Clinical and Molecular Spectrum of Autosomal Recessive CA8-Related Cerebellar Ataxia.

BACKGROUND: Based on a limited number of reported families, biallelic CA8 variants have currently been associated with a recessive neurological disorder named, cerebellar ataxia, mental retardation, and dysequilibrium syndrome 3 (CAMRQ-3). OBJECTIVES: We aim to comprehensively investigate CA8-related disorders (CA8-RD) by reviewing existing literature and exploring neurological, neuroradiological, and molecular observations in a cohort of newly identified patients. METHODS: We analyzed the phenotype of 27 affected individuals from 14 families with biallelic CA8 variants (including data from 15 newly identified patients from eight families), ages 4 to 35 years. Clinical, genetic, and radiological assessments were performed, and zebrafish models with ca8 knockout were used for functional analysis. RESULTS: Patients exhibited varying degrees of neurodevelopmental disorders (NDD), along with predominantly progressive cerebellar ataxia and pyramidal signs and variable bradykinesia, dystonia, and sensory impairment. Quadrupedal gait was present in only 10 of 27 patients. Progressive selective cerebellar atrophy, predominantly affecting the superior vermis, was a key diagnostic finding in all patients. Seven novel homozygous CA8 variants were identified. Zebrafish models demonstrated impaired early neurodevelopment and motor behavior on ca8 knockout. CONCLUSION: Our comprehensive analysis of phenotypic features indicates that CA8-RD exhibits a wide range of clinical manifestations, setting it apart from other subtypes within the category of CAMRQ. CA8-RD is characterized by cerebellar atrophy and should be recognized as part of the autosomal-recessive cerebellar ataxias associated with NDD. Notably, the presence of progressive superior vermis atrophy serves as a valuable diagnostic indicator. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Telehealth in Informal Caregivers of Stroke Survivors: A Systematic Review.

Background: There has been an increase in people with disabilities who require continuous care, which often falls to informal carers (ICs). Stroke is one of the conditions where ICs are most needed. Therefore, it is necessary for ICs to improve their caregiving skills and self-care capacity. Telehealth (TH) can facilitate them. The aim of this systematic review is to summarize the evidence of the effects of interventions on ICs of stroke patients. Methods: The search was conducted in Pubmed, Scopus, Web of Science, CINALH, Psychology and Behavioral Sciences Collection, and APA PsycInfo. Key search terms included "stroke", "informal caregiver" and "telemedicine". Only randomised clinical trials were included. Results: A total of 2031 articles were found in the databases, 476 were screened and 19 clinical trials met the eligibility criteria. Different TH programmes have evaluated many outcomes related to physical and emotional health. The TH tools included phone, videophone, web-based interventions, and social media. The most investigated outcome was depression; although contradictory results were found, the TH may have helped to prevent an increase in depressive symptoms. There were inconsistent results on the caregiving burden and the preparedness of the IC. However, TH has positive effects on the health of the ICs, reducing the number of unhealthy days, anxiety, task difficulty perception, and improving psychological health. Conclusions: TH may be a useful tool to improve the abilities and health of ICs of SS. No adverse effects have been reported. More quality studies evaluating the effects of telemedicine on the ICs of stroke survivors, as well as the most appropriate doses, are needed.

Emergence of lingual dystonia and strabismus in early-onset SCN8A self-limiting familial infantile epilepsy.

Pathogenic variants in SCN8A are associated with a broad phenotypic spectrum, including Self-Limiting Familial Infantile Epilepsy (SeLFIE), characterized by infancy-onset age-related seizures with normal development and cognition. Movement disorders, particularly paroxysmal kinesigenic dyskinesia typically arising after puberty, may represent another core symptom. We present the case of a 1-year-old girl with a familial disposition to self-limiting focal seizures from the maternal side and early-onset orofacial movement disorders associated with SCN8A-SeLFIE. Brain MRI was normal. Genetic testing revealed a maternally inherited SCN8A variant [c.4447G > A; p.(Glu1483Lys)]. After the introduction of valproic acid, she promptly achieved seizure control as well as complete remission of strabismus and a significant decrease in episodes of tongue deviation. Family history, genetic findings, and epilepsy phenotype are consistent with SCN8A-SeLFIE. Movement disorders are an important part of the SCN8A phenotypic spectrum, and this case highlights the novel early-onset orofacial movement disorders associated with this condition. The episodes of tongue deviation and protrusion suggest focal oromandibular (lingual) dystonia. Additionally, while infantile strabismus or esophoria is a common finding in healthy individuals, our case raises the possibility of an ictal origin of the strabismus. This study underscores the importance of recognizing and addressing movement disorders in SCN8A-SeLFIE patients, particularly the rare early-onset orofacial manifestations. It adds to the growing body of knowledge regarding the diverse clinical presentations of SCN8A-associated disorders and suggests potential avenues for clinical management and further research.

An Executive Summary of the National Trauma Research Action Plan (NTRAP).

ABSTRACT: The National Trauma Research Action Plan (NTRAP) project successfully engaged multidisciplinary experts to define opportunities to advance trauma research and has fulfilled the recommendations related to trauma research from the National Academies of Sciences, Engineering and Medicine (NASEM) report. These panels identified more than 4,800 gaps in our knowledge regarding injury prevention and the optimal care of injured patients and laid out a priority framework and tools to support researchers to advance this field. Trauma research funding agencies and researchers can use this executive summary and supporting manuscripts to strategically address and close the highest priority research gaps. Given that this is the most significant public health threat facing our children, young adults, and military service personnel, we must do better in prioritizing these research projects for funding and providing grant support to advance this work. Through the Coalition for National Trauma Research (CNTR), the trauma community is committed to a coordinated, collaborative approach to address these critical knowledge gaps and ultimately reduce the burden of morbidity and mortality faced by our patients.

Psychiatric and Substance Use Disorders and Their Association With Clinical Outcomes in Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic Syndrome.

BACKGROUND AND OBJECTIVE: Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are life-threatening conditions that send nearly 180,000 patients to the intensive care unit each year, with mortality rates up to 5-10%. Little is known about the impact of concurrent psychiatric disorders on specific DKA/HHS outcomes. Identifying these relationships offers opportunities to improve clinical management, treatment planning, and mitigate associated morbidity and mortality. METHODS: We conducted a retrospective review including adult DKA/HHS admissions within a large Massachusetts hospital system from 2010 to 2019. We identified patients admitted inpatient for DKA or HHS, then filtered by International Classification of Disease-9-CM and International Classification of Disease-10-CM codes for psychiatric diagnoses that were present in patients electronic medical record at any point in this observational period. Outcomes included the number of inpatient admissions for DKA/HHS, age of death, rates of discharging against medical advice (AMA) from any inpatient admission, and end-stage renal disease/dialysis status. Multivariate regression was conducted using R software to control for variables across patients and evaluate relationships between outcomes and concurrent psychiatric disorders. Significance was set at P < 0.05. RESULTS: Seven thousand seven hundred fifty-six patients were admitted for DKA or HHS, 66.9% of whom had a concurrent psychiatric disorder. Of these patients, 54.5% were male, 70.4% were White, and they had an average age of 61.6 years. This compares with 26.1% with concurrent psychiatric condition within the general diabetes population, 52.1% of whom were male, 72.1% were White, and an average age of 68.2 years. A concurrent psychiatric disorder was associated with increased odds of rehospitalization (adjusted odds ratio [aOR] = 1.62 95% confidence interval [CI] 1.35-1.95, P < 0.001), of being diagnosed with end-stage renal disease and on dialysis (aOR = 1.02 95% CI 1.002-1.035, P = 0.02), and of leaving AMA (aOR = 6.44 95% CI 4.46-9.63, P < 0.001). The average age of death for those with a concurrent psychiatric disorder had an adjusted mean difference in years of -7.5 years (95% CI -9.3 to 5.8) compared to those without a psychiatric disorder. CONCLUSIONS: Of patients with DKA/HHS, 66.9% have a concurrent psychiatric disorder. Patients with a concurrent psychiatric disorder admitted for DKA/HHS were more likely to have multiple admissions, to leave AMA, to be on renal dialysis, and to have a lower age of mortality.

Determinants of long-term physical and mental health outcomes after intensive care admission for trauma survivors.

INTRODUCTION: Collectively, studies from medical and surgical intensive care units (ICU) suggest that long-term outcomes are poor for patients who have spent significant time in an ICU. We sought to identify determinants of post-intensive care physical and mental health outcomes 6-12 months after injury. METHODS: Adult trauma patients [ISS ≥9] admitted to one of three Level-1 trauma centers were interviewed 6-12 months post-injury to evaluate patient-reported outcomes. Patients requiring ICU admission â€‹≥ â€‹3 days ("ICU patients") were compared with those who did not require ICU admission ("non-ICU patients"). Multivariable regression models were built to identify factors associated with poor outcomes among ICU survivors. RESULTS: 2407 patients were followed [598 (25%) ICU and 1809 (75%) non-ICU patients]. Among ICU patients, 506 (85%) reported physical or mental health symptoms. Of them, 265 (52%) had physical symptoms only, 15 (3%) had mental symptoms only, and 226 (45%) had both physical and mental symptoms. In adjusted analyses, compared to non-ICU patients, ICU patients were more likely to have new limitations for ADLs (OR â€‹= â€‹1.57; 95% CI â€‹= â€‹1.21, 2.03), and worse SF-12 mental (mean Δ â€‹= â€‹-1.43; 95% CI â€‹= â€‹-2.79, -0.09) and physical scores (mean Δ â€‹= â€‹-2.61; 95% CI â€‹= â€‹-3.93, -1.28). Age, female sex, Black race, lower education level, polytrauma, ventilator use, history of psychiatric illness, and delirium during ICU stay were associated with poor outcomes in the ICU-admitted group. CONCLUSIONS: Physical impairment and mental health symptoms following ICU stay are highly prevalent among injury survivors. Modifiable ICU-specific factors such as early liberation from ventilator support and prevention of delirium are potential targets for intervention.

Patients Lost to Follow-up After Injury: Who are They and What are Their Long-Term Outcomes?

INTRODUCTION: Trauma patients are at high risk for loss to follow-up (LTFU) after hospital discharge. We sought to identify risk factors for LTFU and investigate associations between LTFU and long-term health outcomes in the trauma population. METHODS: Trauma patients with an Injury Severity Score ≥9 admitted to one of three Level-I trauma centers, 2015-2020, were surveyed via telephone 6 mo after injury. Univariate and multivariate analyses were performed to assess factors associated with LTFU and several long-term outcomes. RESULTS: Of 3609 patients analyzed, 808 (22.4%) were LTFU. Patients LTFU were more likely to be male (71% versus 61%, P = 0.001), Black (22% versus 14%, P = 0.003), have high school or lower education (50% versus 42%, P = 0.003), be publicly insured (23% versus 13%, P < 0.001), have a penetrating injury (13% versus 8%, P = 0.006), have a shorter length of stay (3.64 d ± 4.09 versus 5.06 ± 5.99, P < 0.001), and be discharged home without assistance (79% versus 50%, P < 0.001). In multivariate analyses, patients who followed up were more likely to require assistance at home (6% versus 11%; odds ratio [OR] 2.23, 1.26-3.92, P = 0.005), have new functional limitations (11% versus 26%; OR 2.91, 1.97-4.31, P = < 0.001), have daily pain (30% versus 48%; OR 2.11, 1.54-2.88, P = < 0.001), and have more injury-related emergency department visits (7% versus 10%; OR 1.93, 1.15-3.22, P = 0.012). CONCLUSIONS: Vulnerable populations are more likely to be LTFU after injury. Clinicians should be aware of potential racial and socioeconomic disparities in follow-up care after traumatic injury. Future studies investigating improvement strategies in follow-up care should be considered.

Additional effects of therapeutic exercise and education on manual therapy for chronic temporomandibular disorders treatment: a randomized clinical trial.

BACKGROUND: Previous studies have evaluated the implementation of behavioral approaches in individuals with chronic temporomandibular disorders (TMDs). OBJECTIVE: To evaluate the benefits of a behavioral approach to craniofacial pain. Second, we assessed the benefits of kinesiophobia, catastrophizing, mouth opening without pain, and forward head posture. METHODS: Individuals with chronic TMDs were treated for five weeks. The intervention group (n = 17) underwent pain neuroscience education, manual therapy, and therapeutic exercise, whereas the control group (n = 17) underwent manual therapy only. Outcomes were evaluated immediately, at seven and 19 weeks follow-up. The assessment tools used were the Craniofacial Pain Disability Inventory, Pain Catastrophizing Scale, Tampa Scale for Kinesiophobia, Mandibular Range of Motion Scale, and Cervical Range of Motion Tool. RESULTS: The interventions did not influence the differences in the improvements between the groups observed for craniofacial pain disability (inter-subject p 0.4). The intervention had a moderate influence on the improvement of kinesiophobia and catastrophizing (Inter-subject p 0.09 and 0.1 respectively) with a clinically significant effect size (Estimated mean (EM) -8.6 standard deviation (SD) ±3.48 p 0.019; and EM -7.6 SD ± 5.11 p 0.15 respectively). CONCLUSION: The behavioral approach improved catastrophizing and kinesiophobia outcomes in individuals with chronic TMDs.

A new early-diverging probainognathian cynodont and a revision of the occurrence of cf. Aleodon from the Chañares Formation, northwestern Argentina: New clues on the faunistic composition of the latest Middle-?earliest Late Triassic Tarjadia Assemblage Zone.

The Chañares Formation (Ischigualasto-Villa Unión Basin) is worldwide known by its exquisitely preserved fossil record of latest Middle-to-early Late Triassic tetrapods, including erpetosuchids, "rauisuchians," proterochampsids, gracilisuchids, dinosauromorphs, pterosauromorphs, kannemeyeriiform dicynodonts, and traversodontid, chiniquodontid and probainognathid cynodonts, coming from the Tarjadia (bottom) and Massetognathus-Chanaresuchus (top) Assemblage Zones of its lower member. Regarding cynodonts, most of its profuse knowledge comes from the traditional layers discovered by Alfred Romer and his team in the 1960s that are now enclosed in the Massetognathus-Chanaresuchus Assemblage Zone (AZ). In this contribution we focus our study on the probainognathian cynodonts discovered in levels of the Tarjadia Assemblage Zone. We describe a new chiniquodontid cynodont with transversely broad postcanine teeth (Riojanodon nenoi gen. et sp. nov.) which is related to the genus Aleodon. In addition, the specimen CRILAR-Pv 567 previously referred to cf. Aleodon is here described, compared, and included in a phylogenetic analysis. It is considered as an indeterminate Aleodontinae nov., a clade here proposed to included chiniquodontids with transversely broad upper and lower postcanines, by having a cuspidated sectorial labial margin and a lingual platform that is twice broader than a lingual cingulum. Cromptodon mamiferoides, from the Cerro de Las Cabras Formation (Cuyo Basin), was also included in the phylogenetic analysis and recovered as an Aleodontinae. The new cynodont and the record of Aleodontinae indet. reinforce the faunal differentiation between the Tarjadia and Massetognathus-Chanaresuchus Assemblage Zones, in the lower member of the Chañares Formation, and inform on the diverse chiniquodontid clade with both sectorial and transversely broad postcanine teeth.

The Invisible Scars: Unseen Financial Complications Worsen Every Aspect of Long-Term Health in Trauma Survivors.

INTRODUCTION: Trauma survivors are susceptible to experiencing financial toxicity (FT). Studies have shown the negative impact of FT on chronic illness outcomes. However, there is a notable lack of data on FT in the context of trauma. We aimed to better understand prevalence, risk factors, and impact of FT on trauma long-term outcomes. METHODS: Adult trauma patients with an Injury severity score (ISS) ≥9 treated at level-1 trauma centers were interviewed 6-14 months after discharge. FT was considered positive if patients reported any of the following due to the injury: income loss, lack of care, newly applied/qualified for governmental assistance, new financial problems, or work loss. The Impact of FT on Patient Reported Outcome Measure Index System (PROMIS) health domains was investigated. RESULTS: Of 577 total patients, 44% (254/567) suffered some form of FT. In the adjusted model, older age (OR 0.4 [95% CI: 0.2 - 0.81]) and stronger social support networks (OR 0.44 [ 95% CI: 0.26 - 0.74]) were protective against FT. In contrast, having two or more comorbidities (OR 1.81 [1.01 - 3.28), lower education levels (OR = 1.95, [CI 95%: 1.26 - 3.03]), and injury mechanisms, including road accidents (OR 2.69 [1.51 -4.77]) and intentional injuries (OR 4.31 [1.44 -12.86]) were associated with higher toxicity. No significant relationship was found with ISS, sex, or single-family household. Patients with FT had worse outcomes across all domains of health. There was a negative linear relationship between the severity of FT and worse mental and physical health scores. CONCLUSION: FT is associated with long-term outcomes. Incorporating FT risk assessment into recovery care planning may help to identify patients most in need of mitigative interventions across the trauma care continuum to improve trauma recovery. Further investigations to better understand, define, and address FT in trauma care are warranted. LEVEL OF EVIDENCE: Prognostic cohort study, level III.

A new blood DNA methylation signature for Koolen-de Vries syndrome: Classification of missense KANSL1 variants and comparison to fibroblast cells.

Pathogenic variants in KANSL1 and 17q21.31 microdeletions are causative of Koolen-de Vries syndrome (KdVS), a neurodevelopmental syndrome with characteristic facial dysmorphia. Our previous work has shown that syndromic conditions caused by pathogenic variants in epigenetic regulatory genes have identifiable patterns of DNA methylation (DNAm) change: DNAm signatures or episignatures. Given the role of KANSL1 in histone acetylation, we tested whether variants underlying KdVS are associated with a DNAm signature. We profiled whole-blood DNAm for 13 individuals with KANSL1 variants, four individuals with 17q21.31 microdeletions, and 21 typically developing individuals, using Illumina's Infinium EPIC array. In this study, we identified a robust DNAm signature of 456 significant CpG sites in 8 individuals with KdVS, a pattern independently validated in an additional 7 individuals with KdVS. We also demonstrate the diagnostic utility of the signature and classify two KANSL1 VUS as well as four variants in individuals with atypical clinical presentation. Lastly, we investigated tissue-specific DNAm changes in fibroblast cells from individuals with KdVS. Collectively, our findings contribute to the understanding of the epigenetic landscape related to KdVS and aid in the diagnosis and classification of variants in this structurally complex genomic region.

Child-to-adult transition: a survey of current practices within the European Reference Network for Rare Neurological Diseases (ERN-RND).

BACKGROUND: Transition from child-centered to adult-centered healthcare is a gradual process that addresses the medical, psychological, and educational needs of young people in the management of their autonomy in making decisions about their health and their future clinical assistance. This transfer is challenging across all chronic diseases but can be particularly arduous in rare neurological conditions. AIM: To describe the current practice on the transition process for young patients in centers participating in the European Reference Network for Rare Neurological Diseases (ERN-RND). METHODS: Members of the ERN-RND working group developed a questionnaire considering child-to-adult transition issues and procedures in current clinical practice. The questionnaire included 20 questions and was sent to members of the health care providers (HCPs) participating in the network. RESULTS: Twenty ERN-RND members (75% adult neurologists; 25% pediatricians; 5% nurses or study coordinators) responded to the survey, representing 10 European countries. Transition usually occurs between 16 and 18 years of age, but 55% of pediatric HCPs continue to care for their patients until they reach 40 years of age or older. In 5/20 ERN-RND centers, a standardized procedure managing transition is currently adopted, whereas in the remaining centers, the transition from youth to adult service is usually assisted by pediatricians as part of their clinical practice. CONCLUSIONS: This survey demonstrated significant variations in clinical practice between different centers within the ERN-RND network. It provided valuable data on existing transition programs and highlighted key challenges in managing transitions for patients with rare neurological disorders.

Critical systolic blood pressure threshold for endovascular aortic occlusion-A multinational analysis to determine when to place a REBOA.

BACKGROUND: Systolic blood pressure (SBP) is a potential indicator that could guide when to use a resuscitative endovascular balloon occlusion of the aorta (REBOA) in trauma patients with life-threatening injuries. This study aims to determine the optimal SBP threshold for REBOA placement by analyzing the association between SBP pre-REBOA and 24-hour mortality in severely injured hemodynamically unstable trauma patients. METHODS: We performed a pooled analysis of the aortic balloon occlusion (ABO) trauma and AORTA registries. These databases record the details related to the use of REBOA and include data from 14 countries worldwide. We included patients who had suffered penetrating and/or blunt trauma. Patients who arrived at the hospital with a SBP pre-REBOA of 0 mm Hg and remained at 0 mm Hg after balloon inflation were excluded. We evaluated the impact that SBP pre-REBOA had on the probability of death in the first 24 hours. RESULTS: A total of 1,107 patients underwent endovascular aortic occlusion, of these, 848 met inclusion criteria. The median age was 44 years (interquartile range [IQR], 27-59 years) and 643 (76%) were male. The median injury severity score was 34 (IQR, 25-45). The median SBP pre-REBOA was 65 mm Hg (IQR, 49-88 mm Hg). Mortality at 24 hours was reported in 279 (32%) patients. Math modeling shows that predicted probabilities of the primary outcome increased steadily in SBP pre-REBOA below 100 mm Hg. Multivariable mixed-effects analysis shows that when SBP pre-REBOA was lower than 60 mm Hg, the risk of death was more than 50% (relative risk, 1.5; 95% confidence interval, 1.17-1.92; p = 0.001). DISCUSSION: In patients who do not respond to initial resuscitation, the use of REBOA in SBPs between 60 mm Hg and 80 mm Hg may be a useful tool in resuscitation efforts before further decompensation or complete cardiovascular collapse. The findings from our study are clinically important as a first step in identifying candidates for REBOA. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level IV.

Broadening the clinical spectrum: molecular mechanisms and new phenotypes of ANO3-dystonia.

Anoctamin 3 (ANO3) belongs to a family of transmembrane proteins that form phospholipid scramblases and ion channels. A large number of ANO3 variants were identified as the cause of craniocervical dystonia, but the underlying pathogenic mechanisms remain obscure. It was suggested that ANO3 variants may dysregulate intracellular Ca2+ signalling, as variants in other Ca2+ regulating proteins like hippocalcin were also identified as a cause of dystonia. In this study, we conducted a comprehensive evaluation of the clinical, radiological, and molecular characteristics of four individuals from four families who carried heterozygous variants in ANO3. The median age at follow-up was 6.6 years (ranging from 3.8 to 8.7 years). Three individuals presented with hypotonia and motor developmental delay. Two patients exhibited generalized progressive dystonia, while one patient presented with paroxysmal dystonia. Additionally, another patient exhibited early dyskinetic encephalopathy. One patient underwent bipallidal deep brain stimulation (DBS) and showed a mild but noteworthy response, while another patient is currently being considered for DBS treatment. Neuroimaging analysis of brain MRI studies did not reveal any specific abnormalities. The molecular spectrum included two novel ANO3 variants (V561L and S116L) and two previously reported ANO3 variants (A599D and S651N). As anoctamins are suggested to affect intracellular Ca2+ signals, we compared Ca2+ signalling and activation of ion channels in cells expressing wild type ANO3 and cells expressing ANO variants. Novel V561L and S116L variants were compared with previously reported A599D and S651N variants and with wtANO3 expressed in fibroblasts isolated from patients or when overexpressed in HEK293 cells. We identified ANO3 as a Ca2+-activated phospholipid scramblase that also conducts ions. Impaired Ca2+ signalling and compromised activation of Ca2+ dependent K+ channels were detected in cells expressing ANO3 variants. In the brain striatal cells of affected patients, impaired activation of KCa3.1 channels due to compromised Ca2+ signals may lead to depolarized membrane voltage and neuronal hyperexcitability and may also lead to reduced cellular viability, as shown in the present study. In conclusion, our study reveals the association between ANO3 variants and paroxysmal dystonia, representing the first reported link between these variants and this specific dystonic phenotype. We demonstrate that ANO3 functions as a Ca2+-activated phospholipid scramblase and ion channel; cells expressing ANO3 variants exhibit impaired Ca2+ signalling and compromised activation of Ca2+-dependent K+ channels. These findings provide a mechanism for the observed clinical manifestations and highlight the importance of ANO3 for neuronal excitability and cellular viability.

Universal Access to On-Demand Treatment of Patients with Hereditary Angioedema, the Chilean Experience.

Background: In Chile, patients with hereditary angioedema (HAE) type I and type II are protected under Ley Ricarte Soto (LRS), which guarantees access to on demand plasma-derived C1-INH (pdC1-INH) since 2018. We aimed to analyze the first 3 years of LRS. Methods: Review of the LRS database between 2018 and 2021. Results: During the study period, 154 patients were covered by LRS, with an estimated prevalence of HAE in Chile at 0.8:100,000 inhabitants. A delay in diagnosis of 22 years was noted, 50 patients received epinephrine during an attack before the diagnosis of HAE. Mean number of attacks per year was 8, with 50% of adults and 42% of children experiencing more than 1 attack per month. Conclusion: Disease awareness must improve to reduce the diagnostic delay of HAE. Long-term prophylactic medications should be included in LRS to treat patients with high attack rates and control the costs of frequent on-demand treatment with pdC1-INH.

Exploring the Spectrum of RHOBTB2 Variants Associated with Developmental Encephalopathy 64: A Case Series and Literature Review.

Background: Rho-related BTB domain-containing protein 2 (RHOBTB2) is a protein that interacts with cullin-3, a crucial E3 ubiquitin ligase for mitotic cell division. RHOBTB2 has been linked to early infantile epileptic encephalopathy, autosomal dominant type 64 (OMIM618004), in 34 reported patients. Methods: We present a case series of seven patients with RHOBTB2-related disorders (RHOBTB2-RD), including a description of a novel heterozygous variant. We also reviewed previously published cases of RHOBTB2-RD. Results: The seven patients had ages ranging from 2 years and 8 months to 26 years, and all had experienced seizures before the age of one (onset, 4-12 months, median, 4 months), including various types of seizures. All patients in this cohort also had a movement disorder (onset, 0.3-14 years, median, 1.5 years). Six of seven had a baseline movement disorder, and one of seven only had paroxysmal dystonia. Stereotypies were noted in four of six, choreodystonia in three of six, and ataxia in one case with multiple movement phenotypes at baseline. Paroxysmal movement disorders were observed in six of seven patients for whom carbamazepine or oxcarbazepine treatment was effective in controlling acute or paroxysmal movement disorders. Four patients had acute encephalopathic episodes at ages 4 (one patient) and 6 (three patients), which improved following treatment with methylprednisolone. Magnetic resonance imaging scans revealed transient fluid-attenuated inversion recovery abnormalities during these episodes, as well as myelination delay, thin corpus callosum, and brain atrophy. One patient had a novel RHOBTB2 variant (c.359G>A/p.Gly120Glu). Conclusion: RHOBTB2-RD is characterized by developmental delay or intellectual disability, early-onset seizures, baseline movement disorders, acute or paroxysmal motor phenomena, acquired microcephaly, and episodes of acute encephalopathy. Early onsets of focal dystonia, acute encephalopathic episodes, episodes of tongue protrusion, or peripheral vasomotor disturbances are important diagnostic clues. Treatment with carbamazepine or oxcarbazepine was found to be effective in controlling acute or paroxysmal movement disorders. Our study highlights the clinical features and treatment response of RHOBTB2-RD.