ERJ Open Res. 2022 Aug 15;8(3):00139-2022. doi: 10.1183/23120541.00139-2022. eCollection 2022 Jul.

ABSTRACT

Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by impaired mucociliary clearance leading to irreversible lung damage. In contrast to other rare lung diseases like cystic fibrosis (CF), there are only few clinical trials and limited evidence-based treatments. Management is mainly based on expert opinions and treatment is challenging due to a wide range of clinical manifestations and disease severity. To improve clinical and translational research and facilitate development of new treatments, the clinical trial network for PCD (PCD-CTN) was founded in 2020 under the framework of the European Reference Network (ERN)-LUNG PCD Core. Applications from European PCD sites interested in participating in the PCD-CTN were requested. Inclusion criteria consisted of patient numbers, membership of ERN-LUNG PCD Core, use of associated standards of care, experience in PCD and/or CF clinical research, resources to run clinical trials, good clinical practice (GCP) certifications and institutional support. So far, applications from 22 trial sites in 18 European countries have been approved, including >1400 adult and >1600 paediatric individuals with PCD. The PCD-CTN is headed by a coordinating centre and consists of a steering and executive committee, a data safety monitoring board and committees for protocol review, training and standardisation. A strong association with patient organisations and industrial companies are further cornerstones. All participating trial sites agreed on a code of conduct. As CTNs from other diseases have demonstrated successfully, this newly formed PCD-CTN operates to establish evidence-based treatments for this orphan disease and to bring new personalised treatment approaches to patients.

PMID:35983540 | PMC:PMC9379353 | DOI:10.1183/23120541.00139-2022

ACS Pharmacol Transl Sci. 2022 Jul 19;5(8):555-561. doi: 10.1021/acsptsci.2c00125. eCollection 2022 Aug 12.

ABSTRACT

There exists a paucity of information on the pathogenesis of pterygium, a benign ocular tumor that scars the cornea and can lead to vision loss. The main recourse for pterygium is surgery; however, recurrence is observed. Matrix metalloproteinases (MMPs) are involved in the pathology of pterygium. The determination of the specific MMP involved among the 24 human enzymes has not been established due to challenges in MMP profiling. We used an affinity resin that binds specifically to the active forms of MMPs in the complex mixture of the cellular proteome. The proteomics analysis identified active MMP-14 and three related metalloproteinases, ADAM9, ADAM10, and ADAM17, in human pterygia. Inhibition of MMP-14 with the small-molecule inhibitor (R)-ND-336 was assessed in cell migration and collagen contraction assays. (R)-ND-336 attenuated human conjunctiva fibroblast migration and mitigated collagen contraction, both activities required for the formation of pterygium. (R)-ND-336 holds the promise of a therapeutic recourse for pterygium as an orphan disease.

PMID:35983271 | PMC:PMC9380204 | DOI:10.1021/acsptsci.2c00125

Autoimmun Rev. 2022 Aug 15:103180. doi: 10.1016/j.autrev.2022.103180. Online ahead of print.

ABSTRACT

This review of Pemphigoid of the Pulmonary System (POPS) is a comprehensive description of pulmonary involvement in patients with mucous membrane pemphigoid (MMP), which is an orphan autoimmune blistering disease. The objective of the review was to analyze clinical features of pulmonary involvement in MMP. This POPS review is a case series in which multiple search engines were utilized from inception to June 2022 for cases of MMP with biopsy and immunopathology proven tracheal and bronchial pemphigoid. Clinical profiles prior to pulmonary involvement, bronchoscopy findings, clinical course and therapy were recorded and cause of death was analyzed. Patients with documented MMP who developed tracheal, bronchial and pulmonary involvement were included in the POPS review. Histology and immunopathology documentation were essential diagnostic criteria. Comparison groups were not possible. Patients were treated with immunosuppressive therapy. Some required surgical interventions. Six of the 11 patients attained complete or partial remission on or off therapy. Five patients died from pulmonary complications. The POPS review had six females and five males. The mean age at onset was 20 years (range 4-76), while 80% of the patients were under 40 years. All had severe widespread MMP involving three to five mucosal tissues. 100% had oral, 82% had ocular and cutaneous involvement. Pulmonary involvement occurred at 24 mo (range 2-372) after the onset of MMP. Bronchoscopy revealed acute inflammation during active disease and scarring of the trachea and bronchi in the later stages. Systemic infections occurred in 45%, while pulmonary infection occurred in 36%. Mortality due to respiratory failure, at the median age of 20 years (range 18-76), occurred in 45% of the patients, and was considered disease related. In spite of the young age, while there are some similarities in the clinical profile and response to systemic therapy, there are definitive differences from other patients with MMP. Early diagnosis with appropriate management could produce better clinical outcomes and prevent mortality in this orphan disease. Consequently, there is a critical need for early identification and diagnosis of POPS.

PMID:35981700 | DOI:10.1016/j.autrev.2022.103180

Disabil Rehabil. 2022 Aug 18:1-11. doi: 10.1080/09638288.2022.2104943. Online ahead of print.

ABSTRACT

PURPOSE: Adults living with a rare or orphan diseases (ROD) experience common psychosocial difficulties that are often poorly addressed in usual care. This realist literature review aims to inform the development, evaluation and implementation of evidence based group therapy programs adapted to shared needs of patients living with various ROD.

METHOD: The review is based on an analysis of Context-Mechanism-Outcome configurations. It included 21 primary studies published between 2010 and April 2022 and used a PRISMA process for study selection and inclusion.

RESULTS: Our results show that group psychosocial interventions can help reduce perception of symptoms and psychological impacts of disease, improve social functioning and support and quality of life in patients.

CONCLUSION: Group therapy programs seem promising for ROD-patients and should be considered within comprehensive treatment and support plans. However, more comprehensive studies of group therapies in context should aim to identify core active components of these interventions with ROD-patients. Implications for Rehabilitation:Rare or Orphan Diseases are varied, difficult to diagnose and have a major impact on all aspects of the patients' lives (physical, emotional, psychological, social, professional).Psychosocial support is a key but underdeveloped component to support the recovery trajectory for these patients.In this review of group interventions, we identified a few promising practices adaptable to patients living with Rare or Orphan Diseases (Acceptance and commitment therapy, cognitive behavioural therapies, psychoeducational programs).Patients who received psychosocial group interventions are likely to experience improvement in their quality of life.

PMID:35979809 | DOI:10.1080/09638288.2022.2104943

Am J Med Genet A. 2022 Aug 17. doi: 10.1002/ajmg.a.62953. Online ahead of print.

ABSTRACT

Bi-allelic loss-of-function variants in Von Willebrand factor type A (VWA1) were recently discovered to lead to an early onset motor neuropathy or neuromyopathy. What makes this discovery particularly notable is the high frequency of one of the VWA1 (NM_022834.5) founder variants, c.62_71dup (p.Gly25ArgfsTer74), which nears 0.01% in European populations, and suggests that there may be a wide spectrum of disease features and severity. Here, we report two cases from nonconsanguineous families in North America that presented in early childhood with lower extremity weakness and prominent foot deformities, and were found to carry bi-allelic variants in VWA1. We draw focus to upper motor neuron signs and abnormal gait phenotypes as presenting symptoms in VWA1-related disorder and expand the clinical and molecular spectrum.

PMID:35975723 | DOI:10.1002/ajmg.a.62953

Brain Commun. 2022 Aug 4;4(4):fcac197. doi: 10.1093/braincomms/fcac197. eCollection 2022.

ABSTRACT

CDKL5 deficiency disorder is a debilitating developmental and epileptic encephalopathy for which no targeted treatment exists. A number of promising therapeutics are under development for CDKL5 deficiency disorder but a lack of validated biomarkers of brain function and clinical severity may limit the ability to objectively assess the efficacy of new treatments as they become available. To address this need, the current study quantified electrophysiological measures in individuals with CDKL5 deficiency disorder and the association between these parameters and clinical severity. Visual and auditory evoked potentials, as well as resting EEG, were acquired across 5 clinical sites from 26 individuals with CDKL5 deficiency disorder. Evoked potential and quantitative EEG features were calculated and compared with typically developing individuals in an age- and sex-matched cohort. Baseline and Year 1 data, when available, were analysed and the repeatability of the results was tested. Two clinician-completed severity scales were used for evaluating the clinical relevance of the electrophysiological parameters. Group-level comparisons revealed reduced visual evoked potential amplitude in CDKL5 deficiency disorder individuals versus typically developing individuals. There were no group differences in the latency of the visual evoked potentials or in the latency or amplitude of the auditory evoked potentials. Within the CDKL5 deficiency disorder group, auditory evoked potential amplitude correlated with disease severity at baseline as well as Year 1. Multiple quantitative EEG features differed between CDKL5 deficiency disorder and typically developing participants, including amplitude standard deviation, 1/f slope and global delta, theta, alpha and beta power. Several quantitative EEG features correlated with clinical severity, including amplitude skewness, theta/delta ratio and alpha/delta ratio. The theta/delta ratio was the overall strongest predictor of severity and also among the most repeatable qEEG measures from baseline to Year 1. Together, the present findings point to the utility of evoked potentials and quantitative EEG parameters as objective measures of brain function and disease severity in future clinical trials for CDKL5 deficiency disorder. The results also underscore the utility of the current methods, which could be similarly applied to the identification and validation of electrophysiological biomarkers of brain function for other developmental encephalopathies.

PMID:35974796 | PMC:PMC9374482 | DOI:10.1093/braincomms/fcac197

Am J Gastroenterol. 2022 Jun 20. doi: 10.14309/ajg.0000000000001888. Online ahead of print.

NO ABSTRACT

PMID:35973172 | DOI:10.14309/ajg.0000000000001888

Epilepsy Res. 2022 Aug 7;185:106996. doi: 10.1016/j.eplepsyres.2022.106996. Online ahead of print.

ABSTRACT

PURPOSE: Pharmaceutical grade cannabidiol (CBD) is one of the newest anti-seizure medications for refractory epilepsy, and the effects of CBD on EEG have not been fully described.

METHODS: Patients enrolled in a CBD expanded access study had EEGs prior to and 12 weeks after initiation of CBD treatment for their refractory epilepsy. In addition to evaluating the clinical EEG reports, a nonbiased quantitative EEG (qEEG) analysis of background EEG was performed to determine whether consistent changes occur in the EEG in response to administration of CBD.

RESULTS: No significant qualitative changes were seen, nor changes in quantitative markers of EEG amplitude (RMS amplitude, standard deviation of the amplitude, skewness, or kurtosis), frequency (relative delta, theta, or alpha power), Spearman correlation, or coherence between brain regions. However, relative beta power and 1/f slope, a measure of signal noise increased with the addition of CBD. When patients were separated into responders and nonresponders based on seizure reduction with CBD, responders also had decreased Spearman correlation between the frontopolar and occipital regions after addition of CBD, suggesting that responders may have quantitatively improved EEG background organization after CBD initiation. The differences in beta and 1/f slope were also seen more robustly in CBD responders compared with nonresponders after CBD initiation. These differences disappeared when analyzing only patients not taking benzodiazepines, suggesting that the effect of CBD on seizures was related to the ability of the brain to further increase beta in response to CBD in patients already taking benzodiazepines. We noted that even before initiation of CBD, 1/f slope was also significantly different in responders compared to nonresponders. Therefore, to explore the baseline EEG in responders and nonresponders, we utilized a variable selection procedure to identify baseline EEG features that could predict whether a patient's seizures would improve with CBD. In the optimal multivariable logistic model, baseline coherence, Spearman correlation, and patient sex jointly predicted whether a patient in this cohort would respond to CBD (defined as a seizure reduction of 40% or greater) with 74% accuracy. This model performed less well on a data set of reduced duration and variability, highlighting the importance of real-world testing of any clinically relevant model.

CONCLUSION: These results suggest that there are subtle changes in certain metrics detected by qEEG even at baseline that may not be perceived during qualitative EEG analysis and that could be used in the future as a biomarker to predict a patient's clinical response to CBD administration. Development of such a predictive EEG biomarker, especially before the initiation of a medication trial, could reduce unnecessary ASM exposure and improve outcomes for patients with epilepsy facing new medication selection.

PMID:35963151 | DOI:10.1016/j.eplepsyres.2022.106996

Molecules. 2022 Aug 7;27(15):5023. doi: 10.3390/molecules27155023.

ABSTRACT

Bladder cancer is one of most common types of cancer diagnosed in the genitourinary tract. Typical tests are costly and characterized by low sensitivity, which contributes to a growing interest in volatile biomarkers. Head space solid phase microextraction (SPME) was applied for the extraction of volatile organic compounds from urine samples, and gas chromatography time of flight mass spectrometry (GC×GC TOF MS) was used for the separation and detection of urinary volatiles. A cohort of 40 adult patients with bladder cancer and 57 healthy persons was recruited. Different VOC profiles were obtained for urine samples taken from each group. Twelvecompounds were found only in the samples from theBC group.The proposed candidate biomarkers are butyrolactone; 2-methoxyphenol; 3-methoxy-5-methylphenol; 1-(2,6,6-trimethylcyclohexa-1,3-dien-1-yl)-2-buten-1-one; nootkatone and 1-(2,6,6-trimethyl-1-cyclohexenyl)-2-buten-1-one.Since most of the studies published in the field are proving the potential of VOCs detected in urine samples for the screening and discrimination of patients with bladder cancer from healthy, but rarely presenting the identity of proposed biomarkers, our study represents a novel approach.

PMID:35956972 | PMC:PMC9370153 | DOI:10.3390/molecules27155023

Int J Mol Sci. 2022 Aug 8;23(15):8803. doi: 10.3390/ijms23158803.

ABSTRACT

Tyrosine kinase substrate with four SH3 domains (Tks4) scaffold protein plays roles in cell migration and podosome formation and regulates systemic mechanisms such as adult bone homeostasis and adipogenesis. Mutations in the Tks4 gene (SH3PXD2b) cause a rare developmental disorder called Frank-Ter Haar syndrome (FTHS), which leads to heart abnormalities, bone tissue defects, and reduced adiposity. We aimed to produce a human stem cell-based in vitro FTHS model system to study the effects of the loss of the Tks4 protein in different cell lineages and the accompanying effects on the cell signalome. To this end, we used CRISPR/Cas9 (clustered, regularly interspaced, short palindromic repeats (CRISPR)/CRISPR associated (Cas9)) to knock out the SH3PXD2b gene in the HUES9 human embryonic stem cell line (hESC), and we obtained stable homo- and heterozygous knock out clones for use in studying the potential regulatory roles of Tks4 protein in embryonic stem cell biology. Based on pluripotency marker measurements and spontaneous differentiation capacity assays, we concluded that the newly generated Tks4-KO HUES9 cells retained their embryonic stem cell characteristics. We propose that the Tks4-KO HUES9 cells could serve as a tool for further cell differentiation studies to investigate the involvement of Tks4 in the complex disorder FTHS. Moreover, we successfully differentiated all of the clones into mesenchymal stem cells (MSCs). The derived MSC cultures showed mesenchymal morphology and expressed MSC markers, although the expression levels of mesodermal and osteogenic marker genes were reduced, and several EMT (epithelial mesenchymal transition)-related features were altered in the Tks4-KO MSCs. Our results suggest that the loss of Tks4 leads to FTHS by altering cell lineage differentiation and cell maturation processes, rather than by regulating embryonic stem cell potential.

PMID:35955935 | PMC:PMC9369304 | DOI:10.3390/ijms23158803

Int J Mol Sci. 2022 Aug 5;23(15):8725. doi: 10.3390/ijms23158725.

ABSTRACT

Advances in research have boosted therapy development for congenital disorders of glycosylation (CDG), a group of rare genetic disorders affecting protein and lipid glycosylation and glycosylphosphatidylinositol anchor biosynthesis. The (re)use of known drugs for novel medical purposes, known as drug repositioning, is growing for both common and rare disorders. The latest innovation concerns the rational search for repositioned molecules which also benefits from artificial intelligence (AI). Compared to traditional methods, drug repositioning accelerates the overall drug discovery process while saving costs. This is particularly valuable for rare diseases. AI tools have proven their worth in diagnosis, in disease classification and characterization, and ultimately in therapy discovery in rare diseases. The availability of biomarkers and reliable disease models is critical for research and development of new drugs, especially for rare and heterogeneous diseases such as CDG. This work reviews the literature related to repositioned drugs for CDG, discovered by serendipity or through a systemic approach. Recent advances in biomarkers and disease models are also outlined as well as stakeholders' views on AI for therapy discovery in CDG.

PMID:35955863 | PMC:PMC9369176 | DOI:10.3390/ijms23158725

J Cancer Res Clin Oncol. 2022 Aug 12. doi: 10.1007/s00432-022-04223-7. Online ahead of print.

ABSTRACT

PURPOSE: Anaplastic thyroid carcinoma (ATC) is an orphan disease with a fatal outcome. Surgery to the primary tumor in metastatic ATC is controversial. Determination of specific surgical techniques may help facilitate local control and, hence, beneficial overall and disease-specific survival.

METHODS: Using individualized patient data derived from our systematic review of literature and our single center study (n = 123), conducting a Surveillance, Epidemiology, and End Results register (SEER)-based study (n = 617) we evaluated surgery, its combination with systemic and local therapies in metastatic ATC.

RESULTS: Pooled cohort study showed surgery (p < 0.001), RT ≥ 30 Gy (p < 0.001), ChT (p < 0.001) and multimodal treatment (p = 0.014) to result in improved OS univariately. In the multivariate analysis, surgery (1.997 [1.162-3.433], p = 0.012) and RT ≥ 30 Gy (1.877 [1.232-2.843], p = 0.012) were independent predictors for OS. In SEER-based study of patients undergoing any tumor-directed treatment (n = 445) total thyroidectomy (p = 0.031), administration of ChT (p = 0.007), RT (p < 0.001), combination of surgery and RT ± ChT (p < 0.001) and multimodal treatment (p < 0.001) correlated with an improved DSS univariately. On the multivariate analysis, debulking surgery was an independent predictor for a worse outcome (HR 0.535, 95%CI 0.332-0.862, p = 0.010), whereas RT administration correlated with a longer DSS (HR 2.316, 95%CI 1.362-3.939, p = 0.002). Among operated patients from SEER register total thyroidectomy (p = 0.031), ChT (p = 0.007), RT (p < 0.001), combination of surgery and RT ± ChT (p < 0.001) and multimodal treatment (p < 0.001) correlated with an improved DSS in the univariate analysis, whereas debulking surgery was inversely correlated with the DSS (p < 0.001). On the multivariate analysis, debulking surgery was an independent predictor for a worse DSS (HR 0.535, 95%CI 0.332-0.862, p = 0.010), whilst RT administration correlated with a longer DSS (HR 2.316, 95%CI 1.362-3.939, p = 0.002).

CONCLUSIONS: Surgery to the primary tumor with the aim of R0/R1 resection, but not debulking, is associated with a significant OS and DSS benefit even in systemically metastasized disease.

PMID:35960373 | DOI:10.1007/s00432-022-04223-7

Pan Afr Med J. 2022 May 18;42:48. doi: 10.11604/pamj.2022.42.48.29515. eCollection 2022.

NO ABSTRACT

PMID:35949470 | PMC:PMC9338714 | DOI:10.11604/pamj.2022.42.48.29515

J Comp Eff Res. 2022 Oct;11(14):999-1010. doi: 10.2217/cer-2022-0120. Epub 2022 Aug 10.

ABSTRACT

Scientific advancements, new US FDA approval pathways and limited competition have contributed to rapid growth in the number of approved rare disease treatments in recent years. While the rising numbers of orphan drug approvals are a sign of success, the rapid growth in approved rare disease treatments has created concerns about the pricing of orphan drugs and their cumulative affordability to the health system. To support efforts to build a policy and practice infrastructure that drives innovation within a platform that is affordable to patients and the health system, this paper provides an analysis of potential risks as well as advantages of reform options related to drug development, pricing and coverage.

PMID:35946484 | DOI:10.2217/cer-2022-0120

JMIR Mhealth Uhealth. 2022 Aug 10;10(8):e38331. doi: 10.2196/38331.

ABSTRACT

BACKGROUND: Large gaps exist in understanding the symptomatic and functional impact of sarcoidosis, a rare multisystem granulomatous disease affecting fewer than 200,000 individuals in the United States. Smartphones could be used for prospective research, especially for rare diseases where organizing large cohorts can be challenging, given their near ubiquitous ownership and ability to track objective and subjective data with increasingly sophisticated technology.

OBJECTIVE: We aimed to investigate whether smartphones could assess the quality of life (QoL) and physical activity of a large cohort of individuals with sarcoidosis.

METHODS: We developed a mobile app (Sarcoidosis App) for a prospective, cross-sectional study on individuals with sarcoidosis. The Sarcoidosis App was made available on both Apple and Android smartphones. Individuals with sarcoidosis were recruited, consented, and enrolled entirely within the app. Surveys on sarcoidosis history, medical history, and medications were administered. Patients completed modules from the Sarcoidosis Assessment Tool, a validated patient-reported outcomes assessment of physical activity, fatigue, pain, skin symptoms, sleep, and lungs symptoms. Physical activity measured by smartphones was tracked as available.

RESULTS: From April 2018 to May 2020, the App was downloaded 2558 times, and 629 individuals enrolled (404, 64.2% female; mean age 51 years; 513, 81.6% White; 86, 13.7% Black). Two-thirds of participants had a college or graduate degree, and more than half of them reported an income greater than US $60,000. Both QoL related to physical activity (P<.001, ρ=0.250) and fatigue (P<.01, ρ=-0.203) correlated with actual smartphone-tracked physical activity. Overall, 19.0% (98/517) of participants missed at least 1 week of school or work in an observed month owing to sarcoidosis, and 44.4% (279/629) reported that finances "greatly" or "severely" affected by sarcoidosis. Furthermore, 71.2% (437/614) of participants reported taking medications for sarcoidosis, with the most common being prednisone, methotrexate, hydroxychloroquine, and infliximab. Moreover, 46.4% (244/526) reported medication side effects, most commonly due to prednisone.

CONCLUSIONS: We demonstrate that smartphones can prospectively recruit, consent, and study physical activity, QoL, and medication usage in a large sarcoidosis cohort, using both passively collected objective data and qualitative surveys that did not require any in-person encounters. Our study's limitations include the study population being weighted toward more educated and wealthier individuals, suggesting that recruitment was not representative of the full spectrum of patients with sarcoidosis in the United States. Our study provides a model for future smartphone-enabled clinical research for rare diseases and highlights key technical challenges that future research teams interested in smartphone-based research for rare diseases should anticipate.

PMID:35947439 | DOI:10.2196/38331

Genome Med. 2022 Aug 9;14(1):85. doi: 10.1186/s13073-022-01094-y.

ABSTRACT

BACKGROUND: Rare diseases collectively affect up to 10% of the population, but often lack effective treatment, and typically little is known about their pathophysiology. Major challenges include suboptimal phenotype mapping and limited statistical power. Population biobanks, such as the UK Biobank, recruit many individuals who can be affected by rare diseases; however, investigation into their utility for rare disease research remains limited. We hypothesized the UK Biobank can be used as a unique population assay for rare diseases in the general population.

METHODS: We constructed a consensus mapping between ICD-10 codes and ORPHA codes for rare diseases, then identified individuals with each rare condition in the UK Biobank, and investigated their age at recruitment, sex bias, and comorbidity distributions. Using exome sequencing data from 167,246 individuals of European ancestry, we performed genetic association controlling for case/control imbalance (SAIGE) to identify potential rare pathogenic variants for each disease.

RESULTS: Using our mapping approach, we identified and characterized 420 rare diseases affecting 23,575 individuals in the UK Biobank. Significant genetic associations included JAK2 V617F for immune thrombocytopenic purpura (p = 1.24 × 10-13) and a novel CALR loss of function variant for essential thrombocythemia (p = 1.59 × 10-13). We constructed an interactive resource highlighting demographic information ( http://www-personal.umich.edu/~mattpat/rareDiseases.html ) and demonstrate transferability by applying our mapping to a medical claims database.

CONCLUSIONS: Enhanced disease mapping and increased power from population biobanks can elucidate the demographics and genetic associations for rare diseases.

PMID:35945607 | DOI:10.1186/s13073-022-01094-y

Am J Physiol Cell Physiol. 2022 Aug 8. doi: 10.1152/ajpcell.00356.2021. Online ahead of print.

ABSTRACT

Hematopoietic cells are instrumental in generating and propagating protective inflammatory responses to infection or injury. However, excessive inflammation contributes to many diseases of the blood, bone marrow, and lymphatic system. We review three clinical categories of hematological inflammatory diseases in which recent clinical and translational advances have been made. The first category are monogenic inflammatory diseases. Genotype-driven research has revealed that previously mysterious diseases with protean manifestations are characterized by mutations which may be germline (e.g. deficiency of ADA2 or GATA2 deficiency) or somatic (e.g. VEXAS syndrome). The second category are the cytokine storm syndromes, including hemophagocytic lymphohistiocytosis and Castleman disease. Cytokine storm syndromes are characterized by excessive production of inflammatory cytokines including interleukin-6 and interferon-gamma, causing end-organ damage and high mortality. Finally, we review disorders associated with monoclonal and polyclonal hypergammaglobulinemia. The serum protein electrophoresis (SPEP) is typically ordered to screen for common diseases such as myeloma and humoral immunodeficiency. However, monoclonal and polyclonal hypergammaglobulinemia on SPEP can also provide important information in rare inflammatory diseases. For example, the autoinflammatory disease Schnitzler syndrome is notoriously difficult to diagnose. While this orphan disease has eluded precise genetic or histological characterization, the presence of a monoclonal paraprotein, typically IgM, is an obligate diagnostic criterion. Likewise, polyclonal hypergammaglobulinemia may be an important early, non-invasive diagnostic clue for patients presenting with rare neoplastic diseases such as Rosai-Dorfman disease and angioimmunoblastic T-cell lymphoma. Applying these three categories to patients with unexplained inflammatory syndromes can facilitate the diagnosis of rare and under-recognized diseases.

PMID:35938681 | DOI:10.1152/ajpcell.00356.2021

Int J Rheum Dis. 2022 Aug 8. doi: 10.1111/1756-185X.14418. Online ahead of print.

ABSTRACT

Pachydermoperiostosis (PDP) is a rare disorder characterized by skin thickening, acropachia, and periostosis. Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome is also an orphan disease featured by different dermatological and osteoarthritic manifestations. Herein, we report the first case of an adolescent male diagnosed with both PDP and SAPHO syndrome, presenting with digital clubbing, polyarthralgia, ostealgia, pachydermia and acne on his face, chest and back. Furthermore, we distinguish the characteristics of both diseases and explore the potential pathological mechanism for this coexistence in one patient. Further investigations are needed to establish the detailed pathophysiological association of these 2 diseases.

PMID:35938529 | DOI:10.1111/1756-185X.14418

Front Public Health. 2022 Jul 19;10:915438. doi: 10.3389/fpubh.2022.915438. eCollection 2022.

ABSTRACT

Patient involvement (PI) in determining medical research priorities is an important way to ensure that limited research funds are allocated to best serve patients. As a disease area for which research funds are limited, we see a particular utility for PI in priority-setting for medical research on rare diseases. In this review, we argue that PI initiatives are an important form of evidence for policymaking. We conducted a study to identify the extent to which PI initiatives are being conducted in the rare disease field, the features of such initiatives, the trends in the priorities elicited, and the extent to which translation into policy is reported in the academic literature. Here, we report the results of this exploratory review of the English-language literature gathered through online databases and search engines, with the aim of identifying journal articles published prior to December 2020, describing PI initiatives focused on determining priorities for medical research funding in the rare disease field. We identified seven recently-published articles and found that the majority made use of structured methodologies to ensure the robustness of the evidence produced, but found little reported practical implementation or concrete plans for implementation of the results of the initiatives. We conclude that priority-setting initiatives are meaningful mechanisms for involving patients in determining research directions. However, we highlight the importance of translation into policy as a necessary next step to fully utilize the results and move beyond well-intentioned exercises. Finally, we draw attention to the benefits of involving patients throughout this process.

PMID:35928485 | PMC:PMC9343727 | DOI:10.3389/fpubh.2022.915438

Mol Cell. 2022 Aug 4;82(15):2735-2737. doi: 10.1016/j.molcel.2022.07.005.

ABSTRACT

Rensvold, Shishkova, et al. (2022) apply an integrated systems biology approach spanning proteomics, lipidomics, and metabolomics to a collection of CRISPR knockout cells targeting 116 distinct human mitochondrial proteins, revealing new mitochondrial biology and guiding orphan disease diagnosis.

PMID:35931038 | DOI:10.1016/j.molcel.2022.07.005