Case Report: Novel SLC9A6 Splicing Variant in a Chinese Boy With Christianson Syndrome With Electrical Status Epilepticus During Sleep

We investigated the existence and potential pathogenicity of a SLC9A6 splicing variant in a Chinese boy with Christianson Syndrome (CS), which was reported for the first time in China. Trio whole-exome sequencing (WES) was performed in the proband and his parents. Multiple computer prediction tools were used to evaluate the pathogenicity of the variant, and reverse transcription-polymerase chain reaction (RT-PCR) analysis and cDNA sequencing were performed to verify the RNA splicing results. The patient presented with characteristic features of CS: global developmental delay, seizures, absent speech, truncal ataxia, microcephaly, ophthalmoplegia, smiling face and hyperkinesis with electrical status epilepticus during sleep (ESES) detected in an electroencephalogram (EEG). A SLC9A6 splicing variant was identified by WES and complete skipping of exon 10 was confirmed by RT-PCR. This resulted in altered gene function and was predicted to be pathogenic. ESES observed early in the disease course is considered to be a significant feature of CS with the SLC9A6 variant. Combined genetic analysis at both the DNA and RNA levels is necessary to confirm the pathogenicity of this variant and its role in the clinical diagnosis of CS.

A Pragmatic Approach to the Management of Severe Awake Bruxism in an Adolescent with Cerebral Palsy and Global Developmental Delay

Cerebral palsy is a neurological and motor condition characterised by muscle balance and posture impairments. Bruxism and malocclusion were frequently observed in patients with cerebral palsy, in contrast to other oral anomalies. The report outlines how severe awake bruxism is managed in a 16-year-old Korean boy who has nonverbal spastic cerebral palsy and global developmental delay. The treatment protocol involved the fabrication of soft occlusal splints of three and four millimetres in thickness, followed by the placement of stainless-steel crowns on all first permanent molars whilst video recording and a bruxism diary was kept. Fixed restorations demonstrate increased endurance in withstanding bruxism force in persons who are dependent on their caretaker.

Disrupted Mitochondrial Network Drives Deficits of Learning and Memory in a Mouse Model of FOXP1 Haploinsufficiency

Reduced cognitive flexibility, characterized by restricted interests and repetitive behavior, is associated with atypical memory performance in autism spectrum disorder (ASD), suggesting hippocampal dysfunction. FOXP1 syndrome is a neurodevelopmental disorder characterized by ASD, language deficits, global developmental delay, and mild to moderate intellectual disability. Strongly reduced Foxp1 expression has been detected in the hippocampus of Foxp1+/− mice, a brain region required for learning and memory. To investigate learning and memory performance in these animals, fear conditioning tests were carried out, which showed impaired associative learning compared with wild type (WT) animals. To shed light on the underlying mechanism, we analyzed various components of the mitochondrial network in the hippocampus. Several proteins regulating mitochondrial biogenesis (e.g., Foxo1, Pgc-1α, Tfam) and dynamics (Mfn1, Opa1, Drp1 and Fis1) were significantly dysregulated, which may explain the increased mitophagy observed in the Foxp1+/− hippocampus. The reduced activity of complex I and decreased expression of Sod2 most likely increase the production of reactive oxygen species and the expression of the pre-apoptotic proteins Bcl-2 and Bax in this tissue. In conclusion, we provide evidence that a disrupted mitochondrial network and the resulting oxidative stress in the hippocampus contribute to the altered learning and cognitive impairment in Foxp1+/− mice, suggesting that similar alterations also play a major role in patients with FOXP1 syndrome.

Complementing the phenotypical spectrum of TUBA1A tubulinopathy and its role in early-onset epilepsies

TUBA1A tubulinopathy is a rare neurodevelopmental disorder associated with brain malformations as well as early-onset and intractable epilepsy. As pathomechanisms and genotype-phenotype correlations are not completely understood, we aimed to provide further insights into the phenotypic and genetic spectrum. We here present a multicenter case series of ten unrelated individuals from four European countries using systematic MRI re-evaluation, protein structure analysis, and prediction score modeling. In two cases, pregnancy was terminated due to brain malformations. Amongst the eight living individuals, the phenotypic range showed various severity. Global developmental delay and severe motor impairment with tetraparesis was present in 63% and 50% of the subjects, respectively. Epilepsy was observed in 75% of the cases, which showed infantile onset in 83% and a refractory course in 50%. One individual presented a novel TUBA1A-associated electroclinical phenotype with evolvement from early myoclonic encephalopathy to continuous spike-and-wave during sleep. Neuroradiological features comprised a heterogeneous spectrum of cortical and extracortical malformations including rare findings such as cobblestone lissencephaly and subcortical band heterotopia. Two individuals developed hydrocephalus with subsequent posterior infarction. We report four novel and five previously published TUBA1A missense variants whose resulting amino acid substitutions likely affect longitudinal, lateral, and motor protein interactions as well as GTP binding. Assessment of pathogenic and benign variant distributions in synopsis with prediction scores revealed sections of variant enrichment and intolerance to missense variation. We here extend the clinical, neuroradiological, and genetic spectrum of TUBA1A tubulinopathy and provide insights into residue-specific pathomechanisms and genotype-phenotype correlations.

Correlation Analyses of Clinical Manifestations and Variant Effects in KCNB1-Related Neurodevelopmental Disorder

Objective:Vitro functional analyses of KCNB1 variants have been done to disclose possible pathogenic mechanisms in KCNB1-related neurodevelopmental disorder. “Complete or partial loss of function (LoF),” “dominant-negative (DN) effect” are applied to describe KCNB1 variant's molecular phenotypes. The study here aimed to investigate clinical presentations and variant effects associations in the disorder.Methods: We reported 10 Chinese pediatric patients with KCNB1-related neurodevelopmental disorder here. Functional experiments on newly reported variants, including electrophysiology and protein expression, were performed in vitro. Phenotypic, functional, and genetic data in the cohort and published literature were collected. According to their variants' molecular phenotypes, patients were grouped into complete or partial LoF, and DN effect or non-dominant-negative (non-DN) effect to compare their clinical features.Results: Nine causative KCNB1 variants in 10 patients were identified in the cohort, including eight novel and one reported. Epilepsy (9/10), global developmental delay (10/10), and behavior issues (7/10) were common clinical features in our patients. Functional analyses of 8 novel variants indicated three partial and five complete LoF variants, five DN and three non-DN effect variants. Patient 1 in our series with truncated variants, whose functional results supported haploinsufficiency, had the best prognosis. Cases in complete LoF group had earlier seizure onset age (64.3 vs. 16.7%, p = 0.01) and worse seizure outcomes (18.8 vs. 66.7%, p = 0.03), and patients in DN effect subgroup had multiple seizure types compared to those in non-DN effect subgroup (65.5 vs. 30.8%, p = 0.039).Conclusion: Patients with KCNB1 variants in the Asian cohort have similar clinical manifestations to those of other races. Truncated KCNB1 variants exhibiting with haploinsufficiency molecular phenotype are linked to milder phenotypes. Individuals with complete LoF and DN effect KCNB1 variants have more severe seizure attacks than the other two subgroups.

The Organization of Diagnosis, Care and Funding for Specific Learning and Developmental Disorders (SLDD): A French Regional Experimental Protocol

Introduction: Access in France to early diagnosis and care for the most severe, but infrequent, Neurodevelopmental Disorders (NDD), autism spectrum disorder and global developmental delay, in children aged 0–7 was improved through measures implemented in 2019. However, there are no such measures for specific learning disorders (SLD), attention, motricity and language disorders (SLDD), despite their annual incidence of between 5 and 8%.Method: We describe the design of a new type of organization and financing of care for SLDD including evaluation procedure, as well as other factors, mainly at the prevention level that will contribute to local and national policy for this frequent health problem. This in response to a national call for projects, commonly called Article 51, targeted innovation in healthcare delivery and funding in the context of medium-term national reform. This provides project stakeholders with the opportunity to set up and implement “bottom-up” projects, mainly using local professionals. A joint initiative by the regional Health Authorities of the Occitanie region, the French Social Security system and a non-profit Association (Occitadys) proposed an experimental new structure of NDD care and funding.Discussion: We here discuss the design of this experiment that aims, over two to three years, to alleviate families' financial burden of care and establish a regional three-tier care system with respect to evaluation, re-education and rehabilitation care. Our approach may benefit SLDD health-care planning, and addresses the questions of prevention, early detection and care-design for families, taking local and socioeconomic disparities into account.

Pregabalin Abuse During Pregnancy and Global Developmental Delay in Infants

Pregabalin is a medication licensed for the treatment of epilepsy and anxiety disorders. In addition, Pregabalin is increasingly recognised as a drug of abuse. Teratogenic effects have been demonstrated in animal models, however, there is a dearth of research relating to potential teratogenic effects in humans. This case highlights the potential role of intrauterine exposure to Pregabalin in contributing to Global Developmental Delay in two children.

Dental Management of Generalised Developmental Defect of Enamel in A Child with Global Developmental Delay

Development Defect of Enamel (DDE) although not common, can bring about serious sequelae and needs immediate action. If we leave the teeth untreated, many complications such as poor dental aesthetics, chipping of teeth and dental pain often set in. These complications are further aggravated if the patient has any coexisting medical issues, such as Global Developmental Delay (GDD). Children with GDD often exhibit poor oral health with an abundance of plaque that leads to caries and periodontal disease progression because of poor motor and cognitive development. Many of them also exhibit negative behaviour toward dental treatment. This case describes the dental care for a Global Developmental Delay (GDD) child with sporadic generalised Development Defect of Enamel (DDE). The case management touches on the appropriate behaviour guidance strategies used to aid the child’s unfavourable behaviour towards treatment and the restorative treatment performed to preserve the structural durability of the affected teeth in a general dental setting.