N Engl J Med. 2023 Jun 22. doi: 10.1056/NEJMe2304147. Online ahead of print.

NO ABSTRACT

PMID:37345865 | DOI:10.1056/NEJMe2304147

Orphanet J Rare Dis. 2023 Jun 21;18(1):154. doi: 10.1186/s13023-023-02771-w.

ABSTRACT

BACKGROUND: During the COVID-19 pandemic people affected by rare diseases (RD) or caregiver of affected children have faced additional challenges. The pandemic has affected physical and mental health, social life and has led to financial consequences. Our objectives were to identify the impact of COVID-19 (1) on health care and (2) on daily life and participation of patients with RDs or caregivers from the perspective of representatives of patient organizations. Moreover, we explored their perspective on experiences of pandemic stress and resources during the pandemic.

RESULTS: We conducted 18 semi-structured interviews with representatives of patient organizations (e.g. chairperson, members of the steering committee), who were asked about the experiences of their members. The interviews were transcribed verbatim and analyzed using the framework approach. We contextualized our findings on the basis of the International Classification of Functioning, Disability and Health (ICF) model and adapted it according to identified subthemes. Patients and caregivers were confronted with aspects of pandemic stress such as lack of information, access and information regarding vaccination and being a risk group for COVID-19 infection. Physical and mental functioning was reported to be negatively impacted. Lock downs and contact restrictions led, e.g., to increasing lack of nursing services or lack of necessary informal support. Participation e.g. in social life and work was reduced. Health care services including medical care and supportive care as well as additional therapies were disrupted and greater effort was necessary to organize care. According to participants, central resources were informal support networks, digitalization, patient organizations and individual characteristics.

CONCLUSIONS: Our study highlights the consequences of the COVID-19 pandemic on the situation of people affected by RDs and caregivers. Contextualization of the results into the biopsychosocial model reinforces the impact of the pandemic on health care as well as daily life and participation. Major challenges and difficulties were experienced during lockdowns and contact restrictions. Depending on the risk of an infection with COVID-19, certain patient groups were still isolated and reduced social contacts or still followed strict hygienic measures (e.g., wearing medical masks). Future pandemic control measures, e.g. on lockdowns and closing facilities, should consider the challenges of people with RDs and caregivers of affected children.

PMID:37344904 | DOI:10.1186/s13023-023-02771-w

J Investig Med High Impact Case Rep. 2023 Jan-Dec;11:23247096231181856. doi: 10.1177/23247096231181856.

ABSTRACT

Porphyrias, particularly acute intermittent porphyria (AIP), are rare, inherited disorders of heme synthesis. On the other hand, systemic lupus erythematosus (SLE) is an uncommon autoimmune disease that affects women predominantly. The coexistence of AIP and SLE is rare. We report a case of concomitant diagnosis of AIP and SLE in a 21-year-old woman who presented with recurrent acute abdominal, chest, and back pain associated with nausea and vomiting, followed by arthralgia, multiple joint pain, and rash. Investigations revealed severe hyponatremia related to SIADH (syndrome of inappropriate antidiuretic hormone secretion) with a positive SLE antibody panel and a positive urine screen for porphobilinogen. Molecular test confirmed the diagnosis of AIP with a pathogenic mutation in the HMBS gene.

PMID:37341437 | DOI:10.1177/23247096231181856

Rev Med Suisse. 2023 Jun 21;19(832):1245-1249. doi: 10.53738/REVMED.2023.19.832.1245.

ABSTRACT

In nephrology, rare disorders are frequently encountered. In children, about 60% of the renal disorders are rare, with congenital abnormalities of the kidney and urinary tract disorders (CAKUT), being highly prevalent. In adults, about 22% of the disorders leading to renal replacement therapies are rare and include glomerulonephritis and genetic disorders. Rarity may preclude the rapid and extensive access to care for patients suffering of renal disorders, especially in Switzerland, which is small and fragmented. Only collaborative network and access to databases, shared resources and to specific competence may help patient management. Lausanne and Geneva University Hospitals have started specialized outpatient clinics for rare renal disorders several years ago and are part of national and international networks.

PMID:37341318 | DOI:10.53738/REVMED.2023.19.832.1245

Am J Bioeth. 2023 Jul;23(7):97-99. doi: 10.1080/15265161.2023.2208073.

NO ABSTRACT

PMID:37339318 | DOI:10.1080/15265161.2023.2208073

Am J Bioeth. 2023 Jul;23(7):100-102. doi: 10.1080/15265161.2023.2207514.

NO ABSTRACT

PMID:37339313 | DOI:10.1080/15265161.2023.2207514

Am J Bioeth. 2023 Jul;23(7):83-85. doi: 10.1080/15265161.2023.2207512.

NO ABSTRACT

PMID:37339309 | DOI:10.1080/15265161.2023.2207512

Am J Bioeth. 2023 Jul;23(7):94-96. doi: 10.1080/15265161.2023.2207511.

NO ABSTRACT

PMID:37339308 | DOI:10.1080/15265161.2023.2207511

Am J Bioeth. 2023 Jul;23(7):91-94. doi: 10.1080/15265161.2023.2207509.

NO ABSTRACT

PMID:37339297 | DOI:10.1080/15265161.2023.2207509

Am J Bioeth. 2023 Jul;23(7):79-82. doi: 10.1080/15265161.2023.2207542.

NO ABSTRACT

PMID:37339296 | DOI:10.1080/15265161.2023.2207542

Am J Bioeth. 2023 Jul;23(7):86-88. doi: 10.1080/15265161.2023.2207540.

NO ABSTRACT

PMID:37339294 | DOI:10.1080/15265161.2023.2207540

Am J Bioeth. 2023 Jul;23(7):88-91. doi: 10.1080/15265161.2023.2207521.

NO ABSTRACT

PMID:37339288 | DOI:10.1080/15265161.2023.2207521

Ann Ist Super Sanita. 2023 Apr-Jun;59(2):122-131. doi: 10.4415/ANN_23_02_05.

ABSTRACT

OBJECTIVES: Gender differences in caregiving may determine social and/or health inequalities among family caregivers (FCs). This study aimed to analyse gender specific differences of burden and quality of life (QoL) in FCs belonging to ten different rare diseases (RD).

METHODS: Burden levels and QoL data, derived from a sample of 210 FCs of RD patients, were analysed by student t-test, Anova and Kruskal-Wallis followed by multiple comparisons and evaluation of factors, including sex, by correlation and multiple regression analyses.

RESULTS: FCs caring for Prader Willi, X-fragile, mucopolysaccharidosis and epidermolysis bullosa patients showed significant higher levels of burden as compared to other RDs. Burden is related to FC's QoL and can be down modulated by the reduction of the number of hours/week devoted to care and by the improvement of patient's QoL. No gender-specific burden differences were observed among all FCs. However, female FCs devoted to care significant more numerous hours/week than men and perceived more emotional/physical burden and poorer psychological health than males. Women, who are more frequently early retired from work, not occupied or homemakers than men, suffered more burden as compared to men in the same conditions.

CONCLUSIONS: This study showed gender specific differences in RD caregiving, which are important for planning personalized health prevention policies.

PMID:37337987 | DOI:10.4415/ANN_23_02_05

Spine J. 2023 Jun 18:S1529-9430(23)00233-4. doi: 10.1016/j.spinee.2023.06.005. Online ahead of print.

ABSTRACT

BACKGROUND CONTEXT: Intervertebral disc degeneration (IVDD) is an incurable, specific treatment-orphan disease with an increasing burden worldwide. Although great efforts have been made to develop new regenerative therapies, their clinical success is limited.

PURPOSE: Characterize the metabolomic and gene expression changes underpinning human disc degeneration. This study also aimed to disclose new molecular targets for developing and optimizing novel biological approaches for IVDD.

STUDY DESIGN: Intervertebral disc cells were obtained from IVDD patients undergoing circumferential arthrodesis surgery or from healthy subjects. Mimicking the harmful microenvironment of degenerated discs, cells isolated from the nucleus pulposus (NP) and annulus fibrosus (AF) were exposed to the pro-inflammatory cytokine IL-1β and the adipokine leptin. The metabolomic signature and molecular profile of human disc cells were unraveled for the first time.

METHODS: The metabolomic and lipidomic profiles of IVDD and healthy disc cells were analyzed by high-performance liquid chromatography-mass spectrometry (UHPLC-MS). Gene expression was investigated by SYBR green-based quantitative real-time RT-PCR. Altered metabolites and gene expression were documented.

RESULTS: Lipidomic analysis revealed decreased levels of triacylglycerols (TG), diacylglycerol (DG), fatty acids (FA), phosphatidylcholine (PC), lysophosphatidylinositols (LPI) and sphingomyelin (SM), and increased levels of bile acids (BA) and ceramides, likely promoting disc cell metabolism changing from glycolysis to fatty acid oxidation and following cell death. The gene expression profile of disc cells suggests LCN2 and LEAP2/GHRL as promising molecular therapeutic targets for disc degeneration and demonstrates the expression of genes related to inflammation (NOS2, COX2, IL-6, IL-8, IL-1β, and TNF-α) or encoding adipokines (PGRN, NAMPT, NUCB2, SERPINE2, and RARRES2), matrix metalloproteinases (MMP9 and MMP13), and vascular adhesion molecules (VCAM1).

CONCLUSIONS: Altogether, the presented results disclose the NP and AF cell biology changes from healthy to degenerated discs, allowing the identification of promising molecular therapeutic targets for intervertebral disc degeneration.

CLINICAL SIGNIFICANCE: Our results are relevant to improving current biological-based strategies aiming to repair IVD by restoring cellular lipid metabolites as well as adipokines homeostasis. Ultimately, our results will be valuable for successful, long-lasting relief of painful IVDD.

PMID:37339697 | DOI:10.1016/j.spinee.2023.06.005

HGG Adv. 2023 May 18;4(3):100206. doi: 10.1016/j.xhgg.2023.100206. eCollection 2023 Jul 13.

ABSTRACT

DHPS deficiency is a rare genetic disease caused by biallelic hypomorphic variants in the Deoxyhypusine synthase (DHPS) gene. The DHPS enzyme functions in mRNA translation by catalyzing the post-translational modification, and therefore activation, of eukaryotic initiation factor 5A (eIF5A). The observed clinical outcomes associated with human mutations in DHPS include developmental delay, intellectual disability, and seizures. Therefore, to increase our understanding of this rare disease, it is critical to determine the mechanisms by which mutations in DHPS alter neurodevelopment. In this study, we have generated patient-derived lymphoblast cell lines and demonstrated that human DHPS variants alter DHPS protein abundance and impair enzyme function. Moreover, we observe a shift in the abundance of the post-translationally modified forms of eIF5A; specifically, an increase in the nuclear localized acetylated form (eIF5AAcK47) and concomitant decrease in the cytoplasmic localized hypusinated form (eIF5AHYP). Generation and characterization of a mouse model with a genetic deletion of Dhps in the brain at birth shows that loss of hypusine biosynthesis impacts neuronal function due to impaired eIF5AHYP-dependent mRNA translation; this translation defect results in altered expression of proteins required for proper neuronal development and function. This study reveals new insight into the biological consequences and molecular impact of human DHPS deficiency and provides valuable information toward the goal of developing treatment strategies for this rare disease.

PMID:37333770 | PMC:PMC10275725 | DOI:10.1016/j.xhgg.2023.100206

iScience. 2023 May 19;26(7):106909. doi: 10.1016/j.isci.2023.106909. eCollection 2023 Jul 21.

ABSTRACT

Characterizing perturbation of molecular pathways in congenital Zika virus (ZIKV) infection is critical for improved therapeutic approaches. Leveraging integrative systems biology, proteomics, and RNA-seq, we analyzed embryonic brain tissues from an immunocompetent, wild-type congenital ZIKV infection mouse model. ZIKV induced a robust immune response accompanied by the downregulation of critical neurodevelopmental gene programs. We identified a negative correlation between ZIKV polyprotein abundance and host cell cycle-inducing proteins. We further captured the downregulation of genes/proteins, many of which are known to be causative for human microcephaly, including Eomesodermin/T-box Brain Protein 2 (EOMES/TBR2) and Neuronal Differentiation 2 (NEUROD2). Disturbances of distinct molecular pathways in neural progenitors and post-mitotic neurons may contribute to complex brain phenotype of congenital ZIKV infection. Overall, this report on protein- and transcript-level dynamics enhances understanding of the ZIKV immunopathological landscape through characterization of fetal immune response in the developing brain.

PMID:37332674 | PMC:PMC10275723 | DOI:10.1016/j.isci.2023.106909

Arthritis Care Res (Hoboken). 2023 Jun 18. doi: 10.1002/acr.25171. Online ahead of print.

ABSTRACT

OBJECTIVES: Juvenile systemic sclerosis (jSSc) is an orphan disease, associated with high morbidity and mortality. New treatment strategies are much needed, but it is necessary to clearly define appropriate outcomes if successful therapies are to be developed. Here, such outcomes are proposed.

METHODS: This proposal is the result of four face to face consensus meetings with a 27-member multidisciplinary team of pediatric rheumatologists, adult rheumatologists, dermatologists, pediatric cardiologists, pulmonologists, gastroenterologists, statistician and patients. Throughout the process, we reviewed the existing adult data in this field, the more limited pediatric literature for jSSc outcomes and data from two jSSc patient cohorts to assist in making informed, data-driven decisions. The use of items for each domain as an outcome measure in an open 12-month clinical trial of jSSc was voted and agreed upon using a nominal group technique.

RESULTS: After voting, the agreed domains were: global disease activity, skin, Raynaud's phenomenon, digital ulcers, musculoskeletal, cardiac, pulmonary, renal, gastrointestinal, and quality of life. Fourteen outcome measures had 100% agreement, one item had 91% agreement and one item had 86% agreement. The domains of biomarker and growth/development were moved to the research agenda.

CONCLUSION: We reached consensus on multiple domains and items which should be assessed in an open label 12-month clinical jSSc trial as well as a research agenda for future development. This article is protected by copyright. All rights reserved.

PMID:37332054 | DOI:10.1002/acr.25171

BMC Med Res Methodol. 2023 Jun 17;23(1):143. doi: 10.1186/s12874-023-01972-y.

ABSTRACT

BACKGROUND: Up to 8% of the general population have a rare disease, however, for lack of ICD-10 codes for many rare diseases, this population cannot be generically identified in large medical datasets. We aimed to explore frequency-based rare diagnoses (FB-RDx) as a novel method exploring rare diseases by comparing characteristics and outcomes of inpatient populations with FB-RDx to those with rare diseases based on a previously published reference list.

METHODS: Retrospective, cross-sectional, nationwide, multicenter study including 830,114 adult inpatients. We used the national inpatient cohort dataset of the year 2018 provided by the Swiss Federal Statistical Office, which routinely collects data from all inpatients treated in any Swiss hospital. Exposure: FB-RDx, according to 10% of inpatients with the least frequent diagnoses (i.e.1.decile) vs. those with more frequent diagnoses (deciles 2-10). Results were compared to patients having 1 of 628 ICD-10 coded rare diseases.

PRIMARY OUTCOME: In-hospital death.

SECONDARY OUTCOMES: 30-day readmission, admission to intensive care unit (ICU), length of stay, and ICU length of stay. Multivariable regression analyzed associations of FB-RDx and rare diseases with these outcomes.

RESULTS: 464,968 (56%) of patients were female, median age was 59 years (IQR: 40-74). Compared with patients in deciles 2-10, patients in the 1. were at increased risk of in-hospital death (OR 1.44; 95% CI: 1.38, 1.50), 30-day readmission (OR 1.29; 95% CI 1.25, 1.34), ICU admission (OR 1.50; 95% CI 1.46, 1.54), increased length of stay (Exp(B) 1.03; 95% CI 1.03, 1.04) and ICU length of stay (1.15; 95% CI 1.12, 1.18). ICD-10 based rare diseases groups showed similar results: in-hospital death (OR 1.82; 95% CI 1.75, 1.89), 30-day readmission (OR 1.37; 95% CI 1.32, 1.42), ICU admission (OR 1.40; 95% CI 1.36, 1.44) and increased length of stay (OR 1.07; 95% CI 1.07, 1.08) and ICU length of stay (OR 1.19; 95% CI 1.16, 1.22).

CONCLUSION(S): This study suggests that FB-RDx may not only act as a surrogate for rare diseases but may also help to identify patients with rare disease more comprehensively. FB-RDx associate with in-hospital death, 30-day readmission, intensive care unit admission, and increased length of stay and intensive care unit length of stay, as has been reported for rare diseases.

PMID:37330464 | PMC:PMC10276905 | DOI:10.1186/s12874-023-01972-y

BMJ Case Rep. 2023 Jun 14;16(6):e249686. doi: 10.1136/bcr-2022-249686.

ABSTRACT

A man in his 40s with no medical history presented with right-sided abdominal and chest pain. A CT scan of the abdomen demonstrated a 7.7 cm heterogeneous mass arising from the second part of the duodenum. Oesophagogastroduodenoscopy confirmed a malignant-appearing duodenal lesion, with biopsy showing features consistent with small cell carcinoma. The patient underwent three cycles of neoadjuvant chemotherapy, followed by elective Kausch-Whipple pancreaticoduodenectomy. A combination of immunohistochemistry and molecular studies confirmed the diagnosis of a rare Ewing's sarcoma tumour originating from the duodenum with invasion into the duodenal lumen. The patient recovered well from surgery and remains disease-free 18 months following resection.

PMID:37316281 | DOI:10.1136/bcr-2022-249686

Magy Onkol. 2023 Jun 13;67(2):102-105. Epub 2023 Apr 23.

ABSTRACT

The term paraneoplastic syndrome refers to the conditions when tumor-related symptoms are not caused by the size, invasion or metastasis of a tumor, but due to soluble mediators produced or an immune reaction induced by a tumor. Paraneoplastic syndromes occur in about 8% of all malignant tumors. Hormone-related paraneoplastic syndromes are termed paraneoplastic endocrine syndromes. In this short synopsis, the main clinical and laboratory characteristics of the most important paraneoplastic endocrine syndromes are presented including humoral hypercalcemia, the syndrome of inappropriate ADH secretion, ectopic ACTH syndrome. Two very rare diseases, paraneoplastic hypoglycemia and tumor-induced osteomalatia are also briefly presented.

PMID:37314070