Biallelic CRELD1 variants cause a multisystem syndrome, including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections.

PURPOSE: We sought to delineate a multisystem disorder caused by recessive cysteine-rich with epidermal growth factor-like domains 1 (CRELD1) gene variants. METHODS: The impact of CRELD1 variants was characterized through an international collaboration utilizing next-generation DNA sequencing, gene knockdown, and protein overexpression in Xenopus tropicalis, and in vitro analysis of patient immune cells. RESULTS: Biallelic variants in CRELD1 were found in 18 participants from 14 families. Affected individuals displayed an array of phenotypes involving developmental delay, early-onset epilepsy, and hypotonia, with about half demonstrating cardiac arrhythmias and some experiencing recurrent infections. Most harbored a frameshift in trans with a missense allele, with 1 recurrent variant, p.(Cys192Tyr), identified in 10 families. X tropicalis tadpoles with creld1 knockdown displayed developmental defects along with increased susceptibility to induced seizures compared with controls. Additionally, human CRELD1 harboring missense variants from affected individuals had reduced protein function, indicated by a diminished ability to induce craniofacial defects when overexpressed in X tropicalis. Finally, baseline analyses of peripheral blood mononuclear cells showed similar proportions of immune cell subtypes in patients compared with healthy donors. CONCLUSION: This patient cohort, combined with experimental data, provide evidence of a multisystem clinical syndrome mediated by recessive variants in CRELD1.

The Impact of COVID-19 on Families With Pediatric Muscular Dystrophy Patients.

The coronavirus disease 2019 (COVID-19) pandemic resulted in unprecedented changes in daily activities and healthcare services. In the United States, stay-at-home orders and social distancing measures were put, and school closures impacted many students. The psychological impact of the COVID-19 pandemic has been shown to have wide-ranging and long-term effects. With school closures and limitations in in-person visits and provider care, we hypothesized that the patients with pediatric muscular dystrophies and neuromuscular conditions were more vulnerable to the restriction posed by this pandemic. This survey-based study examined the psychosocial impact of this pandemic on pediatric patients with neuromuscular disorders and caregiver burden through chart review and self-reports via survey administration using a validated tool (COVID-19 Exposure and Family Impact Scales {CEFIS}). The majority of families reported that they had a stay-at-home order (91.7%), schools/childcare centers were closed (87.5%), their children's education was disrupted (83.3%), and they were unable to visit or care for a family member (58.3%). Parents/caregivers felt that the COVID-19 pandemic made parenting a little bit worse (mean = 2.6 ± 0.96) and made it more difficult to care for the elderly or those with disabilities in the family (mean = 2.6 ± 0.95) and for their child with a neuromuscular disability (mean = 2.6 ± 0.91). Our data highlights the significant impact of the COVID-19 pandemic on the lives of families and caregivers of pediatric patients with muscular dystrophies.

Comparison of antibody response to two different mRNA Covid-19 vaccines in patients on hemodialysis.

INTRODUCTION: In hemodialysis patients, coronavirus disease 2019 is associated with high morbidity and mortality. Aim of the study was to evaluate the antibody level against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients treated with two different mRNA-based vaccines, in a multicenter survey. PATIENTS AND METHODS: Since April 2020, in the 5 participating Centers, periodic screening of all patients with PCR testing has been performed every 2 weeks. The study included two cohorts of patients on maintenance hemodialysis treated with the BNT162b2 or with the mRNA-1273 Covid-19 vaccine. The tests for antibodies against the receptor-binding domain was performed by the anti-SARS-CoV-2 S enzyme immunoassay (Roche Elecsys). RESULTS: Of the 398 included patients, 303 received the BNT162b2 and 95 the mRNA-1273 vaccine. In patients without previous infection, the median levels of anti-S antibodies were 297 U/mL and 1,032 U/mL for those treated with BNT162b2 or mRNA-1273, respectively (p < 0.001). In patients with previous infection, the median levels of SARS-CoV-2 anti-S antibodies were 7,516 U/mL and 17,495 U/mL for those treated with BNT162b2 or mRNA-1273, respectively (p = 0.005). The Charlson comorbidity index (CCI) was significantly associated with protective levels of anti-spike IgG, with 3.6% of low- or non-responders having a CCI of 2-4 versus 18.9% in those with a CCI of 8 or more. The adjusted OR of developing a sufficient antibody level between the two vaccines was 3.91 (p = 0.0766) in favor of mRNA-1273. CONCLUSIONS: Both of the evaluated mRNA-based vaccines for SARS-CoV-2 showed good efficacy. Preliminary data may data suggest a  higher antibody response to the mRNA-1273 vaccine.

Collective Statement Regarding Patient Access to Approved Therapies from the Center Directors of Parent Project Muscular Dystrophy's Certified Duchenne Care Centers.

The dystrophinopathies (Duchenne [DMD] and Becker muscular dystrophy) are progressive diseases that until recently had no specific treatments. New FDA pathways to drug approval in rare diseases have resulted in a dramatic increase in the number of treatment trials for DMD and recently, two approved drugs. Health insurance policies for DMD products have been constructed with limited input from neuromuscular specialists directly involved in patient care and without patient input. These policies often reflect a lack of understanding of the disease, clinical population or the treatment. To ensure that policy determinations reflect best clinical practice, we recommend insurers work with neuromuscular specialists with expertise in care for patients with dystrophinopathy, as well as patients and families, and prominent advocacy organizations, such as Parent Project Muscular Dystrophy, in developing policies.

Mitochondrial Membrane Protein-Associated Neurodegeneration Mimicking Juvenile Amyotrophic Lateral Sclerosis.

BACKGROUND: Mitochondrial membrane protein associated neurodegeneration (MPAN) is the third most common subtype of neurodegeneration with brain iron accumulation (NBIA) and caused by mutations of the orphan gene C19ORF12 encoding a transmembrane mitochondrial protein. Like other NBIA disorders, the hallmark of neuropathology is iron deposition in the basal ganglia, but the clinical presentation is highly variable. METHODS: We present the relevant clinical history, neurological examination, electrophysiological and neuroimaging tests of a currently ten-year-old girl. The genetic analysis was carried out by exome sequencing focused on known NBIA and juvenile amyotrophic lateral sclerosis (ALS) genes. RESULTS: The patient presented at four years of age with progressive lower extremity weakness and generalized hypotonia. She was initially diagnosed with juvenile ALS based on clinical signs, negative brain magnetic resonance imaging (MRI) and electromyography findings. As the disease progressed, a repeat brain MRI showed iron deposition in the basal ganglia at nine years of age. Exome sequencing of genes known to be associated with NBIA revealed a compound heterozygous mutation of C19ORF12 gene. CONCLUSIONS: A C19orf12 gene mutation should be considered in young children with clinical signs of progressive upper and lower motor neuron disease. Finding iron accumulation in the basal ganglia helps to focus the genetic testing, but it may not be apparent for several years.

Impact of Co-management at the Primary-Subspecialty Care Interface on Follow-up and Referral Patterns for Patients With Concussion.

BACKGROUND: Co-management is a collaborative care model that consists of structured tools to define and document care delivered by 2 or more providers. We evaluated the impact of implementing co-management at the interface between pediatric primary care providers (PCPs) and subspecialists. METHODS: Participating PCPs (n = 9) were trained on management of concussion using the co-management tools. Co-managed patients with concussion were prospectively enrolled (n = 148) and compared to a retrospective audit of non-co-managed patients (n = 50). RESULTS: PCPs using co-management demonstrated adherence to the tools. PCPs were significantly more likely to provide follow-up care to patients when using the co-management tools. All participating PCPs reported that co-management enhanced their expertise in caring for patients with concussion. CONCLUSIONS: Co-management can enhance PCPs' capacity to independently manage the care of patients with concussion. Co-management led to an observed change in practice that merits further exploration in terms of cost, quality, and clinical outcomes.

Management of juvenile myasthenia gravis.

Juvenile myasthenia gravis is an uncommon autoimmune disorder. Its management is not standardized. Juvenile myasthenia gravis is pathophysiologically similar to myasthenia gravis in adults. However, a number of significant particularities related to race, age at onset, severity, and antibody status complicate the management. We summarize the unique clinical features of juvenile myasthenia gravis and review the therapeutic options.