MMW Fortschr Med. 2022 Apr;164(7):29. doi: 10.1007/s15006-022-1061-2.

NO ABSTRACT

PMID:35391680 | DOI:10.1007/s15006-022-1061-2

Eur J Med Genet. 2022 May;65(5):104494. doi: 10.1016/j.ejmg.2022.104494. Epub 2022 Apr 3.

ABSTRACT

Although the challenge of access to care for undiagnosed rare disease patients is well documented in the literature, little is known about lack of diagnosis preventing access to social services. Yet this has serious consequences for patients and their families because disability associated with rare disease requires frequent and costly multi-disciplinary support. The aim of this research is to explore, in the French context, access to social assistance for rare disease patients. We investigate the link between diagnosis and access to social services to identify potential barriers and unmet needs for patients. Our study is based on a self-administered online questionnaire, adressed to parents or legal representatives of a child under ten years old with a rare disease and development disorders. The survey has been carried out between November 2019 and the end of January 2020 and includes 103 respondents. While our data does not show any differences in the possibility of obtaining a social benefit depending on the diagnosis status, there are differences in the length of time they are granted and in the satisfaction of families with the assistance obtained. Families with an undiagnosed child obtained social assistance for a shorter period on average. They were also more likely to be dissatisfied with the amount of benefit they received. The results of this pilot study need to be confirmed by further extended studies.

PMID:35385796 | DOI:10.1016/j.ejmg.2022.104494

Orphanet J Rare Dis. 2022 Apr 5;17(1):157. doi: 10.1186/s13023-022-02283-z.

ABSTRACT

Conventional cost-effectiveness analysis-i.e., assessing pharmaceuticals through a cost per quality-adjusted life year (QALY) framework-originated from a societal commitment to maximize population health given limited resources. This "extra-welfarist" approach has produced pricing and reimbursement systems that are not well- aligned with the unique considerations of orphan drugs. This framework has been slow to evolve along with our increased understanding of the impact of rare diseases, which in turn has complicated the assessment of orphan drugs meant to treat rare diseases. Herein, we (i) discuss the limitations of conventional cost-effectiveness analysis as applied to assessing access to, as well as the pricing and reimbursement of, orphan drugs, (ii) critically appraise alternative and supplemental approaches, and (iii) offer insights on plausible steps forward.

PMID:35382853 | DOI:10.1186/s13023-022-02283-z

Orphanet J Rare Dis. 2022 Apr 5;17(1):156. doi: 10.1186/s13023-022-02298-6.

ABSTRACT

BACKGROUND: The small patient populations inherent to rare genetic diseases present many challenges to the traditional drug development paradigm. One major challenge is generating sufficient data in early phase studies to inform dose selection for later phase studies and dose optimization for clinical use of the drug. However, optimizing the benefit-risk profile of drugs through appropriate dose selection during drug development is critical for all drugs, including those being developed to treat rare diseases. Recognizing the challenges of conducting dose finding studies in rare disease populations and the importance of dose selection and optimization for successful drug development, we assessed the dose-finding studies and analyses conducted for drugs recently approved for rare genetic diseases.

RESULTS: Of the 40 marketing applications for new molecular entity (NME) drugs and biologics approved by the United States Food and Drug Administration for rare genetic diseases from 2015 to 2020, 21 (53%) of the development programs conducted at least one dedicated dose-finding study. In addition, the majority of drug development programs conducted clinical studies in healthy subjects and included population pharmacokinetic and exposure-response analyses; some programs also conducted clinical studies in patient populations other than the disease for which the drug was initially approved. The majority of primary endpoints utilized in dedicated dose-finding studies were biomarkers, and the primary endpoint of the safety and efficacy study matched the primary endpoint used in the dose finding study in 9 of 13 (69%) drug development programs where primary study endpoints were assessed.

CONCLUSIONS: Our study showed that NME drug development programs for rare genetic diseases utilize multiple data sources for dosing information, including studies in healthy subjects, population pharmacokinetic analyses, and exposure-response analyses. In addition, our results indicate that biomarkers play a key role in dose-finding studies for rare genetic disease drug development programs. Our findings highlight the need to develop study designs and methods to allow adequate dose-finding efforts within rare disease drug development programs that help overcome the challenges presented by low patient prevalence and other factors. Furthermore, the frequent reliance on biomarkers as endpoints for dose-finding studies underscores the importance of biomarker development in rare diseases.

PMID:35382851 | DOI:10.1186/s13023-022-02298-6

Orphanet J Rare Dis. 2022 Apr 4;17(1):153. doi: 10.1186/s13023-022-02305-w.

ABSTRACT

BACKGROUND: Challenges faced by children diagnosed with a rare disease or complex condition and their family members are often characterized by disease-specific complexities, such as a prolonged diagnostic process, an uncertain prognosis, and the absence of curative treatment. The psychological burden of living with a rare disease or complex condition is often understudied and may present overarching concepts that shape the general experience of having been diagnosed with a rare condition. The present study examines common needs from a comprehensive perspective combining relevant aspects from the rare disease literature in a theoretical perspective from pediatric psychology, such as a family-centred, developmental and interdisciplinary approach. An exploratory study was designed among parents from children with a rare disease or complex condition in an Integrated University Children's Hospital in the Netherlands. Semi-structured interviews were conducted with open-ended questions based around the experience of having a child diagnosed with a rare condition, such as the psychosocial impact on the child and it's development, the impact on the family, and how provided care was experienced.

RESULTS: Twelve interviews were analysed with a thematic content analysis to identify common needs. Eight themes followed from the analysis and uncovered the need for (1) family-focused care, (2) coping with uncertainty, (3) empathic communication, (4) practical support, (5) information, (6) psychological support, (7) interdisciplinary care, and (8) social support.

CONCLUSIONS: The results from our study provide directions for research and health care to support young patients with a rare disease or complex condition and their families. Moreover, our results demonstrated that there are overarching concepts across different rare diseases that may be optimally supported with interdisciplinary care.

PMID:35379257 | DOI:10.1186/s13023-022-02305-w

Nat Neurosci. 2022 Apr 4. doi: 10.1038/s41593-022-01043-3. Online ahead of print.

ABSTRACT

Hydrocephalus, characterized by cerebral ventricular dilatation, is routinely attributed to primary defects in cerebrospinal fluid (CSF) homeostasis. This fosters CSF shunting as the leading reason for brain surgery in children despite considerable disease heterogeneity. In this study, by integrating human brain transcriptomics with whole-exome sequencing of 483 patients with congenital hydrocephalus (CH), we found convergence of CH risk genes in embryonic neuroepithelial stem cells. Of all CH risk genes, TRIM71/lin-41 harbors the most de novo mutations and is most specifically expressed in neuroepithelial cells. Mice harboring neuroepithelial cell-specific Trim71 deletion or CH-specific Trim71 mutation exhibit prenatal hydrocephalus. CH mutations disrupt TRIM71 binding to its RNA targets, causing premature neuroepithelial cell differentiation and reduced neurogenesis. Cortical hypoplasia leads to a hypercompliant cortex and secondary ventricular enlargement without primary defects in CSF circulation. These data highlight the importance of precisely regulated neuroepithelial cell fate for normal brain-CSF biomechanics and support a clinically relevant neuroprogenitor-based paradigm of CH.

PMID:35379995 | DOI:10.1038/s41593-022-01043-3

Crit Care Clin. 2022 Apr;38(2):xiii-xiv. doi: 10.1016/j.ccc.2021.12.001.

NO ABSTRACT

PMID:35369957 | DOI:10.1016/j.ccc.2021.12.001

Crit Care Clin. 2022 Apr;38(2):243-269. doi: 10.1016/j.ccc.2021.11.003.

ABSTRACT

There have been major advances in the understanding of severe cutaneous adverse reactions (SCARs). Early recognition and withdrawal of culprit medications can decrease morbidity and mortality significantly. SCARs encompass a variety of entities that present with extensive mucocutaneous involvement and systemic symptoms, often requiring management in an intensive care setting. Physicians need to recognize SCARs early in their course, including drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis, and their mimicking conditions. This review focuses on common and rare SCARs with an emphasis on defining features, clinical and diagnostic evaluation, treatment, and long-term sequelae.

PMID:35369946 | DOI:10.1016/j.ccc.2021.11.003

Crit Care Clin. 2022 Apr;38(2):159-171. doi: 10.1016/j.ccc.2021.12.002.

ABSTRACT

Critically ill patients with undiagnosed and rare diseases are at high risk for cognitive diagnostic errors as well as delays in diagnosis that are the result of impaired diagnostic access. Local evaluation teams dedicated to undiagnosed and rare diseases can address both the risk and actuality of diagnostic error, as well as shortfalls in diagnostic access, particularly for patients whose diminished access is a result of critical illness. Features of successful teams are discussed.

PMID:35369940 | DOI:10.1016/j.ccc.2021.12.002

Orphanet J Rare Dis. 2022 Apr 4;17(1):87. doi: 10.1186/s13023-022-02192-1.

ABSTRACT

Rare diseases affect > 400 million people globally with a disproportionate burden falling on children, resulting in high morbidity and mortality rates. Affected individuals in some under-resourced countries have limited access to expert care or treatments; moreover, they suffer long diagnostic journeys during which debilitating and life-threatening complications occur. Lysosomal storage disorders (LSD) are prototype rare diseases due, in the main, to inherited deficiencies of lysosomal enzymes/transporters that affect up to 1 in 5000 newborns. Recognizing the need to provide treatment access to people with LSDs everywhere, a collaborative partnership was pioneered and set up 30 years ago. Partnering with local authorities, non-government organizations across six continents, local as well as international experts, a robust, sustainable Humanitarian Program emerged that now represents the most enduring charitable access program for LSD treatment. Here we present the history, process, lasting beneficial effect of the program to develop healthcare systems and infrastructures, and the lessons learned from addressing major unmet needs for LSDs.

PMID:35369888 | DOI:10.1186/s13023-022-02192-1

J Crohns Colitis. 2022 Apr 2:jjac045. doi: 10.1093/ecco-jcc/jjac045. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Over 80 monogenic causes of very early onset inflammatory bowel disease (VEOIBD) have been identified. Prior reports of the natural history of VEOIBD have not considered monogenic disease status. The objective of this study is to describe clinical phenotypes and outcomes in a large single-center cohort of patients with VEOIBD and universal access to whole exome sequencing (WES).

METHODS: Patients receiving IBD care at a single center were prospectively enrolled in a longitudinal data repository starting in 2012. WES was offered with enrollment. Enrolled patients were filtered by age of diagnosis <6 years to comprise VEOIBD cohort. Monogenic disease was identified by filtering proband variants for rare, loss-of-function or missense variants in known VEOIBD genes inherited according to standard Mendelian inheritance patterns.

RESULTS: This analysis included 216 VEOIBD patients, followed for a median of 5.8 years. Seventeen patients (7.9%) had monogenic disease. Patients with monogenic IBD were younger at diagnosis and were more likely to have Crohn's disease phenotype with higher rates of stricturing and penetrating disease and extraintestinal manifestations. Patients with monogenic disease were also more likely to experience outcomes of ICU hospitalization, gastrostomy tube, total parenteral nutrition use, stunting at 3-year follow-up, hematopoietic stem cell transplant, and death. Forty-one patients (19.0%) had infantile-onset disease. After controlling for monogenic disease, patients with infantile-onset IBD did not have increased risk for most severity outcomes.

CONCLUSIONS: Monogenic disease is an important driver of disease severity in VEOIBD. WES is a valuable tool in prognostication and management of VEOIBD.

PMID:35366317 | DOI:10.1093/ecco-jcc/jjac045

PLoS One. 2022 Mar 31;17(3):e0265469. doi: 10.1371/journal.pone.0265469. eCollection 2022.

ABSTRACT

We designed a novel strategy to define codon usage bias (CUB) in 6 specific small cohorts of human genes. We calculated codon usage (CU) values in 29 non-disease-causing (NDC) and 31 disease-causing (DC) human genes which are highly expressed in 3 distinct tissues, kidney, muscle, and skin. We applied our strategy to the same selected genes annotated in 15 mammalian species. We obtained CUB hierarchical clusters for each gene cohort which showed tissue-specific and disease-specific CUB fingerprints. We showed that DC genes (especially those expressed in muscle) display a low CUB, well recognizable in codon hierarchical clustering. We defined the extremely biased codons as "zero codons" and found that their number is significantly higher in all DC genes, all tissues, and that this trend is conserved across mammals. Based on this calculation in different gene cohorts, we identified 5 codons which are more differentially used across genes and mammals, underlining that some genes have favorite synonymous codons in use. Since of the muscle genes clear clusters, and, among these, dystrophin gene surprisingly does not show any "zero codon" we adopted a novel approach to study CUB, we called "mapping-on-codons". We positioned 2828 dystrophin missense and nonsense pathogenic variations on their respective codon, highlighting that its frequency and occurrence is not dependent on the CU values. We conclude our strategy consents to identify a hierarchical clustering of CU values in a gene cohort-specific fingerprints, with recognizable trend across mammals. In DC muscle genes also a disease-related fingerprint can be observed, allowing discrimination between DC and NDC genes. We propose that using our strategy which studies CU in specific gene cohorts, as rare disease genes, and tissue specific genes, may provide novel information about the CUB role in human and medical genetics, with implications on synonymous variations interpretation and codon optimization algorithms.

PMID:35358230 | PMC:PMC8970475 | DOI:10.1371/journal.pone.0265469

Circ Cardiovasc Imaging. 2022 Apr;15(4):e013638. doi: 10.1161/CIRCIMAGING.121.013638. Epub 2022 Mar 29.

NO ABSTRACT

PMID:35345894 | DOI:10.1161/CIRCIMAGING.121.013638

Orphanet J Rare Dis. 2022 Mar 28;17(1):140. doi: 10.1186/s13023-022-02290-0.

ABSTRACT

BACKGROUND: There are more than 7000 rare diseases, most of which have no specific treatment. Disease profiles, such as prevalence and natural history, among the population of a specific country are essential in determining for which disease to research and develop drugs. In Japan, disease profiles of fewer than 2000 rare diseases, called Nanbyo, have been investigated. However, non-Nanbyo rare diseases remain largely uninvestigated. Accordingly, we revealed the prevalence and natural history of rare diseases among the Japanese population. This cross-disease study is the first to analyze rare-disease epidemiology in Japan with high accuracy, disease coverage, and granularity.

METHOD: We applied for permission to use the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB), which covered 99.9% of public health insurance claims from hospitals and 97.9% from clinics as of May 2015. Then, we obtained 10 years of data on the number of patients of approx. 4500 rare diseases, by sex and age. We translated disease names and established correspondences between rare diseases in NDB and those in Orphanet. Accordingly, we compared the prevalence and natural history between them.

RESULTS: About 3000 diseases in NDB are included in Orphanet and other medical databases. The data indicates that even if the Nanbyo systems do not cover a rare disease, its patients survive in many cases. Regarding natural history, genetic diseases tend to be diagnosed later in Japan than in the West. The data shown in this research are available in the Additional file 1 and the website of NanbyoData.

CONCLUSIONS: Our research revealed the basic epidemiology and natural history of Japanese patients with some rare diseases using a health insurance claims database. The results imply that the coverage of the present Nanbyo systems is inadequate for rare diseases. Therefore, fundamental reform might be needed to reduce unfairness between rare diseases. Most diseases in Japan follow a tendency of natural history similar to those reported in Orphanet. However, some are detected later, partly because fewer clinical genetic tests are available in Japan than in the West. Finally, we hope that our data and analysis accelerate drug discovery for rare diseases in Japan.

PMID:35346288 | PMC:PMC8961906 | DOI:10.1186/s13023-022-02290-0

Genet Med. 2022 Mar 24:S1098-3600(22)00676-1. doi: 10.1016/j.gim.2022.02.018. Online ahead of print.

ABSTRACT

PURPOSE: As genomic sequencing becomes more common, medically actionable secondary findings will increasingly be returned to health care providers (HCPs), who will be faced with managing the resulting patient care. These findings are generally unsolicited, ie, unrelated to the sequencing indication and/or ordered by another clinician.

METHODS: To understand the impact of receiving unsolicited results, we interviewed HCPs who received genomic results for patients enrolled in the Electronic Medical Records and Genomics (eMERGE) Phase III Network, which returned results on >100 actionable genes to eMERGE participants and HCPs.

RESULTS: In total, 16 HCPs across 3 eMERGE sites were interviewed about their experience of receiving a positive (likely pathogenic or pathogenic), negative, or variant of uncertain significance result for a patient enrolled in eMERGE Phase III and about managing their patient on the basis of the result. Although unsolicited, HCPs felt responsible for managing the patient's resulting medical care. HCPs indicated that clinical utility depended on the actionability of results, and whereas comfort levels varied, confidence was improved by the availability of subspecialist consults. HCPs were concerned about patient anxiety, insurability, and missing an actionable result in the electronic health record.

CONCLUSION: Our findings help inform best practices for return of unsolicited genomic screening findings in the future.

PMID:35341654 | DOI:10.1016/j.gim.2022.02.018

Genes (Basel). 2022 Mar 11;13(3):496. doi: 10.3390/genes13030496.

ABSTRACT

Dyskeratosis congenital (DC) is the first genetic syndrome described among telomeropathies. Its classical phenotype is characterized by the mucocutaneous triad of reticulated pigmentation of skin lace, nail dystrophy and oral leukoplakia. The clinical presentation, however, is heterogeneous and serious clinical complications include bone marrow failure, hematological and solid tumors. It may also involve immunodeficiencies, dental, pulmonary and liver disorders, and other minor complication. Dyskeratosis congenita shows marked genetic heterogeneity, as at least 14 genes are responsible for the shortening of telomeres characteristic of this disease. This review discusses clinical characteristics, molecular genetics, disease evolution, available therapeutic options and differential diagnosis of dyskeratosis congenita to provide an interdisciplinary and personalized medical assessment that includes family genetic counseling.

PMID:35328050 | PMC:PMC8953471 | DOI:10.3390/genes13030496

Clin Transl Sci. 2022 Apr;15(4):809-812. doi: 10.1111/cts.13270. Epub 2022 Mar 25.

NO ABSTRACT

PMID:35334152 | DOI:10.1111/cts.13270

Orphanet J Rare Dis. 2022 Mar 24;17(1):134. doi: 10.1186/s13023-022-02286-w.

ABSTRACT

BACKGROUND: Congenital Disorders of Glycosylation (CDG) are a complex family of rare metabolic diseases. Robust clinical data collection faces many hurdles, preventing full CDG biological and clinical comprehension. Web-based platforms offer privileged opportunities for biomedical data gathering, and participant recruitment, particularly in rare diseases. The immunology and CDG electronic (e-) questionnaire (ImmunoCDGQ) explores this paradigm, proposing a people-centric framework to advance health research and participant empowerment.

OBJECTIVE: The objectives of this study were to: (1) Describe and characterize the ImmunoCDGQ development, engagement, recruitment, participation, and result dissemination strategies; (2) To critically compare this framework with published literature and making recommendations.

METHODS: An international, multistakeholder people-centric approach was initiated to develop and distribute the ImmunoCDGQ, a multi-lingual e-questionnaire able to collect immune-related data directly from patients and family caregivers. An adapted version was produced and distributed among the general "healthy" population (ImmunoHealthyQ), serving as the control group. Literature screening was performed to identify and analyze comparable studies.

RESULTS: The ImmunoCDGQ attained high participation and inclusion rates (94.6%, 209 out of 221). Comparatively to the control, CDG participants also showed higher and more variable questionnaire completion times as well as increased English version representativeness. Additionally, 20% of the CDG group (42 out of 209) chose not to complete the entire questionnaire in one go. Conditional logic structuring guided participant data provision and accurate data analysis assignment. Multi-channel recruitment created sustained engagement with Facebook emerging as the most followed social media outlet. Still, most included ImmunoCDGQ questionnaires (50.7%, 106 out of 209) were submitted within the first month of the project's launch. Literature search and analysis showed that most e-questionnaire-based studies in rare diseases are author-built (56.8%, 25 out of 44), simultaneously addressing medical and health-related quality of life (HRQoL) and/or information needs (79.5%, 35 out of 44). Also, over 68% of the studies adopt multi-platform recruitment (30 out of 44) actively supported by patient organizations (52.3%, 23 out of 44).

CONCLUSIONS: The ImmunoCDGQ, its methodology and the CDG Community served as models for health research, hence paving a successful and reproducible road to people-centricity in biomedical research.

PMID:35331276 | PMC:PMC8944152 | DOI:10.1186/s13023-022-02286-w

Cold Spring Harb Mol Case Stud. 2022 Mar 24;8(2):a006210. doi: 10.1101/mcs.a006210. Print 2022 Feb.

ABSTRACT

After a long and largely disappointing detour, Genome Research has reidentified Rare Diseases as a major opportunity for improving health care and a clue to understanding gene and genome function. In this Special Issue of CSH Molecular Case Studies on Rare Diseases, several invited Perspectives, numerous Case Reports, and this Editorial itself address recent breakthroughs as well as unsolved problems in this wide field. These range from exciting prospects for gap-free diagnostic whole-genome sequencing to persisting problems related to identifying and distinguishing pathogenic and benign variants; and from the good news that soon, the United Kingdom will no longer be the only country to have introduced whole-genome sequencing into health care to the sobering conclusion that in many countries the clinical infrastructure for bringing Genome Medicine to the patient is still lacking. With less than 5000 genes firmly implicated in disease, the identification of at least twice as many disease genes is a major challenge, and the elucidation of their function is an even larger task. But given the renewed interest in rare diseases, their importance for health care, and the vast and growing spectrum of concepts and methods for studying them, the future of Human Genome Research is bright.

PMID:35332074 | PMC:PMC8958923 | DOI:10.1101/mcs.a006210

Cold Spring Harb Mol Case Stud. 2022 Mar 24;8(2):a006200. doi: 10.1101/mcs.a006200. Print 2022 Feb.

ABSTRACT

Rare neurogenetic disorders are collectively common, affecting 3% of the population, and often manifest with complex multiorgan comorbidity. With advances in genetic, -omics, and computational analysis, more children can be diagnosed and at an earlier age. Innovations in translational research facilitate the identification of treatment targets and development of disease-modifying drugs such as gene therapy, nutraceuticals, and drug repurposing. This increasingly allows targeted therapy to prevent the often devastating manifestations of rare neurogenetic disorders. In this perspective, successes in diagnosis, prevention, and treatment are discussed with a focus on inherited disorders of metabolism. Barriers for the identification, development, and implementation of rare disease-specific therapies are discussed. New methodologies, care networks, and collaborative frameworks are proposed to optimize the potential of personalized genomic medicine to decrease morbidity and improve lives of these vulnerable patients.

PMID:35332073 | PMC:PMC8958924 | DOI:10.1101/mcs.a006200