Int J Mol Sci. 2022 Jun 18;23(12):6792. doi: 10.3390/ijms23126792.

ABSTRACT

Rare diseases impact the lives of 300 million people in the world. Rapid advances in bioinformatics and genomic technologies have enabled the discovery of causes of 20-30% of rare diseases. However, most rare diseases have remained as unsolved enigmas to date. Newer tools and availability of high throughput sequencing data have enabled the reanalysis of previously undiagnosed patients. In this review, we have systematically compiled the latest developments in the discovery of the genetic causes of rare diseases using machine learning methods. Importantly, we have detailed methods available to reanalyze existing whole exome sequencing data of unsolved rare diseases. We have identified different reanalysis methodologies to solve problems associated with sequence alterations/mutations, variation re-annotation, protein stability, splice isoform malfunctions and oligogenic analysis. In addition, we give an overview of new developments in the field of rare disease research using whole genome sequencing data and other omics.

PMID:35743235 | PMC:PMC9224427 | DOI:10.3390/ijms23126792

Int J Mol Sci. 2022 Jun 10;23(12):6525. doi: 10.3390/ijms23126525.

ABSTRACT

A rare disease is defined by its low prevalence in the general population [...].

PMID:35742964 | PMC:PMC9223693 | DOI:10.3390/ijms23126525

Int J Environ Res Public Health. 2022 Jun 18;19(12):7489. doi: 10.3390/ijerph19127489.

ABSTRACT

Hajdu-Cheney syndrome is a rare genetic disease. Its main features include phenotypic variability, age-dependent progression and the presence of acroosteolysis of the distal phalanges and generalized osteoporosis, which have significant disabling potential. Currently, there is no effective curative treatment, so nursing care is essential to ensure the maintenance of the quality of life of these patients. The main objective of this study was to establish a specific standardized nursing care plan using the NANDA-NIC-NOC taxonomy. The application of a care plan as such would improve the quality of life of patients affected by this rare disease, will contribute to increasing healthcare professionals' knowledge on this matter and will support future studies on this disease.

PMID:35742738 | PMC:PMC9223558 | DOI:10.3390/ijerph19127489

J Perinatol. 2022 Jun 24. doi: 10.1038/s41372-022-01428-z. Online ahead of print.

ABSTRACT

Rapid genomic sequencing has been shown to have a high diagnostic yield for critically ill infants, with multiple research studies demonstrating both diagnostic and clinical utility. However, clinical implementation of rapid sequencing in the neonatal intensive care unit (NICU), as well as other aspects of genomic medicine such as precision therapy, may be challenging. We describe the Neonatal Genomics Program, developed at our institution as a multidisciplinary approach to improve clinical genetic diagnosis and outcomes for infants in our NICU through genomic medicine. The creation of a dedicated program implementing genomic medicine to improve care in the NICU allows not only for improved access to genomic sequencing for rapid diagnosis, but also advancement of rare disease research and precision therapeutics. Ongoing efforts will help to define an optimal approach to genomic medicine in the NICU context.

PMID:35750755 | DOI:10.1038/s41372-022-01428-z

Int J Mol Sci. 2022 Jun 18;23(12):6798. doi: 10.3390/ijms23126798.

ABSTRACT

Naturally occurring polyamines are absolutely required for cellular growth and proliferation. Many neoplastic cells are reliant on elevated polyamine levels and maintain these levels through dysregulated polyamine metabolism. The modulation of polyamine metabolism is thus a promising avenue for cancer therapeutics and has been attempted with numerous molecules, including enzyme inhibitors and polyamine analogues. SBP-101 (diethyl dihydroxyhomospermine) is a spermine analogue that has shown efficacy in slowing pancreatic tumor progression both in vitro and in vivo; however, the mechanisms underlying these effects remain unclear. We determined the effects of the SBP-101 treatment on a variety of cancer cell types in vitro, including lung, pancreatic, and ovarian. We evaluated the activity of enzymes involved in polyamine metabolism and the effect on intracellular polyamine pools following the SBP-101 treatment. The SBP-101 treatment produced a modest but variable increase in polyamine catabolism; however, a robust downregulation of the activity of the biosynthetic enzyme, ornithine decarboxylase (ODC), was seen across all of the cell types studied and indicates that SBP-101 likely exerts its effect predominately through the downregulation of ODC, with a minor upregulation of catabolism. Our in vitro work indicated that SBP-101 was most toxic in the tested ovarian cell lines. Therefore, we evaluated the efficacy of SBP-101 as a monotherapy in the immunosuppressive VDID8+ murine ovarian model. Mice treated with SBP-101 demonstrated a delay in tumor progression, a decrease in the overall tumor burden, and a marked increase in median survival.

PMID:35743239 | DOI:10.3390/ijms23126798

BMC Ophthalmol. 2022 Jun 23;22(1):274. doi: 10.1186/s12886-022-02496-7.

ABSTRACT

BACKGROUND: Long anterior lens zonules (LAZs) is a rare disease that was mostly conducted among African Americans. Through the observation of a Chinese patient, we discoverd that the disease may show different characteristics in Asians.

CASE PRESENTATION: A patient with vision loss due to a macular hole was found to have several special clinical signs during vitrectomy combined with phacoemulsification and intraocular lens implantation surgery in our hospital, including radially oriented lines on the anterior capsule with pigment, a shallow anterior chamber, slightly high intraocular pressure, and radial retinal stripes in the peripheral retina. Finally, he was diagnosed with long anterior lens zonule syndrome.

CONCLUSION: Clinicians need to pay more attention to the rare disease LAZs. It is important to tear the appropriate size of the anterior capsule so as to avoid radial capsular tearing and intraocular lens dislocation.

PMID:35739512 | PMC:PMC9219172 | DOI:10.1186/s12886-022-02496-7

Ned Tijdschr Geneeskd. 2022 May 18;166:D6235.

ABSTRACT

BACKGROUND: Lemierre's syndrome is a rare disease with different clinical and microbiological criteria. Without adequate treatment mortality is high. It often concerns healthy adolescents who present with common and usually harmless complaints such as fever and sore throat.

CASE DESCRIPTION: We describe a 19-year-old male who was admitted to our hospital with a septic shock after a few days of fever and a sore throat. He was admitted to our intensive care unit. Further examination showed a jugular vein thrombosis and blood cultures showed Fusobacterium necrophorum; a classic presentation of Lemierre's syndrome. However, a jugular vein thrombosis is not a requirement for the diagnosis.

CONCLUSION: We recommend considering Lemierre's syndrome when a young adult presents with fever and a sore throat. Early recognition of Lemierre's syndrome is very important to decrease complications and mortality.

PMID:35736354

Contemp Clin Trials Commun. 2022 Jun 9;28:100946. doi: 10.1016/j.conctc.2022.100946. eCollection 2022 Aug.

ABSTRACT

BACKGROUNDS: Despite the absolute need for life-long treatment of inherited and genetic diseases, there has been little effort to develop such treatments for most of these conditions due to their rarity. Familial lecithin:cholesterol acyltransferase (LCAT) deficiency is recognized as one such orphan disease. We have been developing an adipocyte-based ex vivo gene therapy/regenerative medicine, a novel methodology that differs from the adeno-associated virus-mediated in vivo gene therapy or ex vivo gene-transduced hematopoietic cell therapy, to treat familial LCAT deficiency. Recently, a first-in-human (FIH) clinical study was conducted under the Act on Securement of Safety of Regenerative Medicine, wherein a patient with familial LCAT deficiency was treated. To obtain approval to put this treatment into practical use, a clinical trial has been designed with reference to the FIH clinical study.

METHODS: An interventional, open-label, unblinded dose-escalation trial was planned, referring to previous FIH clinical study. The trial aims to evaluate the safety of the investigational product in relation to the characteristics of the investigational product (ex vivo gene/cell therapy product by retroviral vector-mediated LCAT gene transduction) using two doses, and the efficacy of the treatment will be evaluated exploratively. A total of three patients will be enrolled sequentially and followed for 24 weeks after administration. This study is designed as a multicenter trial, with Chiba University Hospital administering and evaluating the safety/efficacy of the investigational products at the prescribed visit.

CONCLUSION: This clinical trial is expected to facilitate the provision of lifelong treatment to many patients with LCAT deficiency.

TRIAL REGISTRATION NUMBER: Japan Registry of Clinical Trials (jRCT2033200096).

PMID:35734220 | PMC:PMC9207543 | DOI:10.1016/j.conctc.2022.100946

MMW Fortschr Med. 2022 Jun;164(12):65. doi: 10.1007/s15006-022-1258-4.

NO ABSTRACT

PMID:35731415 | DOI:10.1007/s15006-022-1258-4

MMW Fortschr Med. 2022 Jun;164(12):40-42. doi: 10.1007/s15006-022-1138-y.

NO ABSTRACT

PMID:35731405 | DOI:10.1007/s15006-022-1138-y

MMW Fortschr Med. 2022 Jun;164(12):36-39. doi: 10.1007/s15006-022-1139-x.

NO ABSTRACT

PMID:35731404 | DOI:10.1007/s15006-022-1139-x

MMW Fortschr Med. 2022 Jun;164(12):5. doi: 10.1007/s15006-022-1148-9.

NO ABSTRACT

PMID:35731380 | DOI:10.1007/s15006-022-1148-9

Orphanet J Rare Dis. 2022 Jun 20;17(1):238. doi: 10.1186/s13023-022-02392-9.

ABSTRACT

BACKGROUND: Patient registries provide long-term, real-world evidence that aids the understanding of the natural history and progression of disease, and the effects of treatment on large patient populations with rare diseases. The year 2021 marks the 20th anniversary of the Fabry Outcome Survey (FOS), an international, multicenter, observational registry (NCT03289065). The primary aims of FOS are to broaden the understanding of Fabry disease (FD), an X-linked lysosomal storage disorder, and to improve the clinical management of affected patients. Here, we review the history of FOS and the analyses and publications disseminated from the registry, and we discuss the contributions FOS studies have made in understanding FD.

RESULTS: FOS was initiated in April 2001 and, as of January 2021, 4484 patients with a confirmed diagnosis and patient informed consent have been enrolled from 144 centers across 26 countries. Data from FOS have been published in nearly 60 manuscripts on a wide variety of topics relevant to FD. Analyses of FOS data have investigated the long-term effectiveness and safety of enzyme replacement therapy (ERT) with agalsidase alfa and its effects on morbidity and mortality, as well as the benefits of prompt and early treatment with agalsidase alfa on the progression of cardiomyopathy and the decline in renal function associated with FD. Based on analyses of FOS data, ERT with agalsidase alfa has also been shown to improve additional signs and symptoms of FD experienced by patients. FOS data analyses have provided a better understanding of the natural history of FD and the specific populations of women, children, and the elderly, and have provided practical tools for the study of FD. FOS has also provided methodology and criteria for assessing disease severity which contributed to the continuous development of medical practice in FD and has largely improved our understanding of the challenges and needs of long-term data collection in rare diseases, aiding in future rare disease real-world evidence studies.

CONCLUSION: FOS over the last 20 years has substantially increased the scientific knowledge around improved patient management of FD and continues to expand our understanding of this rare disease.

PMID:35725623 | DOI:10.1186/s13023-022-02392-9

Orphanet J Rare Dis. 2022 Jun 20;17(1):240. doi: 10.1186/s13023-022-02388-5.

ABSTRACT

People affected by rare diseases want to be involved in research and the search for new treatments. Randomized controlled trials remain the best way of finding new interventions, but many elements of traditional study design are not best suited for rare diseases. Barriers to patients and families include the use of specialist hospital sites for recruitment, requiring frequent site-based study visits for data collection, and a high burden of tests and outcome measures in research. While decentralized clinical trial (DCT) designs have been developed in some rare disease trials, changes necessitated by the COVID-19 pandemic present an opportunity for them to become a standard approach. DCT approaches have been shown to be more resilient to changes in enrolment and attrition during COVID-19 than traditional designs and offer benefits in terms of patient burden, convenience, inclusion, and data quality. Digital tools such as wearable devices and electronic clinical outcome assessments may also provide more convenient and environmentally valid measures of how a condition affects the life of an individual in their regular environment (e.g. mobility around the home versus a hospital corridor). Digital solutions have greater ability to support language localization, accessibility, and may lead to increase access to global rare disease trials. In parallel, challenges exist, such as the technical support, the digital divide, ensuring high quality data, and delivering safe trials.

PMID:35725484 | DOI:10.1186/s13023-022-02388-5

Ann Ist Super Sanita. 2022 Apr-Jun;58(2):79-80. doi: 10.4415/ANN_22_02_01.

NO ABSTRACT

PMID:35722792 | DOI:10.4415/ANN_22_02_01

Orphanet J Rare Dis. 2022 Jun 18;17(1):233. doi: 10.1186/s13023-022-02358-x.

ABSTRACT

BACKGROUND: People living with rare disease often have protracted journeys towards diagnosis. In the last decade, programs have arisen around the world that are dedicated to ending this 'diagnostic odyssey', including the Undiagnosed Diseases Program Western Australia (UDP-WA), which has a focus on finding diagnoses for children and young adults. To explore the lived experience of the diagnostic journey semi-structured interviews were conducted with parents of 11 children at commencement of their involvement in the UDP-WA.

RESULTS: Thematic analysis revealed three main themes that captured parents' experiences and perspectives. Parents reported (i) the need to respond to significant care needs of their children, which span not only the health system but other systems such as education and disability services. In doing so, parents become the navigator, expert and advocate for their children. Meanwhile, parents are on (ii) the diagnostic odyssey-the rollercoaster of their journey towards diagnosis, which includes various names applied to their child's condition, and the impact of no diagnosis. Parents described their views on (iii) the value of a diagnosis and the outcomes they expect to be associated with a diagnosis.

CONCLUSION: Analysis showed an overall significant perceived value of a diagnosis. Our study provides new perspectives on the concept of diagnosis and indicates that parents may benefit from supports for their child's care needs that are beyond the scope of the UDP-WA.

PMID:35717227 | DOI:10.1186/s13023-022-02358-x

Life Sci. 2022 Sep 1;304:120716. doi: 10.1016/j.lfs.2022.120716. Epub 2022 Jun 13.

ABSTRACT

INTRODUCTION: Malignant pleural mesothelioma (MPM) is a rare malignancy affecting the mesothelial cells in the pleural lining surrounding the lungs. First approved chemotherapy against MPM was a platinum/antifolate (cisplatin/pemetrexed) (2003). Since then, no USFDA approvals have gone through for small molecules as these molecules have not been proven to be therapeutically able in later stages of clinical studies. An alternative to conventional chemotherapy can be utilization of monoclonal antibodies, which are proven to improve patient survival significantly as compared to conventional chemotherapy (Nivolumab + Ipilimumab, 2020).

AREA COVERED: Drug repurposing has been instrumental in drug discovery for rare diseases such as MPM and multiple repositioned small molecule therapies and immunotherapies are currently being tested for its applicability in MPM management. This article summarizes essential breakthroughs along the pre-clinical and clinical developmental stages of small molecules and monoclonal antibodies for MPM management.

EXPERT OPINION: For rare diseases such as malignant pleural mesothelioma, a drug repurposing strategy can be adapted as it eases the financial burden on pharmaceutical companies along with fast-tracking development. With the rise of multiple small molecule repurposed therapies and innovations in localized treatment, MPM therapeutics are bound to be more effective in this decade.

PMID:35709894 | DOI:10.1016/j.lfs.2022.120716

Genome Med. 2022 Jun 17;14(1):66. doi: 10.1186/s13073-022-01069-z.

ABSTRACT

BACKGROUND: Approximately two third of patients with a rare genetic disease remain undiagnosed after exome sequencing (ES). As part of our post-test counseling procedures, patients without a conclusive diagnosis are advised to recontact their referring clinician to discuss new diagnostic opportunities in due time. We performed a systematic study of genetically undiagnosed patients 5 years after their initial negative ES report to determine the efficiency of diverse reanalysis strategies.

METHODS: We revisited a cohort of 150 pediatric neurology patients originally enrolled at Radboud University Medical Center, of whom 103 initially remained genetically undiagnosed. We monitored uptake of physician-initiated routine clinical and/or genetic re-evaluation (ad hoc re-evaluation) and performed systematic reanalysis, including ES-based resequencing, of all genetically undiagnosed patients (systematic re-evaluation).

RESULTS: Ad hoc re-evaluation was initiated for 45 of 103 patients and yielded 18 diagnoses (including 1 non-genetic). Subsequent systematic re-evaluation identified another 14 diagnoses, increasing the diagnostic yield in our cohort from 31% (47/150) to 53% (79/150). New genetic diagnoses were established by reclassification of previously identified variants (10%, 3/31), reanalysis with enhanced bioinformatic pipelines (19%, 6/31), improved coverage after resequencing (29%, 9/31), and new disease-gene associations (42%, 13/31). Crucially, our systematic study also showed that 11 of the 14 further conclusive genetic diagnoses were made in patients without a genetic diagnosis that did not recontact their referring clinician.

CONCLUSIONS: We find that upon re-evaluation of undiagnosed patients, both reanalysis of existing ES data as well as resequencing strategies are needed to identify additional genetic diagnoses. Importantly, not all patients are routinely re-evaluated in clinical care, prolonging their diagnostic trajectory, unless systematic reanalysis is facilitated. We have translated our observations into considerations for systematic and ad hoc reanalysis in routine genetic care.

PMID:35710456 | DOI:10.1186/s13073-022-01069-z

Orphanet J Rare Dis. 2022 Jun 16;17(1):230. doi: 10.1186/s13023-022-02391-w.

ABSTRACT

The rich and diverse genomics of African populations is significantly underrepresented in reference and in disease-associated databases. This renders interpreting the Next Generation Sequencing (NGS) data and reaching a diagnostic more difficult in Africa and for the African diaspora. It increases chances for false positives with variants being misclassified as pathogenic due to their novelty or rarity. We can increase African genomic data by (1) making consent for sharing aggregate frequency data an essential component of research toolkit; (2) encouraging investigators with African data to share available data through public resources such as gnomAD, AVGD, ClinVar, DECIPHER and to use MatchMaker Exchange; (3) educating African research participants on the meaning and value of sharing aggregate frequency data; and (4) increasing funding to scale-up the production of African genomic data that will be more representative of the geographical and ethno-linguistic variation on the continent. The RDWG of H3Africa is hereby calling to action because this underrepresentation accentuates the health disparities. Applying the NGS to shorten the diagnostic odyssey or to guide therapeutic options for rare diseases will fully work for Africans only when public repositories include sufficient data from African subjects.

PMID:35710439 | DOI:10.1186/s13023-022-02391-w

J Clin Pathol. 2022 Jun 16:jclinpath-2021-207719. doi: 10.1136/jclinpath-2021-207719. Online ahead of print.

ABSTRACT

Triglycerides (TGs) form part of the standard lipid profile. Elevations in TGs are associated with increased cardiovascular disease risk through triglyceride-rich lipoprotein particles found as part of non-HDL cholesterol. Many elevations of TGs are secondary to other causes, but primary hypertriglyceridaemia syndromes need to be identified. The genetic causes of hypertriglyceridaemia range from familial combined hyperlipidaemia through the autosomal recessive remnant hyperlipidaemia (related to apolipoprotein E variants) and familial chylomicronaemia syndromes. Patients with primary hypertriglyceridaemia >10 mmol/L require characterisation and specific intervention. Simple lipid profiles do not provide adequate information for detailed diagnosis and additional assays such as apolipoprotein (apo)B100, apoE genotype and next-generation sequencing may be useful. Management of raised TGs includes optimising diet, reducing exacerbating factors as well as lipid-lowering medications such as statins, fibrates, niacin and omega-3 fatty acids. Novel medications for orphan disease indications such as familial chylomicronaemia syndrome include volanesorsen, evinacumab and other antisense therapeutics. Extreme hypertriglyceridaemia syndromes, especially chylomicronaemia syndromes, which can be exposed by pregnancy or other factors are a medical emergency and require admission and specialist management sometimes including plasma exchange.

PMID:35710321 | DOI:10.1136/jclinpath-2021-207719