Causative Abnormality Research Articles

Clinical and genetic characterisation of childhood-onset sensorineural hearing loss reveal associated phenotypes and enrichment of pathogenic founder mutations in the Finnish population

Objective To examine the clinical and genetic characteristics of childhood-onset bilateral sensorineural hearing loss (SNHL) in Finland. Design Retrospective analysis. Study sample A total of 249 children younger than 18 years were diagnosed with bilateral SNHL in Oulu University Hospital, Finland, from 2017 to 2022. Results Pathogenic or likely pathogenic gene variants or chromosome abnormalities explaining SNHL were identified in 41% (N = 101/249) of children. Likely causative variants were more commonly identified in patients with severe SNHL than in those with moderate or mild SNHL. Our study identified likely causative gene variants in 24 different genes and six different likely causative chromosome abnormalities, demonstrating the genetic heterogeneity of SNHL. Population-enriched founder mutations were identified in the CABP2, CLRN1, MYO7A, SUCLA2, TMC1, and TWNK genes. A significant number of patients had associated phenotypes, including global developmental delay or intellectual disability (16%), language disorder (20%), ophthalmological abnormalities (16%), or malformations other than those involving the ear (10%). Conclusions SNHL is genetically and clinically heterogeneous. Pathogenic variants in GJB2 were the most common. Several population-enriched variants were identified as causing SNHL in the northern Finnish population. Associated medical phenotypes are common and should be taken into account in patients’ follow-up and treatment.

"In their own words": delineating the contours of dyspnea invisibility in patients with advanced chronic obstructive pulmonary disease from quantitative discourse analysis

BackgroundDyspnea conveys an upsetting or distressing experience of breathing awareness. It heavily weighs on chronic respiratory disease patients, particularly when it persists despite maximal treatment of causative abnormalities. The physical, psychological and social impacts of persistent dyspnea are ill-appreciated by others. This invisibility constitutes a social barrier and impedes access to care. This study aimed to better understand dyspnea invisibility in patients with chronic obstructive pulmonary disease (COPD) through quantitative discourse analysis.MethodsWe conducted a lexicometric analysis (lemmatization, descending hierarchical classification, multicomponent analysis, similarity analysis) of 11 patients' discourses (6 men, severe COPD; immediate postexacerbation rehabilitation) to identify semantic classes and communities, which we then confronted with themes previously identified using interpretative phenomenological analysis (IPA).ResultsClass#1 ("experience and need for better understanding"; 38.9% of semantic forms, 50% of patients) illustrates the gap that patients perceive between their experience and what others see, confirming the importance of dyspnea invisibility in patients' concerns. Class#2 ("limitations"; 28.7% of forms) and Class#3 (management"; 13.1% of forms) point to the weight of daily limitations in performing basic activities, of the need to accept or adapt to the constraints of the disease. These three classes matched previously identified IPA-derived themes. Class#4 ("hospitalization"; 18.2% of forms) points to the importance of interactions with the hospital, especially during exacerbations, which constitutes novel information.ConclusionsLexicometry confirms the importance of dyspnea invisibility as a burden to COPD patients.

A Soft Tissue Technique for Treating Knee Hyperextension or Recurvatum: Posterior Oblique Ligament Advancement

Background: Genu recurvatum is a challenging disorder and can negatively affect knee biomechanics, as reflected in its role as a risk factor for knee ligament injury and poor outcomes following ligament reconstruction or arthroplasty. Indication: Pathological recurvatum should be addressed in the presence of a causative correctible structural abnormality, whether due to decreased posterior tibial slope or due to multiligament injury. We described a posterior oblique ligament (POL) advancement technique for the treatment of knee recurvatum. Technique Description: After completion of all concomitant procedures such as ligament reconstructions, the procedure is initiated with a medial approach. The POL is isolated with an inverted L-shaped dissection and mobilized. Mattress sutures are passed through the resulting POL flap, and are re-tensioned and fixed anteriorly and distally, with the knee close to extension, in order for the imbrication to restrain hyperextension. Results: Anecdotal evidence points to satisfactory control of knee recurvatum postoperatively, which can potentially avoid its deleterious effects in surgical outcomes. Discussion/Conclusion: We present a promising option in the treatment of pathological recurvatum, with favorable cost-efficacy, low morbidity relative to slope-altering osteotomy or posterolateral soft tissue procedures, and focused on the biomechanically demonstrated main restrictors to knee hyperextension. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.

Exome Sequencing Identifies a Novel SGCA Gene Mutation in an Iranian Family with Limb Girdle Muscular Dystrophy: A Case Report

Introduction: Autosomal recessive limb-girdle muscular dystrophy (LGMD) is a rare congenital muscular dystrophy type. This inherited disease is one of the most common diseases resulting in severe physical health problems for infants. Genetic studies have shown that several gene mutations cause limb-girdle muscular dystrophy. This study aimed to report the case of a 10-year-old boy from an Iranian consanguineous family diagnosed with congenital muscular dystrophy and a causative genetic abnormality. Case Presentation: In this report, whole exome sequencing (WES) followed by Sanger sequencing was performed to diagnose the possible genetic defects in patients with LGMD. A novel homozygous disease-causing SGCA gene mutation (p.A107fs:c.319-329del) was found in exon 10 (NM_000023.4). Both parents were heterozygous for the detected mutation. Conclusions: It was concluded that the identified SGCA gene mutation was a pathogenic variant causing autosomal recessive LGMD.

Chromosomal abnormalities in recurrent pregnancy loss and its association with clinical characteristics.

To evaluate the distribution of chromosomal abnormalities in a recurrent pregnancy loss (RPL) cohort and explore the associations between chromosomal abnormalities and clinical characteristics. Over a 5-year period, fresh products of conception (POC) from women with RPL were analyzed by single-nucleotide polymorphism (SNP) array at our hospital. After obtaining the information on clinical characteristics, we investigated the associations between the causative chromosomal abnormalities and clinical characteristics by the chi-squared test or Fisher's exact test and logistic regression. A total of 2383 cases were enrolled. Overall, 56.9% (1355/2383) were identified with causative chromosomal abnormalities, of which 92.1% (1248/1355) were numerical abnormalities, 7.5% (102/1355) were structural variants, and 0.4% (5/1355) were loss of heterozygosity (LOH). The risk of numerical abnormalities was increased in women with maternal age ≥ 35years (OR, 1.71; 95% CI, 1.41-2.07), gestational age at pregnancy loss ≤ 12weeks (OR, 2.78; 95% CI, 1.79-4.33), less number of previous pregnancy losses (twice: OR, 2.32; 95% CI, 1.84-2.94; 3 times: OR, 1.59; 95% CI, 1.23-2.05, respectively), and pregnancy with a female fetus (OR, 1.37; 95% CI, 1.15-1.62). The OR of pregnancy loss with recurrent abnormal CMA was 4.00 (95% CI: 1.87-8.58, P < 0.001) and the adjusted OR was 5.05 (95% CI: 2.00-12.72, P = 0.001). However, the mode of conception was not associated with the incidence of numerical abnormality. No association was noted between structural variants and clinical characteristics. Chromosomal abnormality was the leading cause of RPL. Numerical chromosome abnormality was more likely to occur in cases with advanced maternal age, an earlier gestational age, fewer previous pregnancy losses, and pregnancy with a female fetus.

Abstract 3551: Single-cell characterization of pediatric T-cell acute lymphoblastic leukemia transcriptomes

Abstract Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is a rare cancer with a diverse set of causative genomic abnormalities. The variety and limited characterization of genomic mechanisms underlying this disease presents a unique challenge for the development of improved treatments for these patients. Using the 10x Genomics Chromium system, we have generated single-cell gene expression (scRNA) and chromatin accessibility (scATAC) data for blood and/or bone marrow samples collected at diagnosis from eight pediatric T-ALL patients. We sequenced 21,669 high-confidence cells and performed normalization and downstream analysis using the Seurat v4.0.2 package in R 4.0.3. Our data show that patient cancer cells show highly individual transcriptomes and are often characterized by combinatorial expression patterns of genes including MEF2C, BCL11B, HOXA9, NKX2-1, and LMO2, which have been previously implicated for their roles in various T-ALL subtypes. Additionally, we observe that each patient has a unique ratio of cancer cells with a CD4+ T-cell, CD8+ T-cell, and hematopoietic stem cell-like identity, which may be linked to treatment response and patient outcome. This dataset represents one of the first forays into exploring the biology of pediatric T-ALL at the single-cell level. Our comparative analysis of patient cancer cells reveals novel insights into the transcriptional and chromatin-related for distinct subsets of pediatric T-ALL cases, paving the way for future treatment selection and drug development to improve outcomes for these patients. Citation Format: Irina Pushel, Byunggil Yoo, Daniel Louiselle, Margaret Gibson, Midhat S. Farooqi, Keith August. Single-cell characterization of pediatric T-cell acute lymphoblastic leukemia transcriptomes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3551.

Prenatal diagnosis for fetuses with isolated and non-isolated congenital heart defects using chromosomal microarray and exome sequencing.

To investigate the use of chromosomal microarray (CMA) and Exome sequencing (ES) in fetuses with congenital heart disease (CHD). The Fetal Medicine Unit of Shanghai First Maternity and Infant Hospital records were reviewed to ascertain all cases diagnosed with CHD by level 2 ultrasound examination between 2016 and 2019. Cases were categorized as isolated or associated with other abnormalities or fetal growth restriction. CMA was offered to all cases as a first-line genetic test followed by ES when CMA was non-diagnostic. Of the 586 ascertained, 84 (14.3%) had causative CMA abnormality, of which 8.8% (35/400) were in fetuses with isolated CHD and 26.3% (49/186) in those with other abnormalities. ES was performed in 47 cases with a negative CMA. Causative variants were identified in two (10.5%, 2/19) isolated cases and four(14.3%, 4/28) with other abnormalities. Invasive procedures with CMA should be offered in pregnancies complicated by both non-isolated and isolated cardiac abnormalities. When CMA is not diagnostic, ES can add diagnostic value in both groups and should be considered even for fetuses with an isolated CHD.

Mizuo–Nakamura phenomenon in X-linked retinoschisis

PurposeTo determine whether the Mizuo–Nakamura phenomenon, which is an important diagnostic sign of Oguchi's disease, also occurs in patients with genetically proven X-linked retinoschisis (XLRS). MethodsWe examined three patients with a clinical and genetic diagnosis of XLRS and one patient who was clinically diagnosed with Oguchi's disease, with an emphasis on the Mizuo–Nakamura phenomenon. We obtained color fundus photographs, especially in the fully dark-adapted state, using the non-mydriatic mode on a digital retinal camera and infrared observation monitor to avoid the bleaching effects caused by the viewing light, which alters the fundus color in a short time. ResultsThe Mizuo–Nakamura phenomenon was observed in all patients with molecularly proven XLRS, similar to that in the patient with Oguchi's disease. The sets of photographs were obtained in the light- and dark-adapted states using our newly devised techniques needed to witness the Mizuo-Nakamura phenomenon. Conclusions and ImportanceThe Mizuo–Nakamura phenomenon was identified in three patients with genetically proven XLRS. To the best of our knowledge, this study provided the first genetic evidence of the Mizuo–Nakamura phenomenon in a patient with molecularly proven XLRS without the causative genetic abnormalities for Oguchi's disease. Our findings suggest that XLRS is responsible for the Mizuo–Nakamura phenomenon and its presence in XLRS is not a rare exception but may be a consistent manifestation of XLRS.

Spontaneous resolution of fetal ascites secondary to gastrointestinal abnormality

Abstract Objectives Isolated fetal ascites carries an uncertain prognosis and broad differential diagnosis. When detected on prenatal sonography, a thorough evaluation is warranted to exclude development of hydrops and search for an underlying condition. While gastrointestinal abnormalities account for approximately 20% of cases of fetal ascites, surgical correction is commonly required postnatally. While there have been reports of isolated fetal ascites resolving in utero, spontaneous resolution of the causative gastrointestinal abnormality is unusual. Case presentation We report a case of a multiparous 33-year-old found to have moderate fetal ascites and a complex fetal abdominal mass near the small bowel detected by ultrasound at 32 weeks with spontaneous resolution of both ascites and mass by 37 weeks. Following the delivery of a normal neonate, we suspect the mass and ascites to have been produced by a small bowel rupture resulting in meconium peritonitis. Conclusions When fetal ascites with late gestational onset has spontaneous resolution in utero and hydrops never develops, there is generally a favorable prognosis and normal neonatal outcome.

The extracellular matrix as a multitasking player in disease.

Extracellular matrices (ECMs) are highly specialized and dynamic three-dimensional (3D) scaffolds into which cells reside in tissues. ECM is composed of a variety of fibrillar components, such as collagens, fibronectin, and elastin, and non-fibrillar molecules as proteoglycans, hyaluronan, and glycoproteins including matricellular proteins. These macromolecular components are interconnected forming complex networks that actively communicate with cells through binding to cell surface receptors and/or matrix effectors. ECMs exert diverse roles, either providing tissues with structural integrity and mechanical properties essential for tissue functions or regulating cell phenotype and functions to maintain tissue homeostasis. ECM molecular composition and structure vary among tissues, and is markedly modified during normal tissue repair as well as during the progression of various diseases. Actually, abnormal ECM remodeling occurring in pathologic circumstances drives disease progression by regulating cell-matrix interactions. The importance of matrix molecules to normal tissue functions is also highlighted by mutations in matrix genes that give rise to genetic disorders with diverse clinical phenotypes. In this review, we present critical and emerging issues related to matrix assembly in tissues and the multitasking roles for ECM in diseases such as osteoarthritis, fibrosis, cancer, and genetic diseases. The mechanisms underlying the various matrix-based diseases are also discussed. Research focused on the highly dynamic 3D ECM networks will help to discover matrix-related causative abnormalities of diseases as well as novel diagnostic tools and therapeutic targets.

A COMPENDIOUS REVIEW ON THE METABOLIC SYNDROME; ITS IMPACT ON THE QUALITY OF LIFE

Background: Metabolic syndrome (MetS), a comprehensive condition is universally described as a group of several causative factors or abnormalities directly linked with insulin resistance that obviously augment the threat mainly for coronary heart disease, diabetes mellitus Type 2, some types of cancers and sleep disturbances, etc. MetS is a contemporary condition that covers a wide-ranging display of disorders with definite metabolic anomalies demonstrating at different times. Consequently, the threat of MetS remains epidemic. This review will potentially study significant factors such as central adiposity, insulin resistance, hypertension, and dyslipidemia; increased inflammation, environmental factors, and genetic predisposition are involved in MetS development. Purpose: This review provides the available facts to validate the relationship between MetS and quality of life. Methods: A thorough exploration in many search engines such as PubMed, Medline, Science direct, EMBASE, and Google scholar was carried out to recognize qualified studies. Results: Almost all studies suggested that MetS is significantly associated with impair quality of life. Lifestyle intervention holds the early preference and such non-pharmacological therapy combines specific suggestion on diet and physical activity with behavioral strategies. For the individuals, where contributing factors are not sufficiently condensed with lifestyle changes, pharmacological treatment should be considered. Conclusion: Therefore, the current study reviews the outline of literature interrelated with the MetS’s characterization, epidemiological existence, pathological process, and management advance for all the risk factors encompassing metabolic disorder.

Chromosomal microarray analysis as the first-tier clinical diagnostic test for miscarriage analysis

Despite the high failure rate and inherent limitations of conventional cytogenetic/karyotype analysis for products of conception samples (POCs) and high success rate and diagnostic benefits of chromosomal microarray analysis (CMA), testing of this sample type by CMA remains low. This underutilization may be due to a lack of awareness of the technology's diagnostic power, and more importantly, lack of clear opinions or recommendations in support of this testing by professional committees, such as The American College of Obstetricians and Gynecologists (ACOG) and Society for Maternal-Fetal Medicine (SMFM). We undertook a retrospective analysis of over 13 thousand consecutive POCs evaluated by CMA with the purpose of determining analytical success, failure rates, and frequency/rates of causative and non-causative abnormalities. In addition, potential challenges, either sample-related or test-related, were cataloged. Materials and Methods Of the 13,711 cases received for evaluation by CMA, 12,324 were successfully analyzed and reported (90%); 83% of samples were ascertained for recurrent pregnancy loss (RPL) or spontaneous abortion (SAB). About 78% of samples were fresh and 21% of samples were FFPE. The majority of samples (88%) were analyzed by whole-genome SNP-based CMA allowing detection of whole chromosome or segmental copy number changes (greater than 20kb; and greater than 5% mosaicism), triploidy, whole-genome uniparental isodisomy (molar pregnancy), and maternal cell contamination. In 54% (6665/12324) of cases, a clinically significant abnormality was identified, and over 96% of those abnormalities were deemed causative of the pregnancy loss. Normal results were obtained in 44% of cases, and variants of uncertain significance (VOUS) were detected in the remaining2% of cases. The most common abnormalities detected were autosomal trisomies (single trisomy, 62%; multiple trisomies, 4%), triploidy (12%), molar pregnancy (1%) and monosomy X (11%). Autosomal monosomies were rare (<1% of cases). Clinically significant segmental deletions and duplications were detected in 4.6% cases. This data shows the continued diagnostic value of CMA for the evaluation of POCs and further supports its use for miscarriage analysis. The success rates and diagnostic power in providing a high resolution genome-wide evaluation of POCs for causative abnormalities should be the primary determining factors for the establishment of recommendations or guidelines for routine genetic evaluation of RPL and SAB. Unfortunately, recommendations for miscarriage analysis by CMA remain unclear. As seen in this large, retrospective study, the high success rate (90%) and the ability to provide a causative genetic diagnosis for over 50% of samples make CMA the best testing option for POCs and support its use as the first-tier diagnostic test for evaluation of all miscarriages.

High prevalence of abnormalities on CT and MR imaging in children with unilateral sensorineural hearing loss irrespective of age or degree of hearing loss

ObjectiveEvaluation of causal abnormalities identified on CT and MR imaging in children with unilateral sensorineural hearing loss (USNHL), and the association with age and severity of hearing loss. Study designRetrospective cohort study. SettingTertiary referral otology/audiology center. Patients and diagnostic interventions102 children diagnosed with USNHL between 2006 and 2016 were included. They underwent CT and/or MR imaging for the evaluation of the etiology of their hearing loss. Main outcome measuresRadiologic abnormalities of the inner ear and brain associated with USNHL. ResultsUsing CT and/or MR imaging, causal abnormalities were identified in 49%, which is higher than previously reported (25–40%). The most frequently affected site was the labyrinth (29%), followed by the cochlear nerve (9%) and brain (7%). No significant difference in the number or type of abnormalities was found for the degree of hearing loss or age categories. ConclusionsImaging is essential in the etiologic analysis of USNHL because of the high prevalence of causative abnormalities that can be identified with radiology, irrespective of the patients' age or degree of hearing loss. CT and MR imaging are complementary imaging options. The ideal imaging algorithm is controversial. Based on our findings, we conclude that there is limited additional diagnostic value of simultaneous dual modality imaging over sequential diagnostics. We therefore perform a stepwise radiological workup in order to maximize the diagnostic yield while minimizing impact and costs. If the primary imaging modality does not identify a cause for USNHL, performing the alternative imaging modality should be considered. Level of evidenceRetrospective cohort study 2b

Factors Associated with Clinical Outcomes in Patients with Primary Intraventricular Hemorrhage.

BackgroundPrimary intraventricular hemorrhage (PIVH) is an uncommon type of intracerebral hemorrhage. Owing to its rarity, the clinical and radiological factors affecting outcomes in patients with PIVH have not been widely studied.Material/MethodsWe retrospectively reviewed 112 patients (mean age 53 years) treated for PIVH at our institution from January 2004 to December 2014. Clinical and radiological parameters were analyzed 3 months after initial presentation to identify factors associated with clinical outcomes, as assessed by the Glasgow Outcome Scale (favorable ≥4, unfavorable <4).ResultsOf the 99 patients who underwent angiography, causative vascular abnormalities were found in 46%, and included Moyamoya disease, arteriovenous malformation, and cerebral aneurysm. At 3 months after initial presentation, 64% and 36% of patients were in the favorable and unfavorable outcome groups, respectively. The mortality rate was 19%. However, most survivors had no or mild deficits. Age, initial Glasgow Coma Scale (GCS) score, simplified acute physiology score (SAPS II), modified Graeb score, and various radiological parameters reflecting ventricular dilatation were significantly different between the groups. Specifically, a GCS score of less than 13 (p=0.015), a SAPS II score of less than 33 (p=0.039), and a dilated fourth ventricle (p=0.043) were demonstrated to be independent predictors of an unfavorable clinical outcome.ConclusionsIn this study we reveal independent predictors of poor outcome in primary intraventricular hemorrhage patients, and show that nearly half of the patients in our study had predisposing vascular abnormalities. Routine angiography is recommended in the evaluation of PIVH to identify potentially treatable etiologies, which may enhance long-term prognosis.

Template for Reporting Results of Biomarker Testing of Specimens From Patients With Carcinoma of the Endometrium.

Template for Reporting Results of Biomarker Testing of Specimens From Patients With Carcinoma of the Endometrium.

Perimesencephalic Hemorrhage: Yield of Single versus Multiple DSA Examinations-A Single-Center Study and Meta-Analysis.

Purpose To quantify the rate of detection of aneurysms at follow-up digital subtraction angiography (DSA) after initial DSA with results negative for aneurysms in subjects with perimesencephalic (PM) nonaneurysmal subarachnoid hemorrhage. Materials and Methods This single-center retrospective study and meta-analysis was approved by the institutional review board. At a single institution from 2000 to 2013, 252 consecutive patients with subarachnoid hemorrhage at computed tomography (CT) and two DSA examinations negative for aneurysm within 10 days were evaluated for inclusion in the study, and 131 met CT criteria for PM nonaneurysmal subarachnoid hemorrhage (53 women; mean age, 53 years [range, 33-88 years]). DS angiographic reports were reviewed for causative abnormalities. Three reviewers searched MEDLINE and electronic databases for studies that reported detection of aneurysm in subjects with PM hemorrhage who had undergone multiple DSA examinations. Main inclusion criteria were PM hemorrhage at CT per van Gijn classification, head CT performed within 72 hours of symptom onset, initial DS angiographic results negative for aneurysm, and two DSA examinations within 10 days. Studies with fewer than 25 subjects were excluded. Methodology was assessed by using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The summary rate of aneurysm detection for subsequent DSA was calculated by using a fixed-effects model. Results Six studies with 298 subjects and a single-institution study with 131 subjects were included. No aneurysms were seen at follow-up DSA in the single-center study (0.0%). Three aneurysms were detected at follow-up DSA in three of six studies from the literature (one of 29 [3.4%], one of 65 [1.5%], and one of 34 [2.9%] patients). Two occurred in cases that likely preceded the use of the current DSA technique. The summary aneurysm detection rate at subsequent DSA was 1.6% (95% confidence interval: 0.7%, 3.8%; range of individual study detection rate: 0.0%-3.4%). Conclusion In patients with PM nonaneurysmal subarachnoid hemorrhage and initial DSA negative for aneurysms, the yield of follow-up DSA for detection of causative aneurysms is very low. © RSNA, 2016 Online supplemental material is available for this article.

High prevalence of genetic alterations in early-onset epileptic encephalopathies associated with infantile movement disorders

ObjectiveRecent studies have elucidated causative roles for genetic abnormalities in early-onset epileptic encephalopathies (EOEE). Accompanying characteristic features, in addition to seizures, have also been suggested to provide important clues for an early and accurate genetic diagnosis of affected patients. In this study, we investigated the underlying genetic causes in patients with EOEE associated with infantile movement disorders. MethodsWe examined 11 patients with EOEE and involuntary movements (nine with West syndrome and two with nonsyndromic epileptic encephalopathy). All showed severe developmental delay, cognitive impairment, and involuntary movements such as chorea, ballism, dyskinesia or myoclonus, and hand stereotypies. We performed whole-exome sequencing of 10 patients, while the other patient underwent high-resolution melting analysis of candidate EOEE genes. ResultsWe identified mutations in CDKL5, SCN2A, SETD5, ALG13, and TBL1XR1 in seven patients with West syndrome, and in SCN1A and GRIN1 in the two patients with unclassified epileptic encephalopathy. All mutations were validated as de novo events. The genetic cause was undetermined in the remaining two patients. ConclusionsWe found pathogenic mutations in seven genes, in nine of 11 patients with EOEE and involuntary movements. Although the results of our study are preliminary because of the small number of patients, they nevertheless suggest that specific accompanying phenotypes such as hyperkinetic movements or hand stereotypies could be important in narrowing the disease spectrum and identifying causative genetic abnormalities.

Abstract B16: The pro-apoptotic effect of dexamethasone mediated by GILZ and Bim up-regulation is related to genetic heterogeneity of multiple myeloma.

Abstract Multiple myeloma (MM) is heterogeneous with respect to its causative molecular abnormalities and the treatment response of patients. Briefly, MM that are hyperdiploid or have a t(11;14) translocation have a better prognosis than those with t(4;14) or t(14;16) translocations. Dexamethasone (Dex) is widely used in all phases of MM treatment as induction, consolidation or maintenance. However, the mechanism of Dex sensitivity still remains elusive. In the present study, we analyzed the ability of Dex to induce cell death by Apo-2.7 staining in 33 human myeloma cell lines (HMCLs) representative of the molecular subsets carrying t(11;14), t(4;14) or t(14;16) translocations, which deregulate CCND1, MMSET and c-MAF, respectively. The mechanisms controlling Dex-induced apoptosis were evaluated by analyzing glucocorticoid receptor (GR), glucocorticoid-induced leucin zipper (GILZ) and Bcl-2 protein family expression in the different MM molecular subtypes. Transient knock-down of glucocorticoid-responsive proteins were performed to define their role in the pro-apoptotic effect of Dex. We first demonstrated that direct pro-apoptotic effect of Dex was related to the genetic heterogeneity of MM, since sensitive cell lines were restricted to t(14;16) and t(4;14) subgroups. We next demonstrated by transcriptomic Affymetrix analysis that GR expression was heterogeneous among the different molecular subtypes of HMCLs. MAF subgroup significantly expressed higher levels of GR than all other subgroups (p=0.02). This result was also confirmed on 300 newly diagnosed MM patients (p&amp;lt;.0001). We also demonstrated that Dex sensitivity was associated with its ability to down-regulate MAF protein level and its well-known target CCND2. This result was in agreement with the fact that elevated levels of MAF were associated not only with t(14;16) translocation but also with MMSET over-expression, which is a characteristic of t(4;14) subgroup. We next demonstrated that Dex induced an up-regulation of GILZ, a glucocorticoid-responsive molecule, in dex-sensitive and insensitive HMCLs. Nevertheless, resistant HMCLs, which expressed low levels of GR, failed to up-regulate GILZ to the same extent than sensitive HMCLs, suggesting that GR levels could be an important limiting factor for GILZ up-regulation. Of note, GILZ silencing induced a strong reduction of Dex-induced cell death. These results suggest that transactivation has a pivotal role in the induction of cell death by Dex in myeloma cells. Dex also induced an up-regulation of Bim isoforms and a down-regulation of Bcl-xL in all sensitive cell lines. We further demonstrated that Bim up-regulation is required for the apoptotic program in response to Dex. Finally, the silencing of GILZ impaired the up-regulation of Bim and the down-regulation of Bcl-xL under Dex treatment. In conclusion, Dex exerted a direct anti-tumor effect on HMCLs of t(14;16) and t(4;14) molecular subgroups while t(11;14) subgroup was insensitive to it. This result suggested that conventional therapeutic approaches should be re-evaluated within molecular subgroups of MM patients to favor potential molecular subtype therapy based on rational preclinical data. Finally, while Dex interferes with multiple pathways, we begin to unravel its complex mechanism of action demonstrating that transactivation, inducing GILZ up-regulation, plays a pivotal role in Dex induced cell death through the regulation of the Bcl-2 protein network. Citation Format: Charlotte Kervoëlen, Emmanuelle Ménoret, Patricia Gomez-Bougie, Régis Bataille, Philippe Moreau, Catherine Pellat-Deceunynck, Martine Amiot. The pro-apoptotic effect of dexamethasone mediated by GILZ and Bim up-regulation is related to genetic heterogeneity of multiple myeloma. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B16.

Neonatal seizures and brain imaging

Neonatal seizures are a symptom of brain dysfunction and frequently signal the clinician to look further for evidence of a pathologic intracranial or systemic process. Imaging the newborn brain is a critically important part of the evaluation of the newborn with seizures. Determining the underlying diagnosis is critical for appropriate treatment and accurately counseling the caregivers of affected newborns. Brain imaging provides the best aid in identification of causative brain abnormalities, including injury, and ultimately provides important insight into the prognosis of the newborn with seizures. Recent advances in specialized magnetic resonance techniques provide the opportunity to further study the effects of neonatal seizures in vivo, by measuring regional brain metabolism. As these advanced magnetic resonance imaging modalities can identify newborns at high risk of seizures, as well as those newborns at highest risk of adverse neurodevelopmental outcomes, they will further enable the study of emerging anti-seizure therapies on the newborn brain.

De Novo Large Genomic Deletions Involving POU3F4 in Incomplete Partition Type III Inner Ear Anomaly in East Asian Populations and Implications for Genetic Counseling

The aim of this study was to understand the prevalence and molecular genetic etiology of incomplete partition type III (IP type III) anomaly in Koreans. We also attempted to verify the prevalence of genomic deletions in the DFNX2 locus and to look for association between inheritance patterns and mutation type in East Asian IP type III subjects. Retrospective case review. Tertiary referral center. Subjects with IP type III anomaly and their biological mothers. Sanger sequencing, array-comparative genomic hybridization (aCGH), and PCR were performed. We also analyzed the type and inheritance of the causative genetic abnormality in East Asian DFNX2 patients. Mutation type and occurrence. We identified IP type III in 10 (4.8%) of 206 patients with an inner ear abnormality. We confirmed an etiologic homogeneity, DFNX2, of the IP type III in this Korean population. Two (20%) of the 10 DFNX2 carried a large genomic deletion affecting POU3F4, as proved by aCGH. PCR confirmed that the 2 deletions occurred de novo. Genetic alteration occurred de novo in 29.4% (5/17) of all reported Korean IP type III cases. From this study and literature review, we observed a striking difference of de novo occurrence rate (75% versus 12.5%, p = 0.032) between large genomic deletions and point mutations in East Asian population. Our data suggest that different POU3F4 mutations might show different recurrence rate in siblings of the IP type III families, especially in East Asian population. Genetic counseling should be provided accordingly.