Between hope and reality: treatment of genetic diseases through nucleic acid-based drugs.

Rare diseases (RD) affect a small number of people compared to the general population and are mostly genetic in origin. The first clinical signs often appear at birth or in childhood, and patients endure high levels of pain and progressive loss of autonomy frequently associated with short life expectancy. Until recently, the low prevalence of RD and the gatekeeping delay in their diagnosis have long hampered research. The era of nucleic acid (NA)-based therapies has revolutionized the landscape of RD treatment and new hopes arise with the perspectives of disease-modifying drugs development as some NA-based therapies are now entering the clinical stage. Herein, we review NA-based drugs that were approved and are currently under investigation for the treatment of RD. We also discuss the recent structural improvements of NA-based therapeutics and delivery system, which overcome the main limitations in their market expansion and the current approaches that are developed to address the endosomal escape issue. We finally open the discussion on the ethical and societal issues that raise this new technology in terms of regulatory approval and sustainability of production.

Ectropión congénito en síndrome de Noonan / Congenital ectropion in Noonan syndrome

Caso clínico: Niña de 10 años con dismorfia facial, escoliosis, baja talla, hipotonía muscular, foramen oval permeable y retraso madurativo, acude a consulta para corrección de ectropión congénito bilateral. Al examen oftalmológico se constató ectropión palpebral inferior, euribléfaron y lagoftalmos bilaterales, con fenómeno de Bell positivo. Se realizaron injertos cutáneos autólogos de espesor completo en párpados inferiores con cantoplastia lateral bilateral, resolviendo el ectropión y mejorando la oclusión palpebral. Posteriormente, se hizo un estudio genético que reveló una mutación en el gen PTPN11 y permitió, junto a la clínica, hacer el diagnóstico de síndrome de Noonan (SN).DiscusiónEl SN es un trastorno genético multisistémico con una gran variedad de fenotipos, que suele cursar con alteraciones oculares y perioculares. El ectropión palpebral, característica distintiva de la paciente, es una manifestación oftalmológica infrecuente de este síndrome que puede corregirse con injerto cutáneo de espesor completo y cantoplastia lateral. (AU)

Case report: Ten-year-old female patient, with facial dysmorphia, scoliosis, short stature, muscular hypotonia, patent foramen ovale and maturational delay, presented for correction of bilateral congenital ectropion. Ophthalmological examination revealed bilateral lower eyelid ectropion, euryblepharon and lagophthalmos, with a positive Bell's phenomenon. She was treated with full-thickness autologous skin grafts on the lower eyelids with bilateral lateral canthoplasty, resolving the ectropion and improving eyelid occlusion. Subsequently, a genetic study was performed that revealed a mutation in the PTPN11 gene and allowed, together with the clinical picture, to make the diagnosis of Noonan syndrome.DiscussionNoonan syndrome is a multisystem genetic disorder with a wide variety of phenotypes, which usually presents with ocular and periocular disorders. Eyelid ectropion, a distinctive feature of this patient, is a rare ophthalmological manifestation of this syndrome that can be corrected with full-thickness skin graft and lateral canthoplasty. (AU)

[A case of neonatal liver failure]. / 新生儿肝衰竭1例.

The patient was a male infant, born full-term, admitted to the hospital at 28 days of age due to jaundice for 20 days and abdominal distension for 15 days. The patient developed symptoms of jaundice, hepatosplenomegaly, massive ascites, and progressively worsening liver function leading to liver failure, severe coagulation disorders, and thrombocytopenia one week after birth. Various treatments were administered, including anti-infection therapy, fluid restriction, use of diuretics, use of hepatoprotective and choleretic agents, intermittent paracentesis, blood exchange, and intravenous immunoglobulin, albumin, and plasma transfusions. However, the patient's condition did not improve, and on the 24th day of hospitalization, the family decided to discontinue treatment and provide palliative care. Sequencing of the patient's liver tissue and parental blood samples using whole-exome sequencing did not identify any pathogenic variants that could explain the liver failure. However, postmortem liver tissue pathology suggested congenital hepatic fibrosis (CHF). Given the rarity of CHF causing neonatal liver failure, further studies on the prognosis and pathogenic genes of CHF cases are needed in the future. This article provides a comprehensive description of the differential diagnosis of neonatal liver failure and introduces a multidisciplinary diagnostic and therapeutic approach to neonatal liver failure.

Comment on: Severe pulmonary hypertension in pulmonary alveolar microlithiasis: A comprehensive literature review.

This letter commends the study "Severe pulmonary hypertension in pulmonary alveolar microlithiasis: A comprehensive literature review" for its thorough exploration of Pulmonary Alveolar Microlithiasis (PAM) and its association with pulmonary hypertension (PH). The study offers insights into PAM's genetics, clinical manifestations, diagnostic approaches, and treatment modalities. It highlights the importance of early diagnosis and management while discussing limitations such as its retrospective nature and small sample size. Despite these limitations, the study contributes significantly to understanding PAM and PH, emphasizing the need for larger prospective studies to validate findings and explore novel therapeutic avenues.

Functional and in silico analysis of ATP8A2 and other P4-ATPase variants associated with human genetic diseases.

P4-ATPases flip lipids from the exoplasmic to cytoplasmic leaflet of cell membranes, a property crucial for many biological processes. Mutations in P4-ATPases are associated with severe inherited and complex human disorders. We determined the expression, localization and ATPase activity of four variants of ATP8A2, the P4-ATPase associated with the neurodevelopmental disorder known as cerebellar ataxia, impaired intellectual development and disequilibrium syndrome 4 (CAMRQ4). Two variants, G447R and A772P, harboring mutations in catalytic domains, expressed at low levels and mislocalized in cells. In contrast, the E459Q variant in a flexible loop displayed wild-type expression levels, Golgi-endosome localization and ATPase activity. The R1147W variant expressed at 50% of wild-type levels but showed normal localization and activity. These results indicate that the G447R and A772P mutations cause CAMRQ4 through protein misfolding. The E459Q mutation is unlikely to be causative, whereas the R1147W may display a milder disease phenotype. Using various programs that predict protein stability, we show that there is a good correlation between the experimental expression of the variants and in silico stability assessments, suggesting that such analysis is useful in identifying protein misfolding disease-associated variants.

Systemic loss of CD36 aggravates NAFLD-related HCC through MEK1/2-ERK1/2 signaling pathway.

BACKGROUND & AIMS: CD36, a membrane protein widely present in various tissues, is crucial role in regulating energy metabolism. The rise of HCC as a notable outcome of NAFLD is becoming more apparent. Patients with hereditary CD36 deficiency are at increased risk of NAFLD. However, the impact of CD36 deficiency on NAFLD-HCC remains unclear. METHODS: Global CD36 knockout mice (CD36KO) and wild type mice (WT) were induced to establish NAFLD-HCC model by N-nitrosodiethylamine (DEN) plus high fat diet (HFD). Transcriptomics was employed to examine genes that were expressed differentially. RESULTS: Compared to WT mice, CD36KO mice showed more severe HFD-induced liver issues and increased tumor malignancy. The MEK1/2-ERK1/2 pathway activation was detected in the liver tissues of CD36KO mice using RNA sequencing and Western blot analysis. CONCLUSION: Systemic loss of CD36 leaded to the advancement of NAFLD to HCC by causing lipid disorders and metabolic inflammation, a process that involves the activation of MAPK signaling pathway. We found that CD36 contributes significantly to the maintenance of metabolic homeostasis in NAFLD-HCC.

A propósito de un caso de síndrome de Fraser. Autopsia de un feto de 37 semanas de gestación con múltiples malformaciones / About a case of Fraser syndrome. Autopsy of a 37 weeks gestation fetus with multiple malformations

El síndrome de Fraser o síndrome criptoftalmos/sindactilia es una enfermedad genética rara, cuyo diagnóstico se basa en una serie de criterios clínicos mayores y menores, y que puede apoyarse en pruebas genéticas. En este artículo se presenta el caso de una autopsia fetal de 37 semanas de gestación con sospecha de síndrome de CHAOS (síndrome obstructivo congénito de las vías aéreas altas). (AU)

Fraser syndrome or cryptophthalmos-syndactyly syndrome is a rare genetic disease, the diagnosis of which is based on a series of major and minor clinical criteria and that can be supported by genetic tests. This article presents the case of a fetal autopsy at 37 weeks of gestation with suspicion of CHAOS syndrome (congenital obstructive syndrome of the upper airways). (AU)

The first study of 3-M Syndrome in Jordan and Literature Review

The prevalence of 3-M syndrome remains unclear owing to its rarity and the limited number of reported cases in the medical literature. To date, approximately 100 cases of the disorder have been documented in MedlinePlus Genetics. Here, we present the first case study report from Jordan of a boy diagnosed with 3-M syndrome at 9 months of age via karyotyping. The patient exhibited distinct facial features, severe prenatal and postnatal growth retardation, and normal mental development. As rare genetic autosomal recessive mutations are common where consanguineous marriages are prevalent, raising awareness of such rare genetic diseases is critical. This paper aims to provide a case report on 3-M syndrome and a literature review. (AU)

A propósito de un caso de síndrome de Fraser. Autopsia de un feto de 37 semanas de gestación con múltiples malformaciones / About a case of Fraser syndrome. Autopsy of a 37 weeks gestation fetus with multiple malformations

El síndrome de Fraser o síndrome criptoftalmos/sindactilia es una enfermedad genética rara, cuyo diagnóstico se basa en una serie de criterios clínicos mayores y menores, y que puede apoyarse en pruebas genéticas. En este artículo se presenta el caso de una autopsia fetal de 37 semanas de gestación con sospecha de síndrome de CHAOS (síndrome obstructivo congénito de las vías aéreas altas). (AU)

Fraser syndrome or cryptophthalmos-syndactyly syndrome is a rare genetic disease, the diagnosis of which is based on a series of major and minor clinical criteria and that can be supported by genetic tests. This article presents the case of a fetal autopsy at 37 weeks of gestation with suspicion of CHAOS syndrome (congenital obstructive syndrome of the upper airways). (AU)

Severe pulmonary hypertension in pulmonary alveolar microlithiasis: A comprehensive literature review.

This review focuses on Pulmonary Alveolar Microlithiasis (PAM), an autosomal recessive genetic disorder characterized by calcium crystal deposits (microliths) resulting from loss of function of the SLC34A2 gene. PAM is a rare disease with approximately 1100 reported cases globally. The historical context of its discovery and the genetic, epidemiological, and pathophysiological aspects are discussed. PAM falls under interstitial lung diseases and is associated with pulmonary hypertension (PH), primarily categorized as Group 3 PH. The clinical manifestations, diagnostic approaches, and challenging aspects of treatment are explored. A clinical case of PAM with severe pulmonary hypertension is presented, emphasizing the importance of comprehensive evaluation and the potential benefits of phosphodiesterase-5 inhibitors (PDE5i) therapy. Despite limited therapeutic options and challenging diagnosis, this review sheds light on recent developments and emerging treatments for PAM and associated pulmonary hypertension.

Case report: Cardiac arrest after radiofrequency ablation in a 76-year-old male.

RATIONALE: Previous studies have found that the main treatment of sinus arrest is pacemaker treatment. It is rare to have 12 s of sinus arrest after radiofrequency ablation, and whether a permanent pacemaker is implanted immediately in this case is not described in the guidelines. PATIENT CONCERNS: A 76-year-old male patient with persistent atrial fibrillation (AF) developed sinus arrest lasting 12 s in the early morning of the fourth day after using radiofrequency ablation for pulmonary vein isolation. DIAGNOSIS: The patient was diagnosed with AF and sinus arrest. INTERVENTIONS: The patient received cardiopulmonary resuscitation, intravenous injection of atropine 1 mg, and intravenous infusion of isoproterenol 1mg and immediately recovered consciousness thereafter. Approximately, 1.5 h later, the patient underwent surgery to install a temporary pacemaker in the right femoral vein. OUTCOMES: The patient had repeated episodes of sinus arrest after the implantation of a temporary pacemaker. After 3 weeks, the patient stabilized and was discharged. The patient was followed up for 1 year and did not experience any recurrence of sinus arrest or AF. LESSONS: We consider the potential for postoperative myocardial edema, injury to the sinoatrial node during the procedure, propafenone poisoning, and autonomic dysfunction as contributors to the occurrence of sinus arrest after radiofrequency ablation. When sinus arrest occurs after radiofrequency ablation, we can choose the appropriate treatment according to the patient's condition.

Next-generation therapeutics for rare genetic disorders.

The therapeutic potential of the human genome has been explored through the development of next-generation therapeutics, which have had a high impact on treating genetic disorders. Classical treatments have traditionally focused on common diseases that require repeated treatments. However, with the recent advancements in the development of nucleic acids, utilizing DNA and RNA to modify or correct gene expression in genetic disorders, there has been a paradigm shift in the treatment of rare diseases, offering more potential one-time cure options. Advanced technologies that use CRISPR-Cas 9, antisense oligonucleotides, siRNA, miRNA, and aptamers are promising tools that have achieved successful breakthroughs in the treatment of various genetic disorders. The advancement in the chemistry of these molecules has improved their efficacy, reduced toxicity, and expanded their clinical use across a wide range of tissues in various categories of human disorders. However, challenges persist regarding the safety and efficacy of these advanced technologies in translating into clinical practice. This review mainly focuses on the potential therapies for rare genetic diseases and considers how next-generation techniques enable drug development to achieve long-lasting curative effects through gene inhibition, replacement, and editing.

Immune checkpoint inhibitor-induced isolated adrenocorticotropic hormone deficiency: a systematic review.

Background: Immune checkpoint inhibitor-induced isolated adrenocorticotropic hormone deficiency (IAD) is a rare but potentially fatal disease. Methods: We comprehensively searched the PubMed database and made a systematic review of immune checkpoint inhibitor-induced isolated adrenocorticotropic hormone deficiency. If the status of other anterior pituitary hormones was not mentioned, the case was excluded. Results: We identified 123 cases diagnosed as immune checkpoint inhibitor-induced IAD, consisting of 44 female and 79 male patients. The average age of these patients was 64.3 ± 12.6 years old, and 67.5% were 60 years old or above. The majority (78.9%) of these patients received anti-programmed cell death protein-1 (anti-PD-1) antibodies or anti-programmed cell death ligand 1 (anti-PD-L1) antibodies or both, and 19.5% received combined therapy, sequential therapy, or both. A total of 26 patients received anti-cytotoxic T lymphocyte antigen 4 antibodies (anti-CTLA-4). The median ICI treatment cycle before the diagnosis of adrenal insufficiency was 8 (6, 12), and the median ICI treatment duration before the diagnosis of adrenal insufficiency was 6 (4, 8) months. Eleven cases developed IAD 1 to 11 months after discontinuation of ICIs. Fatigue and appetite loss were the most common symptoms, and surprisingly, there were two asymptomatic cases of IAD. Most patients (88 cases) had normal pituitary magnetic resonance imaging, only 14 cases reported mild atrophy or swelling pituitary gland, and 21 cases reported no imaging results. Most diagnoses were made by basal hormone levels, and pituitary stimulation tests were performed in only a part of the cases. No cases had been reported of discontinuation of ICI use due to IAD nor had there been any deaths due to IAD. Conclusion: IAD was predominant in elderly male patients mainly receiving anti-PD-1 or anti-PD-L1 antibodies. It was sometimes difficult to recognize IAD at first glance since non-specific symptoms were common and asymptomatic cases of IAD were also reported. Although IAD can be deadly, it usually does not affect the continued use of ICIs.

Histopathology and molecular pathology confirmed a diagnosis of atypical Caroli's syndrome: a case report.

Caroli's syndrome is a congenital disease characterized by dilation of intrahepatic bile ducts and congenital hepatic fibrosis. It is a rare condition in clinical work. Typically, the diagnosis of this disease is confirmed through medical imaging. Here, we report a case of atypical Caroli's syndrome in a patient who presented with recurrent upper gastrointestinal tract bleeding. The patient underwent imaging examinations, liver biopsy and whole exome sequencing. The results of the imaging examination were non-specific. However, with the aid of pathological examination, the patient was diagnosed with Caroli's syndrome. In conclusion, for cases where the imaging presentation of Caroli's syndrome is inconclusive, an accurate diagnosis should rely on pathology. By discussing this specific case, our aim is to enhance readers' understanding of this disease, provide valuable information that can aid in the early detection and appropriate management of Caroli's syndrome, ultimately improving patient outcomes.

The burden of disease and quality of life in patients with acute hepatic porphyria: COPHASE study / Carga de la enfermedad y calidad de vida en pacientes con porfiria hepática aguda: estudio COPHASE

Background: Acute hepatic porphyria (AHP) comprises a group of rare genetic diseases characterized by neurovisceral crises that are manifested by abdominal pain and neurological and/or psychological symptoms that interfere with the ability to lead a normal life. Our objective was to determine the burden of the disease in one year and the health-related quality of life (HRQoL) in patients with AHP. Results: 28 patients were analyzed. The mean age was 36.6±10.2 years, 89.3% were women, and the average number of crises was 1.9±1.5. The average annual cost per patient was €38,255.40. 80.2% of the costs was direct medical costs, 17.5% was associated with loss of productivity and 2.3% was direct non-medical costs. 85.9% of the total cost corresponded to the crises. The intercrisis period accounted for the remaining 14.1%. The global index of the EQ-5D-5L (HRQoL) was 0.75±0.24. The dimensions of pain/discomfort, anxiety/depression and daily activities were the most affected. Leisure, travel/vacations and household activities were the most affected daily activities. 53.6% of patients required a caregiver due to AHP. 92.9% did not present overload and 7.1% presented extreme overload. Conclusions: Patients with AHP are associated with a high economic impact and an affected HRQoL in the pain/discomfort dimension, with a negative impact on the performance of daily activities and a risk of psychiatric diseases.(AU)

Antecedentes: La porfiria hepática aguda (PHA) comprende un grupo de enfermedades genéticas raras caracterizadas por crisis neuroviscerales que se manifiestan por dolor abdominal y síntomas neurológicos y/o psicológicos que interfieren en la capacidad de llevar una vida normal. Nuestro objetivo fue determinar la carga de la enfermedad en un año y la calidad de vida relacionada con la salud (CVRS) en pacientes con PHA. Resultados: Se analizaron 28 pacientes. La edad media fue de 36,6±10,2 años, el 89,3% eran mujeres y la media de crisis fue de 1,9±1,5. El coste medio anual por paciente fue de 38.255,40€. El 80,2% de los costes fueron costes médicos directos, el 17,5% estuvieron asociados a pérdida de productividad y el 2,3% fueron costes directos no médicos. El 85,9% del coste total correspondió a las crisis. El período entre crisis representó el 14,1% restante. El índice global del EQ-5D-5L (HRQoL) fue de 0,751±0,24. Las dimensiones de dolor/malestar, ansiedad/depresión y actividades cotidianas fueron las más afectadas. Ocio, viajes/vacaciones y actividades del hogar fueron las actividades diarias más afectadas. El 53,6% de los pacientes requirieron un cuidador debido a la PHA. El 92,9% no presentaron sobrecarga y el 7,1% presentaron sobrecarga extrema. Conclusiones: Los pacientes con PHA se asocian con un alto impacto económico y una CVRS afectada en la dimensión dolor/malestar, con impacto negativo en el desempeño de las actividades diarias y riesgo de enfermedades psiquiátricas.(AU)

Agregación familiar en el síndrome de colon irritable en pacientes mexicanos. Un estudio de casos y controles / Familial aggregation in Irritable Colon Syndrome in Mexican patients. A case-control study

Objetivo: Determinar la existencia de un patrón familiar de agregación del síndrome de intestino irritable (SII). Diseño: Es un estudio de casos y controles con proporción 1:2, llevado a cabo en una consulta externa de medicina general-familiar. Participantes: Hombres y mujeres de 18 a 60 años. Participaron 40 casos con SII de acuerdo con criterios de Roma IV, y 80 controles integrados por familiares sin alguna enfermedad gastrointestinal. Las mediciones principales fueron variables sociodemográficas, algún evento estresante relacionado, patrón evacuatorio predominante y patrón de repetición familiar para SII. Se analizaron los datos con estadísticas descriptivas e inferenciales. X2 para datos categóricos, estimación de odds ratio (OR) con intervalo de confianza (IC) 95%. Fue aprobado por el comité de ética institucional. Resultados: Hubo repetición del patrón de presentación del SII en familiares principalmente de primer grado. Fue mayor el riesgo de padecer este síndrome cuando el padre lo reportó (OR de 11,2; IC 95% 2-100,1), que cuando la madre lo presentó (OR 3,7; IC 95% 1,4-9,9), o hermano(a) (OR 2,8; IC 95% 1,1-6,6). En ambos grupos, el familiar que más frecuentemente presentaba SII fue en la línea colateral (hermano/a) (37,5% en los casos vs. 17,5% en los controles [p=0,023]). En ambos grupos el género predominante fue el femenino con 80,0% en los casos y 57,5% en los controles. Conclusión: Existe en la población mexicana un patrón de agregación familiar. La enfermedad es más frecuente en familiares en primer grado. Es importante dilucidar si quien desempeña el rol más importante en SII es el trasfondo genético o el entorno familiar.(AU)

Objective: To determine a family aggregation pattern of Irritable Bowel Syndrome (IBS). Design: it is a case-control study with a 1.2 ratio. Setting. External consultation of a general family medicine practice. Participants: men and women from 18 to 60 years old. Cases (40): people with IBS according to the Rome IV criteria, and Controls (80): relatives without gastrointestinal disease. Main measurements. Sociodemographic variables, related stressful events, predominant evacuation patterns, and family repetition patterns for IBS. Data were analyzed with descriptive and inferential statistics. Chi-square for categorical data (< p.05 as significant) estimate of ORs with 95% confidence interval. The institutional ethics committee approved it. Results: The IBS presentation pattern was repeated in relatives, mainly first-degree. The risk of suffering from IBS was higher when the father reported it (OR 11.2 (95% CI; 1.2 -100.1), than the mother OR 3,7 (95% CI; 1.4 – 9.9), sibling OR 2.8 (95% CI; 1.1 – 6.6. In both groups, the relative who most frequently presented IBS was in the collateral line (sibling) (37.5% in cases vs. 17.5% in controls (p=0.023). In both groups, the predominant gender was female, with 80. 0% in cases and 57.5% in controls. Conclusion: SII has a familial recurrence pattern in the Mexican population. The disease is more frequent in first-degree relatives. It is important to elucidate the importance of the role that plays genetic background vs. the influence of the family environment in SII.(AU)

El manejo multidisciplinar mejora el diagnóstico genético de las enfermedades renales hereditarias en la era de next generation sequencing (NGS) / Multidisciplinary management improves the genetic diagnosis of hereditary kidney diseases in the next generation sequencing (NGS) era

Antecedentes y objetivo Las enfermedades renales hereditarias (ERH) son una causa frecuente de enfermedad renal crónica, habiéndose incrementado su diagnóstico desde la introducción de la secuenciación masiva (NGS). En 2018 se fundó la Unidad multidisciplinar de Enfermedades Renales Hereditarias de la Región de Murcia basándose en el estudio genético de las ERH mediante panel de genes. El objetivo de este estudio es analizar los resultados obtenidos en los primeros tres años de funcionamiento, así como analizar los factores clínicos que se asocian a la obtención de un diagnóstico genético final. Materiales y métodos Se incluyeron los pacientes estudiados mediante panel de genes de ERH y se compararon las características entre los que obtuvieron un diagnóstico genético final y los que no. Resultados Se estudiaron un total de 360 pacientes, detectándose variantes genéticas en 164 pacientes (45,6%) no relacionados familiarmente. Cuarenta y cinco de estas variantes eran de significado clínico incierto precisando estudio de cosegregación familiar, facilitado por la unidad multidisciplinar. Globalmente, considerando los resultados obtenidos con el panel de NGS realizado en el CBGC y los estudios genómicos ampliados, se consiguió un rendimiento diagnóstico final de ERH del 33,3% (120/360), contando hallazgos incidentales, del 35,6% (128/360). Se estudiaron 223 pacientes con sospecha de síndrome de Alport, confirmándose el diagnóstico en un 28,5% (gen más frecuente COL4A4), los cuales eran con más frecuencia mujeres, y con clara historia familiar compatible. También tenían con más frecuencia microhematuria, aunque 5 pacientes sin microhematuria confirmaron diagnóstico. No hubo diferencias en la edad, proteinuria, función renal, hipoacusia o alteraciones oftalmológicas (AU)

Background and objective Hereditary kidney diseases (HKD) are a frequent cause of chronic kidney disease, and their diagnosis has increased since the introduction of next generation sequencing (NGS). In 2018, the Multidisciplinary Unit for Hereditary Kidney Diseases of the Region of Murcia (UMERH-RM) was founded based on the genetic study of HKD. The objective of this study is to analyze the results obtained in the first 3 years of operation, and to analyze the clinical factors associated to a final genetic diagnosis. Materials and methods All the patients studied with the HKD gene panel were included. The characteristics between those who obtained a final genetic diagnosis and those who did not were compared. Results A total of 360 patients were studied, detecting genetic variants in 164 not related patients (45.6%). 45 of these were variants of uncertain significance requiring a family co-segregation study, which was facilitated by the multidisciplinary unit. Overall, considering the results obtained with the NGS panel and the extended genomic studies, a final diagnostic yield of HRD of 33.3% (120/360) was achieved, and including incidental findings 35.6% (128/360). Two hundred and twenty-three patients with suspected Alport syndrome were studied. Diagnosis was confirmed in 28.5% (COL4A4 most frequent gene), more frequently women with an obvious compatible family history. They also had frequently microhematuria, although 5 patients without microhematuria confirmed the diagnosis. There were no differences in age, proteinuria, renal function, hearing loss, or ophthalmologic abnormalities. The most frequent finding in the renal biopsy was mesangial proliferation. We estimate that 39 patients avoided renal biopsy (AU)

New onset of isolated adrenocorticotropin deficiency associated with encephalopathy following coronavirus disease 2019 in a healthy elderly man.

Coronavirus disease 2019 (COVID-19) due to a severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can include various systemic organ disorders including endocrinopathies and neurological manifestations. We report the case of a 65-year-old Japanese man who developed isolated adrenocorticotropic hormone (ACTH) deficiency and encephalopathy following SARS-CoV-2 infection. Two weeks after his COVID-19 diagnosis, he was emergently admitted to our hospital because of subacute-onset delirium. On admission, he presented hyponatremia (128 mEq/L) and secondary adrenal insufficiency (ACTH <1.5 pg/mL, cortisol 0.53 µg/dL). Brain imaging and laboratory examinations including SARS-CoV-2 polymerase chain reaction testing in the cerebrospinal fluid revealed no abnormalities. His consciousness level worsened despite the amelioration of hyponatremia by intravenous hydrocortisone (100 mg/day), but his neurological presentations completely resolved after three consecutive days of high-dose (400 mg/day) hydrocortisone. His encephalopathy did not deteriorate during hydrocortisone tapering. He continued 15 mg/day hydrocortisone after discharge. His encephalopathy might have developed via a disturbance of the autoimmune system, or a metabolic effect associated with adrenal insufficiency, although the time lag between the hyponatremia's improvement and the patient's neurological response to the steroid was incompatible with common cases of delirium concurrent with adrenal insufficiency. At 13 months after his hospitalization, the patient's neurological symptoms have not recurred and he has no endocrinological dysfunctions other than the remaining ACTH deficiency. A thorough consideration of the immunological and metabolic characteristics of SARS-CoV-2 is advisable when clinicians treat patients during and even after their COVID-19 disease period.

'If I Knew More I Would Feel Less Worried': Filipino Americans' Attitudes and Knowledge of Genetic Disease, Counseling, and Testing.

INTRODUCTION: The field of genetics is rapidly expanding and people are increasingly utilizing genetic testing and counseling services. However, the current literature on genetic health topics and Filipinos remains limited, as many minority populations are not adequately studied. This study describes Filipino Americans' attitudes and knowledge of genetic disease, genetic testing, and genetic counseling. To address these knowledge gaps and reduce the burden of health disparities, the informational needs of Filipino Americans regarding genetic disease and genetic services must be understood in order to better tailor these services and outreach methods. METHODS: Fifteen semi-structured, qualitative interviews were held with individuals who self-identified as Filipino American between November 2022 and January 2023. Interviews were transcribed and coded using an iterative process. RESULTS: Most participants were familiar with genetic disease and believed that factors such as biology, as well as cultural factors such as upbringing and food, contributed to its development. The majority of participants had previously heard of genetic testing; however, most participants either did not know much or were only familiar with ancestry direct-to-consumer genetic testing (DTC-GT). Most participants had not heard of genetic counseling and those that had heard of genetic counseling before did not understand its purpose. Overall, most participants had a positive attitude toward genetic testing and counseling. Participants identified the benefits of these services including genetic disease prevention, management, and treatment. Participants stressed the importance of educating the Filipino community and shared their ideas for how to implement outreach efforts. DISCUSSION/CONCLUSION: This study found that Filipino Americans generally had a positive outlook on genetic testing and genetic counseling. We propose participant-generated ideas for outreach and education that may help inform future public health efforts that aim to educate this population about genetic disease, testing and counseling.