Delineating Phenotypes of Rare Disease

Not available

Expanding the phenotype of HNRNPU-related disorders to include brief, resolved, unexplained events (BRUE)

hnRNP-U deficiency is caused by pathogenic variants in HNRNPU, which encodes the heterogeneous nuclear ribonucleoprotein U (HNRNPU), a highly conserved protein responsible for assisting spliceosomes in mediating transcription and alternative splicing activity. HnRNPs are responsible for the regulation of translation at the presynaptic sites as well as the transportation of stabilized mRNAs along the axonal cytoskeleton. Here, we report a 2-year-old-male with a HNRNPU variant with a new presentation of apparent recurrent apneic spells with an underlying epileptic origin. These were described as apnea followed by desaturation and tachycardia in the 180\u27s-200 range prior to resolution of symptoms. He also had autistiform behaviors, hypotonia, global developmental delay, heart defects, and unique facial features. The anesthetist professional parents describe multiple BRUE. At 26 months, he presented to the hospital with hypotonia and unique facial features, global developmental delay, autistiform behaviors, dyspraxia with cognitive disability and a change in mental status. On physical exam, the proband had telecanthus, a broad nasal bridge, short palpebral fissures, mild nevus flammeus changes on his face, a single right palmar crease, and a modified single crease on the left. EKG showed a sinus rhythm with intermittent 1st degree AV block, blocked premature atrial contractions, left axis deviation, right bundle branch block, and an ejection fraction of 67%. Echocardiography re-identified an atrial septal defect. Brain MRI showed a T2/FLAIR hyperintense signal in the white matter of the parietal lobes, left greater than right. EEG identified generalized slowing indicative of a mild nonspecific encephalopathy. History of episodes were determined to be consistent with partial onset seizures with eye opening, deviation, and tachycardia with apnea and medical treatment ensued. Genetic testing including microarray and an epilepsy panel that identified no genomic dosage anomalies and a de novo nonsense mutation (c.803+2T\u3eC; p. unknown in HNRNPU), classified as pathogenic. The study of hnRNP complexes have gained momentum in neurodegenerative and tumorigenesis disease research. hnRNPs have a key role in mediating transcription, alternative splicing, and translation activity. Recently, Durkin et al, 2020 (PMID: 32319732) reported 21 previously unreported probands; nearly doubling the recorded patient population. Probands in the literature to date have had variable presentation, but usually with hypotonia, global developmental delays, and seizures. This suggests the addition of HNRNPU to all seizure-related diagnostic panels. We would also recommend including the HNRNPU-related disorders in a differential diagnosis of BRUE and recurrent apneic episodes as any underlying clonic activity may be profoundly subtle.https://digitalcommons.unmc.edu/chri_forum/1018/thumbnail.jp

Early Systolic Dysfunction and Impact of Gene Mutation Severity in Marfan Syndrome

Background Marfan syndrome is caused by a mutation in the fibrillin-1 gene that manifests with a variety of features including aortic root dilation. Recent research has identified a primary cardiomyopathy in patients with Marfan syndrome, hypothesized to be due to the presence of abnormal fibrillin-1 in the myocardium. Controversy over the nature and significance of this cardiomyopathy remains. Echocardiographic measurement of the first-phase of ejection (defined as the beginning of systole to peak aortic valve flow) may be more sensitive to systolic dysfunction and provide useful clinical information. The purpose of this study is to: Assess systolic dysfunction in patients with Marfan syndrome Describe first-phase fractional area change (FAC1) in patients with Marfan syndrome and determine how it varies between Marfan syndrome patients and a control group Verify there is a difference in propensity for cardiomyopathy in mild vs severe gene mutation Marfan syndrome patients not secondary to increased aortic stiffness Methods Patients were identified from a pre-existing list of patients with Marfan syndrome maintained by the Children\u27s Hospital and Medical Center and University of Nebraska Medical Center. All relevant medical records were reviewed. Echocardiographic parameters will include left ventricular (LV) ejection fraction, LV FAC1, LV end-diastolic volume, global longitudinal strain, aortic root diameter, and aortic stiffness. Patients were excluded if they have more than mild aortic insufficiency or mitral valve regurgitation. Neonatal Marfan syndrome patients and patients with other significant congenital heart disease will also be excluded. Statistical analysis of the data will be performed including basic statistical tests, univariate regression, and multivariate regression to compare data from each group. P values will be calculated and a p value \u3c 0.05 will be considered statistically significant. Results At the time of writing, 126 patients with Marfan syndrome have been identified. 44 were excluded based on significant mitral or aortic valve disease, prior cardiovascular surgery, or poor echocardiographic image quality. Of the 82 patients not excluded, genetic testing results are available for 59 and are being categorized to allow for statistical analysis. Echocardiographic measurements are underway.https://digitalcommons.unmc.edu/chri_forum/1002/thumbnail.jp

Correction: Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation

n/

Why Can't Rodents Vomit? A Comparative Behavioral, Anatomical, and Physiological Study

The vomiting (emetic) reflex is documented in numerous mammalian species, including primates and carnivores, yet laboratory rats and mice appear to lack this response. It is unclear whether these rodents do not vomit because of anatomical constraints (e.g., a relatively long abdominal esophagus) or lack of key neural circuits. Moreover, it is unknown whether laboratory rodents are representative of Rodentia with regards to this reflex. Here we conducted behavioral testing of members of all three major groups of Rodentia; mouse-related (rat, mouse, vole, beaver), Ctenohystrica (guinea pig, nutria), and squirrel-related (mountain beaver) species. Prototypical emetic agents, apomorphine (sc), veratrine (sc), and copper sulfate (ig), failed to produce either retching or vomiting in these species (although other behavioral effects, e.g., locomotion, were noted). These rodents also had anatomical constraints, which could limit the efficiency of vomiting should it be attempted, including reduced muscularity of the diaphragm and stomach geometry that is not well structured for moving contents towards the esophagus compared to species that can vomit (cat, ferret, and musk shrew). Lastly, an in situ brainstem preparation was used to make sensitive measures of mouth, esophagus, and shoulder muscular movements, and phrenic nerve activity-key features of emetic episodes. Laboratory mice and rats failed to display any of the common coordinated actions of these indices after typical emetic stimulation (resiniferatoxin and vagal afferent stimulation) compared to musk shrews. Overall the results suggest that the inability to vomit is a general property of Rodentia and that an absent brainstem neurological component is the most likely cause. The implications of these findings for the utility of rodents as models in the area of emesis research are discussed. © 2013 Horn et al

Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation

Purpose: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. Methods: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. Results: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_297

The SMAD-binding domain of SKI:A hotspot for de novo mutations causing Shprintzen-Goldberg syndrome

Shprintzen–Goldberg syndrome (SGS) is a rare, systemic connective tissue disorder characterized by craniofacial, skeletal, and cardiovascular manifestations that show a significant overlap with the features observed in the Marfan (MFS) and Loeys–Dietz syndrome (LDS). A distinguishing observation in SGS patients is the presence of intellectual disability, although not all patients in this series present this finding. Recently, SGS was shown to be due to mutations in the SKI gene, encoding the oncoprotein SKI, a repressor of TGFβ activity. Here, we report eight recurrent and three novel SKI mutations in eleven SGS patients. All were heterozygous missense mutations located in the R-SMAD binding domain, except for one novel in-frame deletion affecting the DHD domain. Adding our new findings to the existing data clearly reveals a mutational hotspot, with 73% (24 out of 33) of the hitherto described unrelated patients having mutations in a stretch of five SKI residues (from p.(Ser31) to p.(Pro35)). This implicates that the initial molecular testing could be focused on mutation analysis of the first half of exon 1 of SKI. As the majority of the known mutations are located in the R-SMAD binding domain of SKI, our study further emphasizes the importance of TGFβ signaling in the pathogenesis of SGS