 0–100 score) assessed the health-related quality of life (HRQoL) of the caregivers and their families, and the Work Productivity and Activity Impairment General Health (WPAI:GH; 0–100 % score) questionnaire assessed work productivity. ResultsA total of 36 caregivers responded (median [interquartile range (IQR)] age 43.5 [39.5, 48.3] years; 33/36 [92 %] female; 13/36 [36 %] working part-time and 13/36 [36 %] not working). Participants cared for 7/36 (19 %), 19/36 (53 %), and 10/36 (28 %) patients with LGS, DS, and TSC, respectively (median [IQR] age, 11.0 [6.8, 16.3] years; age at first seizure, 0 [0, 0] years). Patients received a median (IQR) of 4 (3, 5) treatment drug types. Patients experienced median (IQR) 3.0 (0, 21.0) epileptic seizures in the previous week; 28/36 (78 %) had severe intellectual disabilities, and 34/36 (94 %) had developmental delays. Caregivers reported stress (17/36 [47 %]), sleep problems (13/36 [36 %]), and anxiety (12/36 [33 %]). They spent a median (IQR) of 50.0 (17.5, 70.0) hours caregiving in the previous week, with 3.0 (1.0, 11.0) hours of seizure-specific care. Caregivers reported that their lives would be easier with a median (IQR) of 1.5 (0, 5.0) hours fewer per week caring for patients during/following seizures. Median HADS scores were 9.5 (‘suspected anxiety diagnosis’) and 7.5 (‘no depression’) for caregivers, and PedsQL FIM Total median score was 60.1, indicating HRQoL impairment for the caregiver and their family. WPAI:GH scores for paid workers indicated important work impairment. Higher caregiving hours (≥ 21 h vs. < 21 h in the previous week) resulted in higher caregiver burden as indicated by the HADS Total score (p = 0.0062) and PedsQL FIM Total score (p = 0.0007). ConclusionsCaregivers of patients with LGS, DS, or TSC in Japan experience a significant time burden, reduced HRQoL, and high level of work/activity impairment. Caregivers provide round-the-clock care to patients and rely on family and specialized caring services to help manage the increased caregiving time, which tends to be associated with greater emotional burden and HRQoL impact.

Heterozygous gain of function variant in GUCY1A2 may cause autonomous ovarian hyperfunction.

The purpose of this study was to characterize the phenotype associated with a de novo gain-of-function variant in the GUCY1A2 gene. An individual carrying the de novo heterozygous variant c.1458G>T p.(E486D) in GUCY1A2 was identified by exome sequencing. The effect of the corresponding enzyme variant α2E486D/β1 was evaluated using concentration-response measurements with wild-type enzyme and the variant in cytosolic fractions of HEK293 cells, UV-vis absorbance spectra of the corresponding purified enzymes, and examination of overexpressed fluorescent protein-tagged constructs by confocal laser scanning microscopy. The patient presented with precocious peripheral puberty resembling the autonomous ovarian puberty seen in McCune-Albright syndrome. Additionally, the patient displayed severe intellectual disability. In vitro activity assays revealed an increased nitric oxide affinity for the mutant enzyme. The response to carbon monoxide was unchanged, while thermostability was decreased compared to wild type. Heme content, susceptibility to oxidation, and subcellular localization upon overexpression were unchanged. Our data define a syndromic autonomous ovarian puberty likely due to the activating allele p.(E486D) in GUCY1A2 leading to an increase in cGMP. The overlap with the ovarian symptoms of McCune-Albright syndrome suggests an impact of this cGMP increase on the cAMP pathway in the ovary. Additional cases will be needed to ensure a causal link.

A Novel Homozygous Variant in the MCOLN1 Gene Associated With Severe Oromandibular Dystonia and Parkinsonism.

Mucolipidosis type IV (MLIV) is a rare, progressive lysosomal storage disorder characterized by severe intellectual disability, delayed motor milestones and ophthalmologic abnormalities. MLIV is an autosomal recessive disease caused by mutations in the MCOLN1 gene, encoding mucolipin-1 which is responsible for maintaining lysosomal function. Here, we report a family of four Iranian siblings with cognitive decline, progressive visual and pyramidal disturbances, and abnormal movements manifested by severe oromandibular dystonia and parkinsonism. MRI scans of the brain demonstrated signal abnormalities in the white matter and thinning of the corpus callosum. Whole-exome sequencing identified a novel homozygous variant, c.362C > T:p. Thr121Met in the MCOLN1 gene consistent with a diagnosis of MLIV. The presentation of MLIV may overlap with a variety of other neurological diseases, and genetic analysis is an important strategy to clarify the diagnosis. This is an important point that clinicians should be familiar with. The novel variant c.362C > T:p. Thr121Met herein described may be related to a comparatively older age at onset. Our study also expands the clinical spectrum of MLIV associated with the MCOLN1 variants and introduces a novel likely pathogenic variant for testing in MLIV cases that remain unresolved.