J Invest Surg. 2022 Nov-Dec;35(11-12):1836-1840. doi: 10.1080/08941939.2022.2130481. Epub 2022 Oct 6.

ABSTRACT

INTRODUCTION: Splenic abscess secondary to endocarditis is a rare complication with high mortality. The treatment modality, splenectomy versus percutaneous drainage, and the best time, before or after valve replacement, are controversial. In the literature, there are only a few small case series about the subject. The objective of this study is to analyze the experience of a referral center in treating such condition.

METHODS: Patients with splenic abscesses due to endocarditis from 2006 to 2020 were retrospectively analyzed.

RESULTS: Thirteen patients (mean age 46 years old, 69% male) were identified. Eight patients (62%) had at least 2 comorbidities and 5 (38%) had a history of cardiac surgery. The diagnosis was incidental in 6 (46%). The mean time of abscess diagnosis after endocarditis definition was 14 days. Six patients (46%) had at least two organ dysfunctions. The median APACHE II score was 12 overall, and 24.5 in patients who died. Six patients (46%) had a valve replacement, and in two the abscess was diagnosed postoperatively. Of the other four patients, splenectomy was performed before the cardiac operation in three and at the same time in one. Splenectomy was performed immediately in 9 (69%) patients while three patients had percutaneous drainage (23%), one of which underwent splenectomy due to drainage failure. Exclusive antibiotic treatment was performed on only one patient. The median length of hospitalization was 24 days and mortality was 46%.

CONCLUSION: Splenic abscess due to endocarditis is a life-threatening condition with controversial treatment that results in a prolonged length of stay and high mortality.

PMID:36202396 | DOI:10.1080/08941939.2022.2130481

J Eur Acad Dermatol Venereol. 2022 Oct 4. doi: 10.1111/jdv.18637. Online ahead of print.

ABSTRACT

BACKGROUND: Epidermolysis bullosa (EB) is a rare genetic disorder manifesting with skin and mucosal membrane blistering in different degrees of severity.

OBJECTIVE: Epidemiological data from different countries have been published, but none are available from Germany.

METHODS: In this population-based cross-sectional study, people living with EB in Germany were identified using the following sources: academic hospitals, diagnostic laboratories, and patient organization.

RESULTS: Our study indicates an overall EB incidence of 45 per million live births in Germany. With 14.23 per million live births for junctional EB, the incidence is higher than in other countries, possibly reflecting the availability of early molecular genetic diagnostics in severely affected neonates. Dystrophic EB was assessed at 15.58 cases per million live births. The relatively low incidence found for EB simplex, 14.93 per million live births, could be explained by late or missed diagnosis, but also by 33% of cases remaining not otherwise specified. Using log-linear models, we estimated a prevalence of 54 per million for all EB types, 2.44 for junctional EB, 12.16 for dystrophic EB, and 28.44 per million for EB simplex. These figures are comparable to previously reported data from other countries.

CONCLUSIONS: Altogether, there are at least 2000 patients with EB in the German population. These results should support national policies and pharmaceutical companies in decision making, allow more precise planning of drug development and clinical trials, and aid patient advocacy groups in their effort to improve quality of life of people with this orphan disease.

PMID:36196047 | DOI:10.1111/jdv.18637

Br J Dermatol. 2022 Oct;187(4):453-454. doi: 10.1111/bjd.21686.

NO ABSTRACT

PMID:36192346 | DOI:10.1111/bjd.21686

Neurology. 2022 Oct 4;99(14):e1511-e1526. doi: 10.1212/WNL.0000000000200927. Epub 2022 Jul 18.

ABSTRACT

BACKGROUND AND OBJECTIVES: ATP1A3 is associated with a broad spectrum of predominantly neurologic disorders, which continues to expand beyond the initially defined phenotypes of alternating hemiplegia of childhood, rapid-onset dystonia parkinsonism, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss syndrome. This phenotypic variability makes it challenging to assess the pathogenicity of an ATP1A3 variant found in an undiagnosed patient. We describe the phenotypic features of individuals carrying a pathogenic/likely pathogenic ATP1A3 variant and perform a literature review of all ATP1A3 variants published thus far in association with human neurologic disease. Our aim is to demonstrate the heterogeneous clinical spectrum of the gene and look for phenotypic overlap between patients that will streamline the diagnostic process.

METHODS: Undiagnosed individuals with ATP1A3 variants were identified within the cohort of the Deciphering Developmental Disorders study with additional cases contributed by collaborators internationally. Detailed clinical data were collected with consent through a questionnaire completed by the referring clinicians. PubMed was searched for publications containing the term "ATP1A3" from 2004 to 2021.

RESULTS: Twenty-four individuals with a previously undiagnosed neurologic phenotype were found to carry 21 ATP1A3 variants. Eight variants have been previously published. Patients experienced on average 2-3 different types of paroxysmal events. Permanent neurologic features were common including microcephaly (7; 29%), ataxia (13; 54%), dystonia (10; 42%), and hypotonia (7; 29%). All patients had cognitive impairment. Neuropsychiatric diagnoses were reported in 16 (66.6%) individuals. Phenotypes were extremely varied, and most individuals did not fit clinical criteria for previously published phenotypes. On review of the literature, 1,108 individuals have been reported carrying 168 different ATP1A3 variants. The most common variants are associated with well-defined phenotypes, while more rare variants often result in very rare symptom correlations, such as are seen in our study. Combined Annotation-Dependent Depletion (CADD) scores of pathogenic and likely pathogenic variants were significantly higher and variants clustered within 6 regions of constraint.

DISCUSSION: Our study shows that looking for a combination of paroxysmal events, hyperkinesia, neuropsychiatric symptoms, and cognitive impairment and evaluating the CADD score and variant location can help identify an ATP1A3-related condition, rather than applying diagnostic criteria alone.

PMID:36192182 | DOI:10.1212/WNL.0000000000200927

Genome Med. 2022 Sep 30;14(1):113. doi: 10.1186/s13073-022-01113-y.

ABSTRACT

BACKGROUND: In medical genetics, discovery and characterization of disease trait contributory genes and alleles depends on genetic reasoning, study design, and patient ascertainment; we suggest a segmental haploid genetics approach to enhance gene discovery and molecular diagnostics.

METHODS: We constructed a genome-wide map for nonallelic homologous recombination (NAHR)-mediated recurrent genomic deletions and used this map to estimate population frequencies of NAHR deletions based on large-scale population cohorts and region-specific studies. We calculated recessive disease carrier burden using high-quality pathogenic or likely pathogenic variants from ClinVar and gnomAD. We developed a NIRD (NAHR deletion Impact to Recessive Disease) score for recessive disorders by quantifying the contribution of NAHR deletion to the overall allele load that enumerated all pairwise combinations of disease-causing alleles; we used a Punnett square approach based on an assumption of random mating. Literature mining was conducted to identify all reported patients with defects in a gene with a high NIRD score; meta-analysis was performed on these patients to estimate the representation of NAHR deletions in recessive traits from contemporary human genomics studies. Retrospective analyses of extant clinical exome sequencing (cES) were performed for novel rare recessive disease trait gene and allele discovery from individuals with NAHR deletions.

RESULTS: We present novel genomic insights regarding the genome-wide impact of NAHR recurrent segmental variants on recessive disease burden; we demonstrate the utility of NAHR recurrent deletions to enhance discovery in the challenging context of autosomal recessive (AR) traits and biallelic variation. Computational results demonstrate new mutations mediated by NAHR, involving recurrent deletions at 30 genomic regions, likely drive recessive disease burden for over 74% of loci within these segmental deletions or at least 2% of loci genome-wide. Meta-analyses on 170 literature-reported patients implicate that NAHR deletions are depleted from the ascertained pool of AR trait alleles. Exome reanalysis of personal genomes from subjects harboring recurrent deletions uncovered new disease-contributing variants in genes including COX10, ERCC6, PRRT2, and OTUD7A.

CONCLUSIONS: Our results demonstrate that genomic sequencing of personal genomes with NAHR deletions could dramatically improve allele and gene discovery and enhance clinical molecular diagnosis. Moreover, results suggest NAHR events could potentially enable human haploid genetic screens as an approach to experimental inquiry into disease biology.

PMID:36180924 | PMC:PMC9526336 | DOI:10.1186/s13073-022-01113-y

Orphanet J Rare Dis. 2022 Sep 29;17(1):366. doi: 10.1186/s13023-022-02458-8.

ABSTRACT

BACKGROUND: Rare diseases are a new global health priority, requiring evidence-based estimates of the global prevalence of diseases to inform public policymakers and provide a serious challenge to the healthcare system that must not be ignored. The purpose of this study is to investigate Iranian future healthcare professionals' knowledge and opinions about rare diseases.

RESULTS: A total of 6838 students responded to the questionnaire. Nursing and medical students had the highest participation. Almost 85% of participants rated their knowledge about rare diseases as poor or insufficient. While nearly 70 percent of participants took courses about rare diseases at university. Finally, 72.7% of future healthcare professionals did not feel ready to take care of a patient with a rare disease.

CONCLUSION: The present study has indicated a gap in Iranian medical students' knowledge of rare diseases. The researchers believe that health science policymakers should make a joint effort to improve knowledge about rare diseases. Including courses with regard to rare diseases would be of benefit to future healthcare professionals.

PMID:36175905 | PMC:PMC9524105 | DOI:10.1186/s13023-022-02458-8

BMJ Case Rep. 2022 Sep 29;15(9):e249986. doi: 10.1136/bcr-2022-249986.

ABSTRACT

Incarceration of the gravid uterus (IGU) is a rare obstetric disorder that may lead to pregnancy-related complications. Acute urinary retention (AUR) is one of the associated symptoms in IGU and it is mostly observed in the first semester and early second trimester. A case of a woman, in her 30s, is described, who presented AUR and lower abdominal pain in the early second trimester. The diagnosis was confirmed upon pelvic examination, and abdominal and transvaginal ultrasound. Management included long-term bladder catheterisation, manual reduction manoeuvres and passive positioning manoeuvres at home. At 24 weeks of gestation, the uterus returned in its correct polarity, the Foley catheter was removed and the patient was able to void spontaneously. A healthy infant was delivered vaginally at term.No specific guidelines have been published for IGU treatment. However, prompt diagnosis and tight follow-up of these patients are essential to define strategies, reduce complications and prevent recurrences.

PMID:36175041 | DOI:10.1136/bcr-2022-249986

World J Surg Oncol. 2022 Sep 28;20(1):317. doi: 10.1186/s12957-022-02784-y.

ABSTRACT

BACKGROUND: Desmoid-type fibromatosis (DTF) is a rare benign lesion that usually arises from the abdominal wall or extremities and rarely from the mesentery or intrabdominal organs. Malignant peritoneal mesothelioma is also a rare, yet aggressive disease. To our knowledge, this is the first case report of desmoid-type fibromatosis in the setting of malignant peritoneal mesothelioma.

CASE PRESENTATION: An early 30-year-old female was referred to our center for large intra-abdominal mass concerning for recurrent malignant peritoneal mesothelioma after previous cytoreductive surgery with hyperthermic intraperitoneal chemotherapy and adjuvant chemotherapy. Further investigation revealed a large mesenteric mass, which was resected en bloc with the cecum and terminal ileum. Pathologic findings confirmed a surprising diagnosis of desmoid-type fibromatosis.

CONCLUSIONS: No adjuvant therapy was offered to this patient due to negative tumor margins; however, close follow-up will be provided for recurrence of both malignant peritoneal mesothelioma and desmoid-type fibromatosis, which can be differentiated in the future via biopsy in this patient.

PMID:36171577 | DOI:10.1186/s12957-022-02784-y

Arch Pathol Lab Med. 2022 Sep 28. doi: 10.5858/arpa.2021-0612-RA. Online ahead of print.

ABSTRACT

CONTEXT.—: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with poor outcome. BPDCN diagnostically overlaps with entities such as acute myeloid leukemia, histiocytic/dendritic cell neoplasms, and natural killer/T-cell lymphomas. Unfortunately, large, patient-centered studies that comprehensively analyze clinical, pathologic, and other diagnostic features are lacking. As such, there is an incomplete understanding of this disease.

OBJECTIVE.—: To better characterize BPDCN, a multicenter working group consisting of hematopathologists and dermatopathologists gathered in person and remotely to review the current understanding of BPDCN, discuss specific issues regarding the diagnosis and differential diagnosis, and perform a retrospective analysis of the literature.

DATA SOURCES.—: The working group curated a database of published BPDCN patient cases (BPDCN Network literature database) following careful discussion and review, 361 articles were identified, comprising a total of 1513 individually annotated patients.

CONCLUSIONS.—: By conducting an in-depth analysis, not only did we confirm known findings such as frequent skin involvement (84% of patients; 861 of 1028) and a male predominance among older patients (>60 years old; male to female ratio of 3.5:1; 617:177), but we also identified a number of underrecognized features, such as significant central nervous system involvement (38% of cases; 24 of 64), and a more equal male to female prevalence among patients younger than 40 years (male to female ratio of 1.25:1; 167:134). Furthermore, we were able to accurately summarize the immunophenotypic, cytogenetic, and molecular features of this disease. BPDCN is a complex disease with distinct morphologic, immunophenotypic, and molecular findings. Continual updates of the literature database generated here and further analysis can allow for prospective refinement of our understanding of this orphan disease.

PMID:36170615 | DOI:10.5858/arpa.2021-0612-RA

J Investig Med High Impact Case Rep. 2022 Jan-Dec;10:23247096221123146. doi: 10.1177/23247096221123146.

ABSTRACT

Central giant cell granuloma (CGCG) is a rare disease characterized by sporadic, benign, intraosseous mandibular lesions of unknown etiology. Histologically, these lesions are indistinguishable from brown tumors of hyperparathyroidism and cherubism, and occasionally have been associated with different syndromes raising a question for genetic etiology. The CGCG has varied presentation ranging from nonaggressive and indolent to aggressive, destructive, and recurrent, often posing diagnostic and therapeutic challenges. Herein, we present the first case of a 10-year-old boy with CGCG and 16p13.11 microdeletion syndrome, highlight the diagnostic challenges inherent to this heterogeneous disorder, and discuss the genetics and treatment approaches of these complex lesions.

PMID:36154495 | DOI:10.1177/23247096221123146

Nat Genet. 2022 Sep 26. doi: 10.1038/s41588-022-01180-2. Online ahead of print.

ABSTRACT

Accurate somatic mutation detection from single-cell DNA sequencing is challenging due to amplification-related artifacts. To reduce this artifact burden, an improved amplification technique, primary template-directed amplification (PTA), was recently introduced. We analyzed whole-genome sequencing data from 52 PTA-amplified single neurons using SCAN2, a new genotyper we developed to leverage mutation signatures and allele balance in identifying somatic single-nucleotide variants (SNVs) and small insertions and deletions (indels) in PTA data. Our analysis confirms an increase in nonclonal somatic mutation in single neurons with age, but revises the estimated rate of this accumulation to 16 SNVs per year. We also identify artifacts in other amplification methods. Most importantly, we show that somatic indels increase by at least three per year per neuron and are enriched in functional regions of the genome such as enhancers and promoters. Our data suggest that indels in gene-regulatory elements have a considerable effect on genome integrity in human neurons.

PMID:36163278 | DOI:10.1038/s41588-022-01180-2

Genes (Basel). 2022 Sep 9;13(9):1619. doi: 10.3390/genes13091619.

ABSTRACT

BACKGROUND: Fabry disease (FD, OMIM #301500) is a rare, progressive, X-linked, inherited genetic disease caused by a functional deficiency of lysosomal α-galactosidase, leading to the accumulation of glycosphingolipids in virtually all of the body's cell types and fluids. Patients with rare genetic diseases and non-specific symptoms often experience substantial diagnostic delays, which can negatively impact the prompt initiation of treatment. If FD is not treated specifically, end organ damage (such as chronic renal failure, hypertrophic cardiomyopathy with arrhythmia, and strokes) impairs quality of life and reduces life expectancy.

PATIENTS AND METHODS: For 83 consecutive patients with FD referred to the Russian reference center for lysosomal storage diseases, family trees were built and genetic testing (cascade genotyping) was offered to family members.

RESULTS: The pathogenic GLA variant associated with FD was identified for all 83 probands. Family testing using cascade genotyping enabled the identification of 165 additional cases of FD among the tested 331 at-risk family members.

DISCUSSION: This is the first study to have described family screening in a large Russian cohort of patients with FD and chronic kidney disease. Raising awareness of FD among clinicians is important for earlier diagnosis and specific treatment.

PMID:36140787 | PMC:PMC9498688 | DOI:10.3390/genes13091619

Am J Med Genet C Semin Med Genet. 2022 Jun;190(2):156-161. doi: 10.1002/ajmg.c.32001. Epub 2022 Sep 22.

ABSTRACT

The National MPS Society, Inc., founded in 1974, is a rare disease advocacy non-profit with a tripartite mission addressing the needs of the mucopolysaccharidosis and mucolipidosis communities through advocacy, research, and family and patient support. The Recommended Uniform Screening Panel (RUSP) of conditions for newborn screening (NBS), legislatively mandated in 2008, was implemented in 2010 by the Secretary of Health and Human Services (HSS), through the adoption of 29 core conditions. Since its inception the RUSP has grown to 35 core conditions. Each addition followed a defined nomination process that has itself undergone further definition over time. Since the adoption of the RUSP, the Society has nominated two conditions that have been approved by the Advisory Committee on Heritable Disorders in Children and Newborns (ACHDNC) and forwarded to the Secretary of HSS for inclusion on the RUSP. This history places the Society in a position to reflect on the process of successfully nominating conditions. Additionally, the Society is well placed by this experience to provide observations on the RUSP process. We will highlight best practices for pending and future nominations and reflect on potential improvements to the process and infrastructure of NBS, the RUSP, and the ACHDNC.

PMID:36135708 | DOI:10.1002/ajmg.c.32001

J Med Chem. 2022 Sep 22. doi: 10.1021/acs.jmedchem.2c01106. Online ahead of print.

ABSTRACT

LIMKs are important regulators of actin and microtubule dynamics, and they play essential roles in many cellular processes. Deregulation of LIMKs has been linked to the development of diverse diseases, including cancers and cognitive disabilities, but well-characterized inhibitors known as chemical probes are still lacking. Here, we report the characterization of three highly selective LIMK1/2 inhibitors covering all canonical binding modes (type I/II/III) and the structure-based design of the type II/III inhibitors. Characterization of these chemical probes revealed a low nanomolar affinity for LIMK1/2, and all inhibitors 1 (LIMKi3; type I), 48 (TH470; type II), and 15 (TH257; type III) showed excellent selectivity in a comprehensive scanMAX kinase selectivity panel. Phosphoproteomics revealed remarkable differences between type I and type II inhibitors compared with the allosteric inhibitor 15. In phenotypic assays such as neurite outgrowth models of fragile X-chromosome, 15 showed promising activity, suggesting the potential application of allosteric LIMK inhibitors treating this orphan disease.

PMID:36136092 | DOI:10.1021/acs.jmedchem.2c01106

Nervenarzt. 2022 Oct;93(10):1062-1073. doi: 10.1007/s00115-022-01393-0.

ABSTRACT

Myalgia describes pain in the skeletal muscles. According to the current German clinical guidelines from 2020 (AWMF register number: 030/051), the initial diagnostic assessment consists of the anamnesis, clinical examination, electrophysiological examination and standard laboratory tests. Additional special examinations, such as molecular genetic investigations, special laboratory tests, medical imaging and muscle biopsy are only needed in certain cases. This article focuses on rare neurological diseases that are classically associated with myalgia. In this context etiologically different diseases are considered, whereby some genetically linked diseases (fascioscapulohumeral dystrophy, FSHD, dystrophia myotonica, McArdle's disease, Pompe's disease, limb girdle muscular dystrophy) are contrasted with diseases with an (auto)immune-related pathogenesis (stiff-person syndrome, Isaacs syndrome). The aspects relevant for the diagnosis are particularly highlighted. The therapeutic aspects of the diseases are not part of this article.

PMID:36121449 | DOI:10.1007/s00115-022-01393-0

Biomedica. 2022 Sep 2;42(3):508-521. doi: 10.7705/biomedica.6281.

ABSTRACT

Introduction: Rare diseases are characterized by their low prevalence, chronically debilitating and life-threatening nature. Objective: To determine the characteristics and factors associated with mortality due to rare diseases in Chile from 2002 to 2017. Materials and methods: We conducted an analytical cross-sectional study based on secondary mortality database from the Departamento de Estadística e Información en Salud (DEIS), Ministerio de Salud de Chile (Department of Statistics and Health Information, Chile Ministry of Health) from 2002 to 2017. The specific mortality rates adjusted by age and sex were calculated. A normality analysis was conducted using the Kolmogorov-Smirnov test. In addition, a chi-square test of independence for associations and multivariate logistic regression was applied to determine the probability of death. Results: Between 2008 and 2012 there were 10,718 deaths due to rare diseases, 53.2% of them occurred among women. The average annual mortality rate was 3.9 per 100,000 inhabitants: 4.1 in women and 3.8 in men. The main causes of mortality among women were Creutzfeldt-Jakob disease, anencephaly and autoinmune hepatitis, and among men, Creutzfeldt-Jakob disease, muscular dystrophy and anencephaly. Women are 1.75 times more likely to die than men (adjusted Odds Ratio (aOR) = 1.75; 95% CI: 1.69 - 1.82). The highest probability of dying occurred among children aged 0-4 years (aOR = 15.30; 95% CI: 14.10 - 19.20). Conclusion: Overall, the burden of mortality due to rare disease was higher among women of all ages in Chile between 2002 and 2017.

PMID:36122290 | DOI:10.7705/biomedica.6281

Front Endocrinol (Lausanne). 2022 Aug 30;13:947708. doi: 10.3389/fendo.2022.947708. eCollection 2022.

ABSTRACT

BACKGROUND: This research aimed to build an m6A-associated lncRNA prognostic model of esophageal cancer that can be used to predict outcome in esophageal cancer patients.

METHODS: RNA sequencing transcriptome data and clinical information about patients with esophageal cancer were obtained according to TCGA. Twenty-four m6A-associated genes were selected based on previous studies. m6A-associated lncRNAs were determined through Pearson correlation analysis. Three m6A-associated lncRNA prognostic signatures were built through analysis of the training set using univariate, LASSO, and multivariate Cox regression. To validate the stabilization of the risk signature, Kaplan-Meier and ROC curve analyses were performed on the testing and complete sets. The prognoses of EC patients were predicted quantitatively by building a nomogram. GSEA was conducted to analyze the underlying signaling pathways and biological processes. To identify the underlying mechanisms through which the lncRNAs act, we constructed a PPI network and a ceRNA network and conducted GO and KEGG pathway analyses. EC samples were evaluated using the ESTIMATE algorithm to compute stromal, immune, and estimate scores. The ssGSEA algorithm was used to quantitatively infer immune cell infiltration and immune functions. The TIDE algorithm was performed to simulate immune evasion and predict the response to immunotherapy.

RESULTS: We identified and validated an m6A-associated lncRNA risk model in EC that could correctly and reliably predict the OS of EC patients. The ceRNA network, PPI network, and GO and KEGG pathway analyses confirmed and the underlying mechanisms and functions provided enlightenment regarding therapeutic strategies for EC. Immunotherapy responses were better in the low-risk subgroup, and PD-1 and CTLA4 checkpoint immunotherapy benefited the patients in the low-risk subgroup.

CONCLUSIONS: We constructed a new m6A-related lncRNA prognostic risk model of EC, based on three m6A-related lncRNAs: LINC01612, AC025166.1 and AC016876.2, that can predict the prognoses of EC patients.

PMID:36111294 | PMC:PMC9468245 | DOI:10.3389/fendo.2022.947708

Trials. 2022 Sep 15;23(1):783. doi: 10.1186/s13063-022-06713-y.

ABSTRACT

BACKGROUND: Academic-sponsored trials for rare diseases face many challenges; the present paper identifies hurdles in the set-up of six multinational clinical trials for drug repurposing, as use cases.

METHODS: Six academic-sponsored multinational trials aiming to generate knowledge on rare diseases drug repurposing were used as examples to identify problems in their set-up. Coordinating investigators leading these trials provided feedback on hurdles linked to study, country, and site set up, on the basis of pre-identified categories established through the analysis of previous peer-reviewed publications.

RESULTS: Administrative burden and lack of harmonization for trial-site agreements were deemed as a major hurdle. Other main identified obstacles included the following: (1) complexity and restriction on the use of public funding, especially in a multinational set up, (2) drug supply, including procurement tendering rules and country-specific requirements for drug stability, and (3) lack of harmonization on regulatory requirements to get trial approvals.

CONCLUSION: A better knowledge of the non-commercial clinical research landscape and its challenges and requirements is needed to make drugs-especially those with less commercial gain-accessible to rare diseases patients. Better information about existing resources like research infrastructures, clinical research programs, and counseling mechanisms is needed to support and guide clinicians through the many challenges associated to the set-up of academic-sponsored multinational trials.

PMID:36109818 | PMC:PMC9479412 | DOI:10.1186/s13063-022-06713-y

Sci Rep. 2022 Sep 15;12(1):15497. doi: 10.1038/s41598-022-19707-2.

ABSTRACT

Alpha-1 antitrypsin deficiency (AATD, OMIM #613490) is a rare metabolic disorder affecting lungs and liver. The purpose of this study is to assess the impact of the US orphan drug act on AATD by providing a quantitative clinical-regulatory insight into the status of FDA orphan drug approvals and designations for compounds intended to treat AATD. This is across-sectional analysis of the FDA database for orphan drug designations. Primary endpoint: orphan drug approvals. Secondary endpoint: orphan drug designations by the FDA. Close of database was 16 July 2021. STROBE criteria were respected. Primary outcome: one compound, alpha-1-proteinase inhibitor (human) was approved as an orphan drug in 1987 with market exclusivity until 1994. Secondary outcome: sixteen compounds received FDA orphan drug designation including protein, anti-inflammatory, mucolytic, gene, or cell therapy. Drug development activities in AATD were comparable to other rare conditions and led to the FDA-approval of one compound, based on a relatively simple technological platform. The current unmet medical need to be addressed are extrapulmonary manifestations, in this case the AATD-associated liver disease. Orphan drug development is actually focusing on (1) diversified recombinant AAT production platforms, and (2) innovative gene therapies, which may encompass a more holistic therapeutic approach.

PMID:36109566 | PMC:PMC9477815 | DOI:10.1038/s41598-022-19707-2

Medicine (Baltimore). 2022 Sep 2;101(35):e30414. doi: 10.1097/MD.0000000000030414.

ABSTRACT

RATIONALE: A uterine tumor resembling an ovarian sex cord tumor (UTROSCT) is a clinically rare disease with an unclear origin and biological behavior.

PATIENT CONCERNS: We present a case of UTROSCT in a 42-year-old woman who presented with abnormally increased menstrual volume for 2 years.

DIAGNOSES: Initially, only ultrasound examination was performed to diagnose uterine fibroids, and then the tumor was surgically removed and sent for pathological examination. The patient was ultimately diagnosed with UTROSCT mainly based on pathological immunohistochemical examination and was further diagnosed with low malignant potential for recurrence based on genetic testing.

INTERVENTIONS AND OUTCOMES: The patient underwent hysterectomy and bilateral adnexectomy, and no adjuvant radiotherapy or chemotherapy was performed after the surgery. Follow-up to date has indicated that she is in good condition.

LESSONS: UTROSCT is a rare disease that requires pathological immunohistochemical examination to confirm the diagnosis and genetic testing when necessary so that a clear diagnosis can inform better decision-making regarding treatment measures.

PMID:36107540 | PMC:PMC9439761 | DOI:10.1097/MD.0000000000030414