Neurological Abnormalities Research Articles

Fetal Alcohol Syndrome: Impact on Neurodevelopment, Diagnosis, Early Intervention and Motor Disorders in Children under 3 Years

Fetal Alcohol Syndrome (FAS) is the most severe outcome of prenatal alcohol exposure, characterized by a combination of somatic and neurological abnormalities, including facial dysmorphism, growth deficits, and neurocognitive impairments. Fetal Alcohol Spectrum Disorders (FASD) encompass a broader range of outcomes from prenatal alcohol exposure, with varying degrees of severity. Alcohol consumption during pregnancy can disrupt fetal development, with no known safe threshold for its intake at any stage of gestation. The consequences are particularly profound on the central nervous system (CNS), where damage to structures like the cerebellum can lead to motor dysfunctions, balance issues, and cognitive impairments. Early identification and diagnosis of FAS or FASD, especially during the critical first years of life, is essential for improving developmental outcomes. Intervention strategies, including physical and cognitive therapy, can help mitigate long-term disabilities associated with these conditions. Diagnostic methods, such as ultrasound for fetal structural abnormalities and the AUDIT screening tool, are integral for early detection. This review highlights the impact of prenatal alcohol exposure on motor skill development, particularly the persistence of primitive reflexes in infants with FAS, which is indicative of CNS immaturity and necessitates early therapeutic interventions. Understanding these motor and neurological markers is critical for providing appropriate support and improving outcomes for affected children.

Angiostrongylus cantonensis Meningo-Encephalitis in Children-Heightened Awareness Needed During Prolonged Wet Weather Conditions.

Angiostrongylus cantonensis, the leading cause of eosinophilic meningoencephalitis, is well established in eastern Australia. Prolonged wet weather in Queensland during 2021-2022 coincided with anecdotal reports of increased neuroangiostrongyliasis cases, prompting an evaluation of paediatric cases from 2013 to 2022. This retrospective observational study reviewed children (0-16 years) with cerebrospinal fluid (CSF) eosinophilia (≥ 10% of the total CSF leukocyte count) and/or A. cantonensis testing (serology or polymerase chain reaction) between 01/01/2013 and 31/12/2022, using statewide laboratory data and patient records. Eighty children were identified: 59 (74%) had CSF eosinophilia without A. cantonensis testing, 9 (11%) had CSF eosinophilia with A. cantonensis testing, and 12 (15%) had A. cantonensis testing without CSF eosinophilia. Neuroangiostrongyliasis was either proven or probable in seven children: five (71%) during 2021-2022, coinciding with prolonged wet weather. A significant positive correlation was observed between rainfall and case numbers (r = 0.88, p < 0.01). Median age of diagnosed children was 4 years (IQR 1.8-8.5, range 1.5-13 years) and five (71%) were male. Snail or slug exposure was reported in four (57%) children. All children presented with vomiting, and six also had a headache and focal neurology (86%). Abnormal neuroimaging was noted in six (86%) cases. Five children received corticosteroid therapy alone (71%), while two (29%) were managed conservatively. There were no deaths, but one child had persistent focal neurological abnormalities at discharge. Awareness of A. cantonensis and exposure risks is crucial, especially during prolonged wet weather conditions. While most children in this study had good outcomes, this is not always the case.

Captopril attenuates oxidative stress and neuroinflammation implicated in cisplatin-induced cognitive deficits in rats.

One of the most debilitating drawbacks of cisplatin chemotherapy is neurotoxicity which elicits memory impairment and cognitive dysfunction (chemobrain). This is primarily triggered by oxidative stress and inflammation. Captopril, an angiotensin-converting enzyme inhibitor, has been reported as a neuroprotective agent owing to its antioxidant and anti-inflammatory effects. We examined the possible neuroprotective effect of captopril against cisplatin-induced neurological and behavioral abnormalities in rats. Chemobrain was induced in rats by cisplatin (5mg/kg, i.p.) on the 7th and 14th days of the study while captopril was administered orally (25mg/kg) daily for three weeks. The effects of captopril were assessed by performing behavioral tests, histological examination, and evaluation of oxidative stress and inflammatory markers. Cisplatin caused learning/memory dysfunction assessed by passive avoidance and Y-maze tests, decline in locomotion, and rotarod motor balance loss which were further verified by neurodegeneration observed in histological examination. Also, cisplatin aggravated oxidative stress by elevating lipid peroxidation (MDA) levels and diminishing catalase activity. Moreover, cisplatin upregulated the neuroinflammatory markers (TNF, IL-6, GFAP, and NF-κB). Captopril successfully ameliorated cisplatin damage on the levels of neurobehavioral and histopathological changes. Mechanistically, captopril significantly diminished MDA production and preserved catalase antioxidant activity. Captopril also counteracted neuroinflammation through inhibiting NF-κB and its downstream proinflammatory cytokines besides repressing astrocyte activity by reducing GFAP expression. Our findings revealed that captopril could abrogate cisplatin neurotoxicity via reducing oxidative stress and neuroinflammation thus enhancing cognitive and behavioral performance. This could suggest the repurposing of captopril as a neuroprotective agent, especially in hypertensive cancer patients receiving cisplatin.

Cerebral vasculitis related to neurosarcoidosis: a case series and systematic literature review

Cerebral vasculitis is a rare but severe manifestation of neurosarcoidosis (NS) that has received little attention. The aim of the present study was to characterize clinical and diagnostic features as well as potential treatment strategies of cerebral vasculitis related to NS. We assessed 29 patients with cerebral vasculitis related to NS (15 female, mean age at time of diagnosis 45 years, SD = 11.85) among these were four new cases from our hospital records and 25 previously published cases from a systematic literature review. The demographic, clinical, and diagnostic features of those 29 patients with cerebral vasculitis related to NS were compared with a group of 73 NS patients without vasculitic involvement (37 female, mean age at time of diagnosis 47 years, SD = 14.79). Neurologic deficits and MRI abnormalities were significantly more frequent in cerebral vasculitis related to NS than in NS without vasculitic involvement. Patients with cerebral vasculitis related to NS significantly more often presented with headache, motor symptoms, and cognitive and/or behavioral changes. Non-neurologic manifestations of sarcoidosis did not significantly differ in character or frequency between both groups. Glucocorticoids in combination with methotrexate, cyclophosphamide, or infliximab were the most frequently used treatment strategies in cerebral vasculitis related to NS. Within the complex diagnostic work-up that is required in cerebral vasculitis related to NS sufficient angiographic imaging as digital subtraction angiography or MRI vessel wall imaging and tissue biopsy are of particular significance as they can detect vascular changes caused by inflammatory processes.

Q241R mutation of Braf causes neurological abnormalities in a mouse model of cardio-facio-cutaneous syndrome, independent of developmental malformations.

Constitutively active mutants of BRAF cause cardio-facio-cutaneous (CFC) syndrome, characterized by growth and developmental defects, cardiac malformations, facial features, cutaneous manifestations, and mental retardation. An animal model of human CFC syndrome, the systemic BrafQ241R/+ mutant mouse, has been reported to exhibit multiple CFC syndrome-like phenotypes. In this study, we analyzed the effects of Braf mutations on neural function, separately from their effects on developmental processes. To this end, we generated Braf mutant mice expressing BRAFQ241R specifically in mature excitatory neurons (n-BrafQ241R/+). We found no growth retardation or cardiac malformations in n-BrafQ241R/+ mice, indicating normal development. Behavioral analysis revealed that n-BrafQ241R/+ mice exhibited reduced home cage activity and learning disability, which were similar to those of systemic BrafQ241R/+ mice. The active form of ERK was increased in the hippocampus of n-BrafQ241R/+ mice, whereas basal synaptic transmission and synaptic plasticity in hippocampal Schaffer collateral-CA1 synapses seems to be normal. Transcriptome analysis of the hippocampal tissue revealed significant changes in the expression of genes involved in regulation of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway, synaptic function and memory formation. These data suggest that the neuronal dysfunction observed in the systemic CFC mouse model is due to the disruption of homeostasis of the RAS/MAPK signaling pathway by the activated Braf mutant after maturation, rather than abnormal development of the brain. A similar mechanism may be possible in human CFC syndrome.

Carbendazim led to neurological abnormalities by interfering metabolic profiles in zebrafish brain after short-term exposure

Carbendazim is an agricultural fungicide and a widely present ecotoxic pollutant, but its damaging effects on the nervous system are not fully understood. Here, we assessed effects of short-term exposure to carbendazim on zebrafish brains. It has been revealed firstly that carbendazim can accumulate in the brain after a 7-day exposure, with the maximum concentration of 68.22 ± 9.84 μg/kg, which caused tissue vacuolization and neuronal damage, then led to a decline in motor behavioral abilities, especially a significant reduction in the distance moved. These changes may be attributed to metabolism abnormalities. Based on metabolomics and lipidomics, substantial alterations were observed in 264 lipids and 135 metabolites, with notable enrichment in 5 metabolic pathways, including glycerophospholipid metabolism, glycerolipid metabolism, and sphingolipid metabolism. To investigate system-level variations, weighted correlation network analysis was utilized to screen for 4 biomarkers strongly associated with carbendazim exposure: citric acid, guanosine-5′-monophosphate, sphingosine, and monoacylglycerol. The alterations of these markers confirmed damages of carbendazim to zebrafish nervous system, further elucidating that metabolic disorders caused by carbendazim in brains led to tissue damage and subsequent changes in motor behavior. This study provides scientific evidence for neurotoxicities of carbendazim and offers new insights into ecological risks.

Clinical and genetic characterization of a progressive RBL2-associated neurodevelopmental disorder.

Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2 dysfunction has been linked to a severe neurodevelopmental disorder. However, to date, clinical features have only been described in six individuals carrying five biallelic predicted loss of function (pLOF) variants. To define the phenotypic effects of RBL2 mutations in detail, we identified and clinically characterized a cohort of 35 patients from 20 families carrying pLOF variants in RBL2, including fifteen new variants that substantially broaden the molecular spectrum. The clinical presentation of affected individuals is characterized by a range of neurological and developmental abnormalities. Global developmental delay and intellectual disability were uniformly observed, ranging from moderate to profound and involving lack of acquisition of key motor and speech milestones in most patients. Disrupted sleep was also evident in some patients. Frequent features included postnatal microcephaly, infantile hypotonia, aggressive behaviour, stereotypic movements, seizures, and non-specific dysmorphic features. Neuroimaging features included cerebral atrophy, white matter volume loss, corpus callosum hypoplasia and cerebellar atrophy. In parallel, we used the fruit fly, Drosophila melanogaster, to investigate how disruption of the conserved RBL2 orthologue Rbf impacts nervous system function and development. We found that Drosophila Rbf LOF mutants recapitulate several features of patients harbouring RBL2 variants, including developmental delay, alterations in head and brain morphology, locomotor defects, and perturbed sleep. Surprisingly, in addition to its known role in controlling tissue growth during development, we found that continued Rbf expression is also required in fully differentiated post-mitotic neurons for normal locomotion in Drosophila, and that adult-stage neuronal re-expression of Rbf is sufficient to rescue Rbf mutant locomotor defects. Taken together, our study provides a clinical and experimental basis to understand genotype-phenotype correlations in an RBL2-linked neurodevelopmental disorder, and suggests that restoring RBL2 expression through gene therapy approaches may ameliorate some symptoms caused by RBL2 pLOF.

Lifespan in rodents with MYT1L heterozygous mutation.

MYT1L syndrome is a newly recognized disorder characterized by intellectual disability, speech and motor delay, neuroendocrine disruptions, ADHD, and autism. In order to study this gene and its association with these phenotypes, our lab recently created a Myt1l heterozygous mutant mouse inspired by a clinically relevant mutation. This model recapitulates several of the physical and neurologic abnormalities seen in humans with MYT1L syndrome, such as weight gain, microcephaly, and behavioral disruptions. The majority of patients with this syndrome are young, and little is known about the impact of age on health and mortality in these patients. Using a Myt1l mutant mouse, we examined the impact of Myt1l mutation on body weights, lifespan, and histopathology findings of mice at the end of life. This cohort of heterozygous mice demonstrated increased body weight across the lifespan, however there was no significant difference in lifespan, apparent cause of death, or end of life histopathological findings between Myt1l heterozygous and wildtype mice. These findings suggest while Myt1l heterozygous mutation may influence overall brain development, it does not strongly impact other organ systems in the body over time.

Assessment of Risk Factors Leading to Amputation Among Diabetic Septic Foot Patients in Khartoum, Sudan.

Introduction Diabetes is a rapidly growing global health concern, with the World Health Organization (WHO) estimating that 300 million adults will have diabetes by 2025. This chronic condition is associated with complications, including nephropathy, retinopathy, neuropathy, cardiovascular disease, and diabetic foot ulcers (DFUs), which can lead to amputation. Diabetic septic foot (DSF), a severe form of diabetic foot disease, is defined by the WHO as the presence of infection, ulceration, or tissue destruction in the lower limb, often accompanied by neurological abnormalities, peripheral vascular disease, and metabolic complications of diabetes. In Sudan, the incidence of lower limb amputations due to DSF is increasing, with various healthcare centers employing different management strategies, making it challenging to identify which factors are most strongly linked to the highest rates of amputations.This study aims to identify the key risk factors contributing to amputations in patients with diabetic foot syndrome (DFS) in Khartoum, Sudan. Specifically, it seeks to assess the common risk factors for amputation in diabetic septic foot patients at hospital wards and dressing centers in Khartoum State, Sudan. Objectives include identifying risk factors associated with amputations, determining the types and frequency of amputations, and evaluating diabetes control and foot self-care practices. Methods This was a descriptive cross-sectional study that was conductedanonymously between 01/11/2017 and 08/11/2017in various hospital wards and dressing centers in Khartoum, Sudan, on 46 diabetic septic foot patients. Data was collected using an interview questionnaire and checklist administered to the attending patients. Quantitative data was analyzed using IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.This paper aims to explore the pathophysiology, risk factors, and clinical management of diabetic foot complications, with a focus on preventing the devastating outcome of amputation. Results The findings revealed that the most significant risk factors for amputation included a raised HbA1c level (74%), male gender (78%), age over 50 years (96%), and a history of preceding non-healing ulcers (93.5%). Other factors, such as smoking, diabetes-related comorbidities, and the type of diabetes management, showed no significant association with amputation. Normal saline and iodine were the most commonly used wound care solutions (52%). Regarding foot care habits, the most frequently practiced measures among patients included wearing special diabetic shoes (63%), avoiding walking barefoot (63%), and refraining from smoking (59%). Conclusions This study identified key risk factors for amputations in diabetic septic foot (DSF) patients, including elevated HbA1C levels, male gender, age over 50, and a history of unhealing ulcers, with poor foot care practices contributing to higher amputation rates. The findings highlight the importance of glycemic control, foot hygiene, and patient education in preventing amputations. Additionally, the study underscores the need for comprehensive management strategies that address both metabolic control and foot care, particularly in resource-limited settings. These insights can guide local healthcare policies focused on prevention, early intervention, and better resource allocation to reduce diabetes-related complications and improve patient outcomes.

Amyloid‐related imaging abnormalities in a woman with apolipoprotein E ε4 homozygotes treated with lecanemab for Alzheimer's disease

AbstractBackgroundLecanemab (Leqembi®) is an anti‐amyloid monoclonal antibody used for the treatment of Alzheimer's disease (AD). However, side effects may occur with lecanemab, including amyloid‐related imaging abnormalities (ARIA), especially in patients with apolipoprotein E ε4 (APOE4) homozygous.Case PresentationA 69‐year‐old woman had a 2‐year history of worsening memory symptoms and was diagnosed with mild cognitive impairment due to AD. Because she carries two copies of the E4 allele of APOE, her doctor did not recommend lecanemab treatment. However, she strongly desired lecanemab treatment and received four infusions of lecanemab. She had no symptoms or neurological abnormalities, but a head MRI before the fifth infusion showed moderate radiographic ARIA; therefore, she was admitted and treated with steroids. One month later, a head MRI showed the ARIA had disappeared.ConclusionThe indications of lecanemab treatment for patients with APOE4 homozygous must be carefully considered due to the higher risk of ARIA.

Autoimmune Psychosis as a Differential Diagnosis of Primary Schizophreniform Psychosis in Children and Adolescents.

Objective: Autoimmune psychosis (AP), defined as an isolated schizophreniform psychosis with no or only minimal neurological abnormalities stemming from autoantibody-associated cerebral processes, is a very rare and potentially underdiagnosed disorder in children and adolescents. Methods: This article reports the case of a 13-year-old boy who became acutely ill with a psychotic disorder following a respiratory infection. We describe the diagnosis and course of treatment in detail. Results: Following an extensive interdisciplinary workup, a probable glutamic acid decarboxylase (GAD)-associated AP was diagnosed that ultimately remitted completely with treatment. Conclusions: Autoimmune psychoses remain a relatively uncharted territory for the specialty of child and adolescent psychiatry. Good interdisciplinary cooperation is essential for patients with somewhat atypical psychotic symptoms, both in terms of diagnosis and treatment.

Unravelling Chikungunya’s Neurological Toll: Section A Case Report with Insights from Magnetic Resonance Imaging of Brain

Chikungunya, an emerging neurotropic virus, has the potential to induce various neurological abnormalities. When suspecting encephalitis, it is imperative to test for the Chikungunya virus, which requires an early diagnosis and course of treatment. This is a case report of a 54-year-old male who presented with fever, giddiness, ataxia and slurred speech. Magnetic Resonance Imaging (MRI) brain revealed typical hallmark features of chikungunya encephalitis, with an incidental right cerebellopontine angle tumour. A positive serum chikungunya antigen Polymerase Chain Reaction (PCR) validated the diagnosis. The patient was initially managed in the Intensive Care Unit (ICU), showing a dramatic response to the treatment, and then shifted to the medicine ward for further observation and management. This case underscores the importance of considering chikungunya in patients presenting with encephalitis differential diagnosis, especially in endemic regions like India. Comprehensive imaging and PCR testing were instrumental in diagnosis. Treatment included supportive care, intravenous antibiotics, antivirals and steroids, leading to significant improvement. By day 12, notable recovery was observed, and follow-up MRI brain showed no new abnormalities. This case adds to the evidence of severe neurological manifestations of Chikungunya virus, highlighting the need for early recognition and management to improve outcomes. The concurrent presentation of chikungunya encephalitis and a cerebello-pontine angle tumour emphasises the necessity for thorough neuroimaging and PCR testing in suspected cases. The patient’s dramatic recovery following timely intervention demonstrates the potential for positive outcomes with appropriate management.

Smartphone-Based Digitized Neurological Examination Toolbox for Multi-test Neurological Abnormality Detection and Documentation.

Understanding the efficacy of digital biomarkers in vision-based human motion analysis is essential, not only for interpreting the computer-aided exam results but also for advancing the next generation of digital health tool solutions. This study extensively analyzes digitized neurological examination (DNE) biomarkers for detecting and documenting exam features of Parkinson's disease (PD) and other neurological disorders (OD). Collected over 113 participants, DNE-113, a multi-test DNE database of finger tapping, finger to finger, forearm roll, stand-up and walk, and facial activation tests, covering a broader range of neurological abnormalities beyond PD is first proposed. Subsequently, DNE-113 is integrated into pyDNE - a convenient open-source toolbox, streamlining the creation and assessment of digital biomarkers. This toolbox empowers us to assess the quality of DNE biomarkers across diverse classification tasks. We showcase the discriminative potency of DNE biomarkers, successfully characterizing abnormal signals in neurological patients. Our findings highlight not only the potential use cases but also the persisting challenges in constructing digital biomarkers for computer-aided movement analysis on PD and OD patients.

Introduction of voice therapy

Voice disorders, resulting from structural and functional abnormalities in the larynx, significantly impact communication, daily activities, and emotional expression, ultimately lowering quality of life. Voice therapy is a key non-invasive intervention for managing voice disorders that arise from structural, functional, or neurological abnormalities in the larynx. Voice therapy includes techniques such as phonation exercises, breath control, resonance training, muscle relaxation, and posture adjustments, all aimed at restoring optimal vocal function. Indications for voice therapy cover a broad range of conditions, including vocal fold nodules, polyps, paralysis, spasmodic dysphonia, and aging-related vocal atrophy. Various voice therapy methods, such as vocal function exercises, resonance voice therapy, and Lee Silverman Voice Treatment, demonstrate improved outcomes in vocal quality, endurance, and overall vocal health. Recent trends in self-managed voice programs, facilitated by smartphone apps and social media resources, are expanding the accessibility of voice therapy. The integration of behavioral, medical, and technological interventions supports a multidisciplinary approach to meet diverse needs in managing voice disorders. This review underscores voice treatment approaches, highlighting their efficacy in addressing various voice disorders and supporting a multidisciplinary framework for optimizing therapeutic outcomes.

Overview of Pediatric Respiratory Syncytial Virus (RSV) infections: has risk perception for RSV changed in children with comorbid conditions?

Respiratory syncytial virus (RSV) is the primary etiology of lower respiratory tract infection in children. The fluctuating incidence of RSV, particularly in light of the COVID-19 pandemic, has shifted the spotlight onto preventive strategies. Our study aims to investigate both the risk factors and clinical symptoms of RSV. From February 2015 to February 2023, samples were analyzed during all seasons to identify viral respiratory infections. RSV was identified in a total of 835 individuals. In 2021, following the easing of limitations after the COVID-19 pandemic, the largest number of identified cases was recorded. January was the most commonly used month. The median age were 5 months (min-max: 1-204 months) and 128 (17.7%) cases had a history of prematurity. Around 24.7% of the patients had a preexisting medical condition. Neurological disease patients were followed up in the intensive care unit more often than others (53.3 vs. 35.8% p = 0.036). While the hospital stay of pediatric patients born under the 29th week of gestation is almost twice as long compared to other groups, the hospital stay is almost twice as long as that of patients between 29 and 32 weeks. (p = 0.046, p = 0.012 respectively). RSV was a powerful companion during the pandemic and a persistent reminder of its severity. Our initial data suggest that RSV prevention is difficult for children with pre-existing diseases, notably neurological abnormalities, who are not advised for preventive treatments. Given this outcome, late-premature newborns and children with medical issues should receive RSV prophylaxis first.

Investigations into disease associations with feline immunodeficiency virus (FIV) infection in lions (Panthera leo) in Australia: a case-control study.

Feline immunodeficiency virus (FIV) is a highly mutable retrovirus with numerous species-specific strains, such as those infecting domestic cats (Felis catus, FIVFca) and wild populations of nondomestic cats including lions (Panthera leo, FIVPle). When FIVFca infection manifests as disease in domestic cats, common presentations include lymphadenopathy, lymphoid malignancies, oral cavity disease, immunological dysfunctions and neurological abnormalities. In contrast to domestic cats, there has been little published evidence of direct FIVPle disease associations in lions. The objective of the study, therefore, was to conduct a longitudinal case-control comparison of clinical findings and survival analysis of FIVPle-infected and FIVPle-uninfected captive lions to investigate possible FIVPle disease associations in nondomestic felids in Australia. Between 2005 and 2023, 38 lions were recruited from zoos across Australia. Lions had been FIV tested as part of a routine diagnostic service. The 38 lions included in the study comprised 15 FIV-infected (9 males, 6 females) and 23 FIV-uninfected (9 males, 14 females) animals. Lifetime longitudinal clinical histories and clinicopathological data collected by zoos for these lions were interrogated, including survival data. FIV-infected lions were more likely to be reported with lower mean corpuscular volume (MCV) (fL) (P = 0.015), monocytes (%) (P = 0.023), chloride (mmol/L) (P = 0.016) and phosphate (mmol/L) (P = 0.029), but with a higher mean corpuscular hemoglobin concentration (MCHC) (g/L) (P = 0.001) and bicarbonate (mmol/L) (P = 0.035), than FIV-uninfected lions. The disease associations usually seen in domestic cats with FIV infection were not observed in lions, and there was no difference in survival between FIV-infected and FIV-uninfected lions. The main limitation of the study was a small sample size dictated by the number of lions able to be recruited from zoos in Australia over an 18-year period. Few differences were found between case and control groups, suggesting that FIV-infected lions did not experience clinicopathological changes that predisposed them to future disease compared with FIV-uninfected lions. Further research will help to determine whether these results are indicative of a general absence of FIV-associated disease in captive lions, or the result of nonpathogenic FIVPle subtype(s) present in Australia.

Engineered CRISPR-Base Editors as a Permanent Treatment for Familial Dysautonomia.

Familial dysautonomia (FD) is a fatal inherited congenital neuropathy characterized by both progressive neurological symptoms and systemic abnormalities, and patients have a reduced life expectancy. FD is caused by a T-to-C mutation in intron 20 of the Elongator acetyltransferase complex subunit 1 ( ELP1 ) gene, which affects the ELP1 splicing process by causing tissue-specific skipping of exon 20. Here, we developed a CRISPR base editor (BE) approach capable of precisely correct this mutation. Using Cas9 variants and screening multiple gRNAs, we selected an optimized BE combination that was able to promote up to 70% on-target editing in HEK293T cells harboring the ELP1 T-to-C mutation. These editing levels were sufficient to rescue more than 50% of ELP1 transcripts with precise exon 20 inclusion. Moreover, an engineered dual intein-split system was optimized to deliver these constructs in vivo . We packaged these novel constructs in adeno-associated virus (AAV) vectors for further testing in iPSC-derived sympathetic neurons and a mouse model harboring the human ELP1 T6C gene. Our strategy could effectively correct the ELP1 splicing defects in vivo and culminated in phenotypic recovery in human neurons. Minimal off-target editing was observed demonstrating high levels of specificity with these optimized base editors. Therefore, we engineered and validated novel base editor approaches to correct the ELP1 TC6 mutation and ELP1 splicing defect and provided essential proof of concept data towards a permanent treatment for FD.

A NOTCH2 pathogenic variant and HES1 regulate osteoclastogenesis in induced pluripotent stem cells

Hajdu Cheney Syndrome (HCS), a monogenic disorder associated with NOTCH2 pathogenic variants, presents with neurological, craniofacial and skeletal abnormalities. Mouse models of the disease exhibit osteopenia. To determine the consequences of a HCS pathogenic variant in human cells, induced pluripotent NCRM1 and NCRM5 stem (iPS) cells harboring a NOTCH26949C>T mutation or null for HES1 alleles were created. Parental iPSCs, NOTCH26949C>T, HES1 null and control cells, free of chromosomal aberrations were cultured under conditions of neural crest, mesenchymal and osteogenic cell differentiation, or of embryoid body, hematopoietic and osteoclast cell differentiation. The expected cell phenotype was confirmed by cell surface markers and gene signature. NOTCH26949C>T cells displayed enhanced expression of Notch target genes demonstrating the presence of a NOTCH2 gain-of-function. There was a modest enhancement of osteogenesis in NOTCH26949C>T cells manifested by increased mineralized nodule formation and SP7, ALPL and BGLAP mRNA expression. There was enhanced osteoclastogenesis in NOTCH26949C>T cells as evidenced by increased number of osteoclasts and a transient increase in ACP5, CALCR and CTSK transcripts. Osteoblastogenesis was minimally affected by the HES1 deletion, but osteoclast differentiation was significantly impaired. In conclusion, a NOTCH2 pathogenic variant causes modest increases in osteoblastogenesis and osteoclastogenesis and HES1 is required for osteoclast differentiation in human iPS cells in vitro.

Genotype-Phenotype Correlation in Lipoid Proteinosis: 15 Cases from Turkiye

Introduction: Lipoid proteinosis (LP), a rare autosomal recessive disorder typified by generalized thickening of the skin, mucosa, and certain viscera, is associated with pathogenic ECM1 variants. Skin lesions like beaded eyelid papules, acneiform scars, wavy, yellow papules and nodules typically appear in early childhood. Some patients may exhibit neurological abnormalities like temporal lobe or hippocampi-amygdala complex calcification, epilepsy, and neuropsychiatric abnormalities. Methods: We included 15 individuals with LP from 10 unrelated families. The study includes clinical evaluations of family history, radiological findings, histopathological examination of the skin, and genetic investigations. Results: All affected individuals exhibited skin and mucosal lesions. Among the 15 cases, five (33%) showed neurological symptoms, four (26%) presented neuropsychiatric findings, and three (20%) had diabetes mellitus. We observed characteristic intracranial calcifications in all patients with epileptic seizures. Four out of the five cases with epilepsy and intracranial calcifications also had neuropsychiatric findings. All patients with neurological and neuropsychiatric findings had a frame-shift variant, but the same frame-shift variant was not associated with these findings in other individuals. In our study, no patient with variants other than frame-shift variants exhibited neurological or neuropsychiatric findings. Adrenal calcification, which was observed in 1 patient, was not previously linked to LP. Conclusion: Our study observed diverse variations in LP cases among the Turkish population, with varying clinical presentation even among individuals with identical variations within the same family. In our series, the lack of correlation between genotype and phenotype makes providing specific genetic counseling to families challenging.

Assessment of Immunological, Skeletal, and Thyroid Function Abnormalities in Paediatric Morphoea

Abstract Background: Morphoea is a sclerosing disorder of skin and subcutaneous tissue. Paediatric morphoea shows increased prevalence of various auto-immune diseases, bone deformities, and systemic abnormalities. There is paucity of studies on various immunological, skeletal, and thyroid function abnormalities in paediatric morphoea. Aims and Objectives: To describe immunological, skeletal, and thyroid function abnormalities present in paediatric morphoea patients. Materials and Methods: This cross-sectional study was conducted from January 2021 to March 2023 in the Dermatology outpatient department in a tertiary care hospital. All paediatric morphoea patients were included in this study. All were subjected to detailed history, clinical examination, and investigations including complete blood count, serum IgE, anti-nuclear antibody, thyroid function tests, anti-thyroid peroxidase antibodies, and radiological investigations. Results: A total of 42 children were recruited, out of which 61.90% were females and 38.09% were males. The majority were in the age group of 4–8 years. The most common type of morphoea was encoup de sabre. Anaemia was present in 14.28% patients. Serum IgE levels were raised in 33.33% patients. Thyroid stimulating hormone was raised in 11.9% patients. 33.33% had raised anti-thyroid peroxidase levels. Anti-nuclear antibody titres and rheumatoid factor were raised in 7.14% and 4.76% patients, respectively. Magnetic resonance imaging brain revealed abnormalities in three patients as hyper-intensities in subcortical white matter. Conclusion: Morphoea in children can be associated with varied immunological, osteoarticular, and neurological abnormalities. This study highlights the multi-system involvement in morphoea and the need for larger data and well-designed therapeutic trials for generating evidence-based treatment of this potentially disfiguring disease.