Virtual self-care simulations for third-year pharmacy skills laboratory courses in three institutions.

BACKGROUND AND PURPOSE: This study was designed to determine whether a virtual, self-care activity improved knowledge and confidence in third-year student pharmacists. EDUCATIONAL ACTIVITY AND SETTING: Third-year student pharmacists (n = 386) from three institutions participated in the virtual self-care simulation during their respective practice laboratory course. A pre- and post-assessment collected 10 knowledge and five confidence questions, self-reported on 0-100 scale, mapped to learning outcomes and pharmacy standards. Responses for participants who provided consent and had linked assessments were analyzed. Additionally, students participated in a perception assessment following the simulation with the post-assessment. Each knowledge question was scored as binary (correct/incorrect), presented as percentage, and significance identified with a McNemar's test. Total knowledge score and confidence changes were presented as means with standard deviations and significance with a paired t-test. Student perceptions were presented as frequencies and percentages. FINDINGS: Total knowledge assessment demonstrated a significant improvement (p < 0.001) for the entire cohort of 198 study participants. Upon additional analysis, a single institution led the cohort to significant increase, with variable improvement and significance for each individual question. Confidence improved for the entire cohort of students and at each institution individually. The students perceived the virtual self-care activity favorably. SUMMARY: The third-year student virtual self-care activity improved knowledge and confidence with varying significance between institutions. Future studies will focus on the impact of continued reinforcement of self-care activities on student growth in knowledge and confidence.

Heterozygous MAP3K20 variants cause ectodermal dysplasia, craniosynostosis, sensorineural hearing loss, and limb anomalies.

Biallelic pathogenic variants in MAP3K20, which encodes a mitogen-activated protein kinase, are a rare cause of split-hand foot malformation (SHFM), hearing loss, and nail abnormalities or congenital myopathy. However, heterozygous variants in this gene have not been definitively associated with a phenotype. Here, we describe the phenotypic spectrum associated with heterozygous de novo variants in the linker region between the kinase domain and leucine zipper domain of MAP3K20. We report five individuals with diverse clinical features, including craniosynostosis, limb anomalies, sensorineural hearing loss, and ectodermal dysplasia-like phenotypes who have heterozygous de novo variants in this specific region of the gene. These individuals exhibit both shared and unique clinical manifestations, highlighting the complexity and variability of the disorder. We propose that the involvement of MAP3K20 in endothelial-mesenchymal transition provides a plausible etiology of these features. Together, these findings characterize a disorder that both expands the phenotypic spectrum associated with MAP3K20 and highlights the need for further studies on its role in early human development.

Implementation of genomic medicine for rare disease in a tertiary healthcare system: Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD).

BACKGROUND: In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education. METHODS: Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers. RESULTS: Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1152 patients have been evaluated with an overall solved or likely solved rate of 17.5% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results. CONCLUSION: Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities.

Loss-of-Function Variants in DRD1 in Infantile Parkinsonism-Dystonia.

The human dopaminergic system is vital for a broad range of neurological processes, including the control of voluntary movement. Here we report a proband presenting with clinical features of dopamine deficiency: severe infantile parkinsonism-dystonia, characterised by frequent oculogyric crises, dysautonomia and global neurodevelopmental impairment. CSF neurotransmitter analysis was unexpectedly normal. Triome whole-genome sequencing revealed a homozygous variant (c.110C>A, (p.T37K)) in DRD1, encoding the most abundant dopamine receptor (D1) in the central nervous system, most highly expressed in the striatum. This variant was absent from gnomAD, with a CADD score of 27.5. Using an in vitro heterologous expression system, we determined that DRD1-T37K results in loss of protein function. Structure-function modelling studies predicted reduced substrate binding, which was confirmed in vitro. Exposure of mutant protein to the selective D1 agonist Chloro APB resulted in significantly reduced cyclic AMP levels. Numerous D1 agonists failed to rescue the cellular defect, reflected clinically in the patient, who had no benefit from dopaminergic therapy. Our study identifies DRD1 as a new disease-associated gene, suggesting a crucial role for the D1 receptor in motor control.

An Introductory Over-the-Counter Simulation for First-Year Pharmacy Students Using a Virtual Pharmacy.

Objective. First-year pharmacy students at two institutions were required to complete a virtual over-the-counter (OTC) simulation during their community pharmacy practice skills laboratory course. The simulation was designed to introduce first-year pharmacy students to OTC product selection and consultation prior to didactic coursework and community introductory pharmacy practice experiences. The objective of this study was to assess the impact of the OTC simulation on students' knowledge and confidence of OTC medications and overall perceptions of the activity.Methods. Patient simulation cases in the virtual community pharmacy setting were developed and delivered to students using the MyDispense platform. Students concurrently completed a Google Form that provided directions for the virtual activity, including a combination of didactic and active learning strategies within the online platform. Student surveys assessed knowledge and confidence before and after the activity, with perceptions added to the postsurvey.Results. Total knowledge scores for the 142 students from two institutions who completed both the pre- and postsurvey significantly improved and, when assessed individually, improved for seven out of 10 individual knowledge questions. All five confidence statements significantly increased after students completed the OTC simulation. Student perceptions were overall very positive.Conclusion. Introduction of OTC counseling processes to first-year pharmacy students through a virtual pharmacy simulation resulted in increased student knowledge and confidence in providing OTC recommendations. Students perceived the activity favorably.

Autoimmune Disease and Breast Implants: Systematic Review of Outcomes.

ABSTRACT: Given that the use of breast implants for both cosmetic and reconstructive purposes is growing in the United States, an evaluation of factors that may affect the outcome of breast implant surgery is needed. A systematic review was conducted to evaluate the question: Does a personal or family history of autoimmune disease affect outcomes in breast implant surgery? The literature search yielded 2425 records, but after removal of duplicates, abstract screening, and full-text assessment, only 2 studies met the inclusion criteria for the final review. Both studies provided level III evidence and the average Methodological Index for Non-Randomized Studies score was 16.5 (range, 15-18 of 24), indicating a fair level of evidence overall. This systematic review found no evidence to support that a diagnosis of an autoimmune disease and/or a family history of autoimmune diseases will lead to poor surgical outcomes in breast implant surgery. Further study is warranted.

A Randomized Trial of Mesenchymal Stromal Cells for Moderate to Severe Acute Respiratory Distress Syndrome from COVID-19.

Rationale: There are limited therapeutic options for patients with coronavirus disease (COVID-19)-related acute respiratory distress syndrome with inflammation-mediated lung injury. Mesenchymal stromal cells offer promise as immunomodulatory agents. Objectives: Evaluation of efficacy and safety of allogeneic mesenchymal cells in mechanically-ventilated patients with moderate or severe COVID-19-induced respiratory failure. Methods: Patients were randomized to two infusions of 2 million cells/kg or sham infusions, in addition to the standard of care. We hypothesized that cell therapy would be superior to sham control for the primary endpoint of 30-day mortality. The key secondary endpoint was ventilator-free survival within 60 days, accounting for deaths and withdrawals in a ranked analysis. Measurements and Main Results: At the third interim analysis, the data and safety monitoring board recommended that the trial halt enrollment as the prespecified mortality reduction from 40% to 23% was unlikely to be achieved (n = 222 out of planned 300). Thirty-day mortality was 37.5% (42/112) in cell recipients versus 42.7% (47/110) in control patients (relative risk [RR], 0.88; 95% confidence interval, 0.64-1.21; P = 0.43). There were no significant differences in days alive off ventilation within 60 days (median rank, 117.3 [interquartile range, 60.0-169.5] in cell patients and 102.0 [interquartile range, 54.0-162.5] in control subjects; higher is better). Resolution or improvement of acute respiratory distress syndrome at 30 days was observed in 51/104 (49.0%) cell recipients and 46/106 (43.4%) control patients (odds ratio, 1.36; 95% confidence interval, 0.57-3.21). There were no infusion-related toxicities and overall serious adverse events over 30 days were similar. Conclusions: Mesenchymal cells, while safe, did not improve 30-day survival or 60-day ventilator-free days in patients with moderate and/or severe COVID-19-related acute respiratory distress syndrome.

Machine Learning-Based Exploratory Clinical Decision Support for Newly Diagnosed Patients With Acute Myeloid Leukemia Treated With 7 + 3 Type Chemotherapy or Venetoclax/Azacitidine.

PURPOSE: There are currently limited objective criteria to help assist physicians in determining whether an individual patient with acute myeloid leukemia (AML) is likely to do better with induction with either standard 7 + 3 chemotherapy or targeted therapy with venetoclax plus azacitidine. The study goal was to address this need by developing exploratory clinical decision support methods. PATIENTS AND METHODS: Univariable and multivariable analysis as well as comparison of a range of machine learning (ML) predictors were performed using cohorts of 120 newly diagnosed 7 + 3-treated AML patients compared with 101 venetoclax plus azacitidine-treated patients. RESULTS: A variety of features in the two patient cohorts were identified that may potentially correlate with short- and long-term outcomes, toxicities, and other considerations. A subset of these diagnostic features was then used to develop ML-based predictors with relatively high areas under the curve of short- and long-term outcomes, hospital stays, transfusion requirements, and toxicities for individual patients treated with either venetoclax/azacitidine or 7 + 3. CONCLUSION: Potential ML-based approaches to clinical decision support to help guide individual patients with newly diagnosed AML to either 7 + 3 or venetoclax plus azacitidine induction therapy were identified. Larger cohorts with separate test and validation studies are necessary to confirm these initial findings.

Mesenchymal stromal cell therapy for acute respiratory distress syndrome due to coronavirus disease 2019.

BACKGROUND AIMS: The acute respiratory distress syndrome (ARDS) resulting from coronavirus disease 2019 (COVID-19) is associated with a massive release of inflammatory cytokines and high mortality. Mesenchymal stromal cells (MSCs) have anti-inflammatory properties and have shown activity in treating acute lung injury. Here the authors report a case series of 11 patients with COVID-19-associated ARDS (CARDS) requiring mechanical ventilation who were treated with remestemcel-L, an allogeneic MSC product, under individual patient emergency investigational new drug applications. METHODS: Patients were eligible if they were mechanically ventilated for less than 72 h prior to the first infusion. Patients with pre-existing lung disease requiring supplemental oxygen or severe liver or kidney injury were excluded. Each patient received two infusions of remestemcel-L at a dose of 2 million cells/kg per infusion given 48-120 h apart. RESULTS: Remestemcel-L infusions were well tolerated in all 11 patients. At the end of the 28-day follow-up period, 10 (91%, 95% confidence interval [CI], 59-100%) patients were extubated, nine (82%, 95% CI, 48-97%) patients remained liberated from mechanical ventilation and were discharged from the intensive care unit and two (18%, 95 CI%, 2-52%) patients died. The median time to extubation was 10 days. Eight (73%, 95% CI, 34-100%) patients were discharged from the hospital. C-reactive protein levels significantly declined within 5 days of MSC infusion. CONCLUSIONS: The authors demonstrate in this case series that remestemcel-L infusions to treat moderate to severe CARDS were safe and well tolerated and resulted in improved clinical outcomes.

CT cisternography to visualize epidermoid tumors for stereotactic radiosurgery treatment planning.

The visualization of intracranial epidermoid tumors is often limited by difficulties associated with distinguishing the tumor from the surrounding cerebrospinal fluid using traditional computed tomography (CT) or magnetic resonance imaging (MRI) modalities. This report describes our experience using CT cisternography to visualize intracranial epidermoid tumors in three illustrative cases. CT cisternography of the epidermoid tumor provides more clarity and precision compared to traditional neuroimaging modalities. We demonstrate the feasibility of using CT cisternography to produce high-resolution images with well-defined tumor margins that can be used effectively for precise SRS treatment planning.

Utilization of the Ballast Long Guiding Sheath for Neuroendovascular Procedures: Institutional Experience in 68 Cases.

Background: The rise of neurointerventional devices has created a demand for guide systems capable of navigating to the carotid artery consistently regardless of tortuosity. The shift toward large distal access catheters (DACs) and desire for greater trackability have inspired the creation of flexible, supportive, large-lumen long guiding sheaths. Recently, the Ballast long guiding sheath was introduced to provide stability and flexibility while navigating neurointerventional devices through tortuous intracranial anatomy. Objective: To report our experience using the Ballast long guiding sheath in a series of patients undergoing a variety of neuroendovascular procedures. Methods: We retrospectively identified all patients who underwent neuroendovascular treatment with a long guiding sheath were selected from a prospectively maintained endovascular database from January 2019 to November 2019. Baseline clinical characteristics and procedural details were collected. Results: A total of 68 patients were included, mean patient age 67.6 ± 13.6 years. Of the patients treated, 52.9% (36/68) presented with stenosis, 25% (17/68) with aneurysms, 13.2% (9/68) with stroke or emboli, 1.5% (1/68) with a tumor, 1.5% (1/68) with an arteriovenous fistula (AVF), and 4.4% (3/68) with a carotid web. Of the patients with stenosis, 20/36 (55.6%) were extracranial, and 16/36 (44.4%) were intracranial. The Ballast long guiding sheath was used to deliver treatment devices for stenting (37/68, 54.4%), flow diversion (12/68, 17.6%), mechanical thrombectomy (8/68, 11.8%), endovascular coiling (5/68, 7.4%), liquid embolization (3/68, 4.4%), balloon angioplasty (2/68, 2.9%), and balloon angioplasty with stenting (1/68, 1.5%). No Ballast-related complications or adverse events were encountered. Conclusions: We demonstrate the feasibility of the Ballast long guiding sheath to successfully deliver modern neurointerventional treatment devices through tortuous anatomy.

Compound heterozygous KCTD7 variants in progressive myoclonus epilepsy.

KCTD7 is a member of the potassium channel tetramerization domain-containing protein family and has been associated with progressive myoclonic epilepsy (PME), characterized by myoclonus, epilepsy, and neurological deterioration. Here we report four affected individuals from two unrelated families in which we identified KCTD7 compound heterozygous single nucleotide variants through exome sequencing. RNAseq was used to detect a non-annotated splicing junction created by a synonymous variant in the second family. Whole-cell patch-clamp analysis of neuroblastoma cells overexpressing the patients' variant alleles demonstrated aberrant potassium regulation. While all four patients experienced many of the common clinical features of PME, they also showed variable phenotypes not previously reported, including dysautonomia, brain pathology findings including a significantly reduced thalamus, and the lack of myoclonic seizures. To gain further insight into the pathogenesis of the disorder, zinc finger nucleases were used to generate kctd7 knockout zebrafish. Kctd7 homozygous mutants showed global dysregulation of gene expression and increased transcription of c-fos, which has previously been correlated with seizure activity in animal models. Together these findings expand the known phenotypic spectrum of KCTD7-associated PME, report a new animal model for future studies, and contribute valuable insights into the disease.

Remestemcel-L Therapy for COVID-19-Associated Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children (MIS-C) is a serious postinfectious immune dysregulation associated with coronavirus disease 2019 that may present with severe and life-threatening cardiovascular dysfunction, hemodynamic instability, shock, and multisystem organ failure. Optimal treatment is unknown. Current standard of care consists of nonspecific anti-inflammatory and antithrombotic therapies. Interventions that target MIS-C's distinctive clinical features and immunophenotype are indicated. Remestemcel-L, an investigational mesenchymal stromal cell therapy, is a promising candidate for treatment of MIS-C because of its beneficial anti-inflammatory, immunomodulatory, endothelial function and vascular stabilizing effects, which align well with the pathophysiology of MIS-C. Here, we present the first two patients with life-threatening MIS-C ever treated with remestemcel-L under an expanded access program. Both were previously healthy children without any indication of previous coronavirus disease 2019 infection or exposure. They presented with severe clinical illness including myocardial dysfunction, hemodynamic instability, hypotension, acute kidney injury, and shock. At the time of hospital admission, both had negative polymerase chain reaction (PCR) test results and positive serology results for severe acute respiratory syndrome coronavirus 2. Both children received standard of care MIS-C treatment. Although the patients showed some clinical improvement, left ventricular ejection fraction remained reduced and inflammatory biomarkers remained significantly elevated. When treated with two intravenous doses of remestemcel-L separated by 48 hours, rapid normalization of left ventricular ejection fraction, notable reductions in biomarkers of systemic and cardiac inflammation, and improved clinical status occurred. Neither child experienced adverse effects associated with remestemcel-L administration. This treatment appears promising as a novel immunomodulatory cellular therapy for children with clinically significant cardiovascular manifestations of MIS-C.

Exploring and reconciling discordance between documented and preferred resuscitation preferences for hospitalized patients: a quality improvement study.

PURPOSE: A discordance, predominantly towards overtreatment, exists between patients' expressed preferences for life-sustaining interventions and those documented at hospital admission. This quality improvement study sought to assess this discordance at our institution. Secondary objectives were to explore if internal medicine (IM) teams could identify patients who might benefit from further conversations and if the discordance can be reconciled in real-time. METHODS: Two registered nurses were incorporated into IM teams at a tertiary hospital to conduct resuscitation preference conversations with inpatients either specifically referred to them (group I, n = 165) or randomly selected (group II, n = 164) from 1 August 2016 to 31 August 2018. Resuscitation preferences were documented and communicated to teams prompting revised resuscitation orders where appropriate. Multivariable logistic regression was used to determine potential risk factors for discordance. RESULTS: Three hundred and twenty-nine patients were evaluated with a mean (standard deviation) age of 80 (12) and Charlson Comorbidity Index Score of 6.8 (2.6). Discordance was identified in 63/165 (38%) and 27/164 (16%) patients in groups I and II respectively. 42/194 patients (21%) did not want cardiopulmonary resuscitation (CPR) and 15/36 (41%) did not prefer intensive care unit (ICU) admission, despite these having been indicated in their initial preferences. 93% (84/90) of patients with discordance preferred de-escalation of care. Discordance was reconciled in 77% (69/90) of patients. CONCLUSION: Hospitalized patients may have preferences documented for CPR and ICU interventions contrary to their preferences. Trained nurses can identify inpatients who would benefit from further in-depth resuscitation preference conversations. Once identified, discordance can be reconciled during the index admission.

RéSUMé: OBJECTIF: Il existe une discordance, qui tend surtout vers un sur-traitement, entre les préférences exprimées par les patients pour les interventions de maintien de la vie et celles documentées lors de l'admission à l'hôpital. Cette étude d'amélioration de la qualité avait pour objectif d'évaluer cette discordance au sein de notre institution. Les objectifs secondaires de notre étude étaient d'explorer la possibilité que les équipes de médecine interne (MI) identifient les patients qui pourraient bénéficier de conversations approfondies et de voir si la discordance pouvait être corrigée en temps réel. MéTHODE: Deux infirmières ont intégré des équipes de MI dans un hôpital tertiaire pour discuter avec les patients hospitalisés de leurs préférences en matière de réanimation entre le 1er août 2016 et le 31 août 2018; les patients leur étaient soit spécifiquement référés (groupe I, n = 165), ou sélectionnés au hasard (groupe II, n = 164). Les préférences en matière de réanimation ont été documentées et communiquées aux équipes, entraînant une révision des ordonnances de réanimation, le cas échéant. La régression logistique multivariée a été utilisée afin de déterminer les facteurs de risque potentiels de discordance. RéSULTATS: Trois cent vingt-neuf patients ont été évalués, d'un âge moyen (écart type) de 80 ans (12) et avec un score de 6,8 (2,6) à l'Indice de comorbidité de Charlson. Une discordance a été identifiée chez 63/165 (38 %) et 27/164 (16 %) patients dans les groupes I et II, respectivement. Au total, 42/194 patients (21 %) ne souhaitaient pas de réanimation cardiorespiratoire (RCR) et 15/36 (41 %) préféraient ne pas être admis à l'unité de soins intensifs (USI), malgré une mention dans leurs préférences initiales. Parmi les patients chez lesquels une discordance a été notée, 93 % (84/90) ont préféré une désescalade des soins. La discordance a pu être corrigée pour 77 % (69/90) des patients. CONCLUSION: La documentation des patients hospitalisés pourrait indiquer des préférences pour des interventions de RCR et d'admission à l'USI contraires aux véritables préférences. Des infirmières formées à cet effet peuvent identifier les patients hospitalisés qui bénéficieraient d'une conversation approfondie sur leurs préférences en matière de réanimation. Une fois identifiée, une discordance peut être corrigée lors de l'admission initiale.

Adenosine-induced transient asystole to control intraoperative rupture of intracranial aneurysms: institutional experience and systematic review of the literature.

BACKGROUND: Intraoperative rupture of an intracranial aneurysm is a life-threatening situation that carries a high risk of morbidity and mortality. Since 2000, adenosine has been used successfully to induce transient hypotension and/or asystole to control bleeding and facilitate surgical clipping of aneurysms that rupture intraoperatively. Given the paucity of reports describing this method in a limited number of patients, we performed a systematic review of the literature detailing the use and outcomes of this technique. METHODS: The authors performed a systematic review and identified all studies in which adenosine was used in the setting of an intracranial aneurysm that ruptured intraoperatively. We then determined overall morbidity and mortality rates, adding an additional six of our own patients. RESULTS: Data was analyzed for a total of 29 patients, including 23 previously reported patients from the literature and 6 additional cases from our own experience (mean age 54.8 years, 58.6% female). Most patients (82.8%, 24/29) presented with subarachnoid hemorrhage (SAH). Overall mean dose of adenosine was 51.8 mg. Successful clipping was achieved in 100% of patients. Transient or permanent morbidity was reported in 5/29 (17.2%) and the overall mortality rate was 31% (9/29), which occurred primarily due to an initial severe SAH and its resultant complications. CONCLUSIONS: Adenosine-induced circulatory arrest appears to safely control intraoperative bleeding and facilitate the clipping of ruptured intracranial aneurysms based on the limited published literature available. Further studies comparing patient outcomes using this technique to traditional approaches are required to validate the safety and efficacy of adenosine in this high-risk setting.

Neonatal apneic phenotype in a murine congenital central hypoventilation syndrome model is induced through non-cell autonomous developmental mechanisms.

Congenital central hypoventilation syndrome (CCHS) represents a rare genetic disorder usually caused by mutations in the homeodomain transcription factor PHOX2B. Some CCHS patients suffer mainly from deficiencies in CO2 and/or O2 respiratory chemoreflex, whereas other patients present with full apnea shortly after birth. Our goal was to identify the neuropathological mechanisms of apneic presentations in CCHS. In the developing murine neuroepithelium, Phox2b is expressed in three discrete progenitor domains across the dorsal-ventral axis, with different domains responsible for producing unique autonomic or visceral motor neurons. Restricting the expression of mutant Phox2b to the ventral visceral motor neuron domain induces marked newborn apnea together with a significant loss of visceral motor neurons, RTN ablation, and preBötzinger complex dysfunction. This finding suggests that the observed apnea develops through non-cell autonomous developmental mechanisms. Mutant Phox2b expression in dorsal rhombencephalic neurons did not generate significant respiratory dysfunction, but did result in subtle metabolic thermoregulatory deficiencies. We confirm the expression of a novel murine Phox2b splice variant which shares exons 1 and 2 with the more widely studied Phox2b splice variant, but which differs in exon 3 where most CCHS mutations occur. We also show that mutant Phox2b expression in the visceral motor neuron progenitor domain increases cell proliferation at the expense of visceral motor neuron development. We propose that visceral motor neurons may function as organizers of brainstem respiratory neuron development, and that disruptions in their development result in secondary/non-cell autonomous maldevelopment of key brainstem respiratory neurons.

NMIHBA results from hypomorphic PRUNE1 variants that lack short-chain exopolyphosphatase activity.

Neurodevelopmental disorder with microcephaly, hypotonia and variable brain anomalies (NMIHBA) is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by global developmental delay and severe intellectual disability. Microcephaly, progressive cortical atrophy, cerebellar hypoplasia and delayed myelination are neurological hallmarks in affected individuals. NMIHBA is caused by biallelic variants in PRUNE1 encoding prune exopolyphosphatase 1. We provide in-depth clinical description of two affected siblings harboring compound heterozygous variant alleles, c.383G > A (p.Arg128Gln), c.520G > T (p.Gly174*) in PRUNE1. To gain insights into disease biology, we biochemically characterized missense variants within the conserved N-terminal aspartic acid-histidine-histidine (DHH) motif and provide evidence that they result in the destabilization of protein structure and/or loss of exopolyphosphatase activity. Genetic ablation of Prune1 results in midgestational lethality in mice, associated with perturbations to embryonic growth and vascular development. Our findings suggest that NMIHBA results from hypomorphic variant alleles in humans and underscore the potential key role of PRUNE1 exopolyphoshatase activity in neurodevelopment.