Genome Med. 2023 Jan 27;15(1):5. doi: 10.1186/s13073-023-01157-8.

ABSTRACT

BACKGROUND: Rare diseases collectively impose a significant burden on healthcare systems, especially in underserved regions, like the Middle East, which lack access to genomic diagnostic services and the associated personalized management plans.

METHODS: We established a clinical genomics and genetic counseling facility, within a multidisciplinary tertiary pediatric center, in the United Arab Emirates to locally diagnose and manage patients with rare diseases. Clinical genomic investigations included exome-based sequencing, chromosomal microarrays, and/or targeted testing. We assessed the diagnostic yield and implications for clinical management among this population. Variables were compared using the Fisher exact test. Tests were 2-tailed, and P < .05 was considered statistically significant.

RESULTS: We present data on 1000 patients with rare diseases (46.2% females; average age, 4.6 years) representing 47 countries primarily from the Arabian Peninsula, the Levant, Africa, and Asia. The cumulative diagnostic yield was 32.5% (95% CI, 29.7-35.5%) and was higher for genomic sequencing-based testing than chromosomal microarrays (37.9% versus 17.2%, P = 0.0001) across all indications, consistent with the higher burden of single gene disorders. Of the 221 Mendelian disorders identified in this cohort, the majority (N = 184) were encountered only once, and those with recessive inheritance accounted for ~ 62% of sequencing diagnoses. Of patients with positive genetic findings (N = 325), 67.7% were less than 5 years of age, and 60% were offered modified management and/or intervention plans. Interestingly, 24% of patients with positive genetic findings received delayed diagnoses (average age, 12.4 years; range 7-37 years), most likely due to a lack of access to genomic investigations in this region. One such genetic finding ended a 15-year-long diagnostic odyssey, leading to a life-threatening diagnosis in one patient, who was then successfully treated using an experimental allogenic bone marrow transplant. Finally, we present cases with candidate genes within regions of homozygosity, likely underlying novel recessive disorders.

CONCLUSIONS: Early access to genomic diagnostics for patients with suspected rare disorders in the Middle East is likely to improve clinical outcomes while driving gene discovery in this genetically underrepresented population.

PMID:36703223 | PMC:PMC9881316 | DOI:10.1186/s13073-023-01157-8

Orphanet J Rare Dis. 2023 Jan 26;18(1):18. doi: 10.1186/s13023-022-02611-3.

ABSTRACT

BACKGROUND: Rare bone diseases (RBDs) are a set of inherited rare diseases that can cause disability and have a devastating impact on families affected, which may lead to a particular high prevalence of psychological disorders in patients and caregivers. Social support plays a role in the well-being of families with rare disease patients, but its effect on psychology of RBD families remains unclear. The purpose of the current cross-sectional quantitative study was to investigate the frequency of depression and anxiety, and their relationship with social support among RBD patients and family caregivers.

RESULTS: A total of 196 participants responded to the questionnaire, including 72 patients and 124 caregivers. Depression was detected among 33.8% of patients and 57% of caregivers, and anxiety disorder was presented in 28.6% of patients and 50% of caregivers. Higher depression scores and anxiety scores were found in both patients and caregivers with an education level of ≤ middle school and monthly income of ≤ ￥2000 (all P < 0.05). The mean (SD) scores of Social Support Rating Scales in patients and caregivers were 37.06 (8.05) and 38.31 (5.76), respectively. After adjusting for gender, age, monthly income, education, employment and marital status, the reverse associations between depression scores, anxiety scores and social support were found merely in caregivers (depression & social support: β = - 0. 46, P < 0.001, anxiety & social support: β = - 0. 44, P < 0.001), specifically for subjective support (depression & subjective support: β = - 0.94, P < 0.001, anxiety & subjective support: β = - 0.87, P < 0.001).

CONCLUSIONS: The study identified a high prevalence of depression and anxiety among RBD patients and caregivers, and pointed out the significance of social support in alleviating psychological distress. In order to provide RBD families with comprehensive assistance, the government should actively develop programs aimed at psychological aid, policy advocacy and tangible support.

PMID:36703212 | PMC:PMC9878818 | DOI:10.1186/s13023-022-02611-3

J Patient Exp. 2023 Jan 17;10:23743735231151768. doi: 10.1177/23743735231151768. eCollection 2023.

ABSTRACT

Systemic sclerosis (SSc) is a rare orphan disease, characterized by skin thickening, vascular insufficiency, and fibrosis of internal organs. SSc affects about 100,000 people in the United States. This study explored perceived benefits and challenges of patient partners and stakeholders, who were team members on a project to revise and test a self-management program (Taking Charge of Systemic Sclerosis). Five patient partners, 1 stakeholder from the Scleroderma Foundation and 1 stakeholder from a state chapter of the Scleroderma Foundation were interviewed. Conversations were audio recorded and transcribed verbatim and analyzed. Four themes emerged from the analysis with corresponding subthemes: contributions to study, benefits of involvement, challenges, and project leadership. The themes and subthemes were generally similar to those expressed in other studies. However, additional benefits from engagement were identified: acceptance, increased knowledge of SSc, and helping others. Participants reported feeling supported and valued as members of the team and that their opinions mattered which is in contrast with findings from other studies.

PMID:36698624 | PMC:PMC9869235 | DOI:10.1177/23743735231151768

Bioorg Med Chem. 2023 Feb 15;80:117170. doi: 10.1016/j.bmc.2023.117170. Epub 2023 Jan 18.

ABSTRACT

Many new drugs have been approved over the past decade for rare or orphan diseases. The passage of the Orphan Drug Act (ODA) in 1983 has provided key economic and regulatory incentives to provide medicines for patients who are suffering from rare diseases that may not be commercially attractive for research and development. We have analyzed 497 novel drugs approved from 2010 - June 13, 2022, of which 220 were given orphan designation status. We discuss trends over this time period, potential risks for long development times, and provide example case studies of successful development and launch of novel drugs for rare diseases.

PMID:36696875 | DOI:10.1016/j.bmc.2023.117170

BMJ Case Rep. 2023 Jan 25;16(1):e252359. doi: 10.1136/bcr-2022-252359.

ABSTRACT

A young adult man presented to an outlying emergency department with a sore throat, fever and chills. Upon failure of symptomatic management and a course of amoxicillin, he developed rectal pain and loose stools. Despite outpatient doxycycline treatment for presumed chlamydial proctitis, he developed worsening rectal pain and bloody stools. Results on abdominal and pelvic CT were consistent with proctitis. His symptoms worsened despite added metronidazole for bacterial proctitis. Workup revealed an elevated erythrocyte sedimentation rate, C reactive protein and calprotectin, suggestive of a diagnosis of inflammatory bowel disease (IBD). A colonoscopy revealed proximal tightness of the rectum, and pathology reported features suggestive of IBD. He was treated with prednisone and mesalamine. However, immunostaining positive for cytomegalovirus (CMV) confirmed a diagnosis of tissue-invasive CMV proctitis. This was further supported by serological testing for CMV consistent with a diagnosis of CMV proctitis preceded by a primary CMV infection of the pharynx.

PMID:36697111 | DOI:10.1136/bcr-2022-252359

Healthc Pap. 2023 Jan;21(1):74-80. doi: 10.12927/hcpap.2023.26992.

ABSTRACT

Expensive drugs for rare diseases pose unique economic, evidentiary and ethical challenges, and these will continue to escalate unless steps are taken urgently to address these challenges. We propose concrete actions that all stakeholders (federal and provincial/territorial governments, patients, healthcare providers, the public and drug manufacturers) could take now as a first step toward enhancing sustainability in the use of innovative (albeit expensive) therapies within our publicly funded healthcare system.

PMID:36692920 | DOI:10.12927/hcpap.2023.26992

Healthc Pap. 2023 Jan;21(1):66-72. doi: 10.12927/hcpap.2023.26993.

ABSTRACT

Significant challenges are associated with the availability of and access to treatments for rare diseases. In this issue, Sirrs et al. (2023) frame challenges in terms of evidence, economics and ethics and describe how they manifest in the Canadian context. This short response paper argues that although interesting initiatives exist internationally to deal with some of these challenges, a plug-and-play approach will not suffice given the particularities of the Canadian system. Rather than seeking international lessons on how to deal with Canadian challenges, the emerging interdisciplinary framework of social pharmaceutical innovation is advanced here as a whole-systems approach that stands to address interconnected components of the rare disease ecosystem, and in doing so, a made-in-Canada approach is advocated for.

PMID:36692919 | DOI:10.12927/hcpap.2023.26993

Healthc Pap. 2023 Jan;21(1):59-65. doi: 10.12927/hcpap.2023.26994.

ABSTRACT

Expensive drugs for rare diseases (EDRDs) pose challenges for regulatory and reimbursement decision makers. Managed access agreements (MAAs), conditional reimbursement schemes that use a variety of price and evidence generation mechanisms to support value-based decision making, have the potential to address the evidentiary, economic and ethical issues associated with EDRDs. Several jurisdictions have successfully used MAAs to manage budget impact and evidentiary uncertainties, demonstrating the promise of this approach. We comment on the feasibility of adopting MAAs in Canada to address challenges associated with EDRDs. Adopting MAAs in the Canadian context requires attention to Canada's federated healthcare and drug coverage system and will require investing in robust data infrastructure and governance systems.

PMID:36692918 | DOI:10.12927/hcpap.2023.26994

Healthc Pap. 2023 Jan;21(1):52-58. doi: 10.12927/hcpap.2023.26995.

ABSTRACT

Patient advocacy groups can push regulators to approve and pay for expensive drugs despite weak evidence of efficacy and/or safety. Advocacy organizations that critique high prices for rare diseases are less publicized but can also influence policy. The funding and relationships many groups have with the pharmaceutical industry may contribute to patient advocates' differing perspectives, but the leaders' values and experiences are an overlooked factor. We need to understand the dominant public-private partnership model of patient advocacy, its historical roots, justification and how key advocacy actors respond to it if we are to advance policies that will contain expensive drugs for rare diseases.

PMID:36692917 | DOI:10.12927/hcpap.2023.26995

Healthc Pap. 2023 Jan;21(1):44-51. doi: 10.12927/hcpap.2023.26996.

ABSTRACT

Cancer medicines comprise the largest proportion of expensive drugs for rare diseases (EDRDs). The US Orphan Drug Act (ODA) (Office of Inspector General, Department of Health and Human Services 2001) encourages pharmaceutical manufacturers to develop medicines for rare diseases through a range of financial incentives, which has shifted the development of cancer medicines to rare cancer subtypes. Although certain medicines approved through the ODA have revolutionized cancer treatment, only half demonstrate added therapeutic benefit compared to existing alternatives. Canadian regulators should ensure that cancer medicines that receive fast-track approval through the Health Canada Notice of Compliance with conditions offer benefit to Canadian patients. Furthermore, payers might engage in methods for reassessment and renegotiations over the medicines' lifespan.

PMID:36692916 | DOI:10.12927/hcpap.2023.26996

Healthc Pap. 2023 Jan;21(1):34-37. doi: 10.12927/hcpap.2023.26998.

ABSTRACT

Canadian and foreign governments are struggling with determining whether to reimburse expensive drugs for rare diseases. The problem is that although insurers want to offer fair access to medicines for patients with rare diseases, the drugs are often priced far above normal cost-effectiveness thresholds. This leaves insurers with no tools to determine how much to pay. This article notes one reasonable standard: prices should not, in these circumstances, allow for profiteering by innovative companies.

PMID:36692914 | DOI:10.12927/hcpap.2023.26998

Healthc Pap. 2023 Jan;21(1):28-33. doi: 10.12927/hcpap.2023.26999.

ABSTRACT

In Canada, the focus on value for money and evaluating efficacy according to traditional ways has presented challenges to the funding of drugs for rare diseases (DRDs). This commentary validates and extends two worthy recommendations from the lead paper in this issue of Healthcare Papers (Sirrs et al. 2023). The paper's first recommendation, for a pan-Canadian approach for collecting evidentiary data, is critical. In the commentary, I add to this finding by suggesting that we enable patients to track and measure their response to treatment through data capture. The second recommendation is a pan-Canadian framework for funding DRDs. I extend the recommendation with an argument for public and private payer guidance as well as a fair and transparent funding framework solely for DRDs.

PMID:36692913 | DOI:10.12927/hcpap.2023.26999

Healthc Pap. 2023 Jan;21(1):10-26. doi: 10.12927/hcpap.2023.27000.

ABSTRACT

There has been explosive growth in the market for expensive drugs for rare diseases (EDRDs). Traditional standards of evidence are not achievable for rare diseases, so lower standards are applied. The price of these drugs is extremely high. This combination of lower standards and higher prices make EDRDs attractive to manufacturers. Legislation designed to incentivize drug development for rare diseases contains loopholes that drive prices up worldwide. Canada compounds those problems with a complex network of agencies that impede communication between those providing market authorization and those purchasing drugs. Drug pricing is not related to metrics like investment or value, but rather willingness to pay. Without high-quality evidence to assess value, we inadvertently prioritize patients with rare diseases over those with common diseases, creating conflict among ethical principles such as social utility, justice and the rule of rescue. Lack of transparency over what is being funded and for whom makes it hard to mitigate challenges through effective policy development. We review the evidentiary, economic and ethical issues around EDRDs and ways to move forward, including enhanced transparency and the development of high-quality evidence to ensure that we do not pay for drugs that do not work.

PMID:36692912 | DOI:10.12927/hcpap.2023.27000

Healthc Pap. 2023 Jan;21(1):4-8. doi: 10.12927/hcpap.2023.27001.

ABSTRACT

This issue of Healthcare Papers on expensive drugs for rare diseases (EDRDs) is very timely. According to the recently released Patented Medicine Prices Review Board's 2021 annual report, EDRDs have gone from 1.7% of pharmaceutical expenditures in 2012 to 12.2% in 2021, with a compound annual growth rate between 2012 and 2021 of 31.7% compared to 6.0% for all prescription medicines (PMPRB 2022).

PMID:36692911 | DOI:10.12927/hcpap.2023.27001

Med Klin Intensivmed Notfmed. 2023 Feb;118(1):2-3. doi: 10.1007/s00063-023-00989-x. Epub 2023 Jan 24.

NO ABSTRACT

PMID:36692505 | DOI:10.1007/s00063-023-00989-x

BMC Cancer. 2023 Jan 24;23(1):82. doi: 10.1186/s12885-022-10498-3.

ABSTRACT

Mastocytosis is a very rare disorder and is divided into three prognostically distinct variants by World Health Organization: Cutaneous mastocytosis (CM), systemic mastocytosis (SM), and mast cell sarcoma or localized mast cell (MC) tumors. The wide range of complaints may cause patients to consult various clinics, with resulting mis- or underdiagnosis. Therefore, cooperation between different subspecialties is of paramount importance. In this article, we have compiled 104 adult mastocytosis cases diagnosed and followed in our Hematology and other clinics. 86 (82.7%) of 104 patients had systemic mastocytosis. Osteoporosis, disease-related complications, and secondary malignancies are important topics in this group. We know that indolent form has great survival. But smoldering or aggressive mastocytosis has a poor prognosis. CM and indolent SM have a significantly better prognosis compared to aggressive SM (p < 0.001). We found that the presence of more than 25% of mast cells in the bone marrow, the presence of concomitant marrow dysplasia, and the presence of disease-related complications affect survival (p < 0.001). In addition to the WHO classification, the IPSM scoring system is indicative of the prognosis in this rare disease.

PMID:36694141 | DOI:10.1186/s12885-022-10498-3

Front Public Health. 2023 Jan 4;10:1049349. doi: 10.3389/fpubh.2022.1049349. eCollection 2022.

ABSTRACT

Rare disease patients constitute a significant part of the healthcare system of all countries. However, the information on the experiences during disease processes and daily life of rare disease patients is still limited. So far, there is a small number of studies conducted in Türkiye, and they mainly cover specific issues like education or anxiety. Here we present a comprehensive survey analysis conducted among the patients and their families within the scope of the Istanbul Solution Platform for Undiagnosed and Rare Diseases-ISTisNA project. A total of 498 individuals responded to the survey, and 58% of the participants answered all questions. The majority of the patients were in the age range of 1-10 years (44.7%), and 91% of all the patients had a precise diagnosis. The diagnosis rate in the first 6 months was 69%, and almost 10% of the patients remained undiagnosed. The mothers were the primary caregivers (72%). Nearly 30% of the caregivers had to quit their jobs and 25% of the patients (0-18 years) had to leave school. Accessing physicians with relevant specialization and reaching treatments/medications/supplements were the two main obstacles the participants mentioned, with a frequency of 81% and 73%, respectively. Around 50% of participants noted that they commonly faced difficulties at work/school and in their social lives. The highest expectation or priority was the establishment of rare disease-specific diagnosis and treatment centers, accurate and detailed information on diseases in the Turkish language, and easy access to physicians, treatments, and supportive therapies. To the best of our knowledge, this is the most comprehensive survey conducted on the rare disease community in Türkiye. These results show that regardless of the country, the individuals affected by rare diseases and their families have similar problems and expectations. On the other hand, regional and country-specific issues are still in the line to be solved. These studies can provide a deeper insight into rare diseases and guide the activities of Türkiye's national rare disease action plan.

PMID:36684907 | PMC:PMC9846031 | DOI:10.3389/fpubh.2022.1049349

Orphanet J Rare Dis. 2023 Jan 23;18(1):15. doi: 10.1186/s13023-023-02613-9.

NO ABSTRACT

PMID:36691034 | DOI:10.1186/s13023-023-02613-9

Eur J Hum Genet. 2023 Jan 23. doi: 10.1038/s41431-023-01291-2. Online ahead of print.

ABSTRACT

Clinical exome/genome sequencing is increasingly being utilized by clinicians to diagnose various likely genetic conditions, but many cases remain undiagnosed. In a subset of those undiagnosed cases, a single heterozygous variant in an autosomal recessive (AR) condition with consistent phenotype may be identified, raising the question if a second variant is missing. Here, we report two cases of recessive conditions in which only one heterozygous variant was initially reported by clinical exome sequencing, and on research reanalysis a second heterozygous variant in trans was identified. We performed a review of the existing exome reanalysis literature and found that this aspect is often not emphasized. These findings highlight the importance of data reanalysis in undiagnosed cases where only a single disease-associated variant is identified in an AR condition with a strong link to presenting phenotype.

PMID:36690831 | DOI:10.1038/s41431-023-01291-2

Biochem Biophys Res Commun. 2023 Jan 13;645:164-172. doi: 10.1016/j.bbrc.2023.01.032. Online ahead of print.

ABSTRACT

Matrin 3 is a nuclear matrix protein that has many roles in RNA processing including splicing and transport of mRNA. Many missense mutations in the Matrin 3 gene (MATR3) have been linked to familial forms of amyotrophic lateral sclerosis (ALS) and distal myopathy. However, the exact role of MATR3 mutations in ALS and myopathy pathogenesis is not understood. To demonstrate a role of MATR3 mutations in vivo, we generated a novel CRISPR/Cas9 mediated knock-in mouse model harboring the MATR3 P154S mutation expressed under the control of the endogenous promoter. The P154S variant of the MATR3 gene has been linked to familial forms of ALS. Heterozygous and homozygous MATR3 P154S knock-in mice did not develop progressive motor deficits compared to wild-type mice. In addition, ALS-like pathology did not develop in nervous or muscle tissue in either heterozygous or homozygous mice. Our results suggest that the MATR3 P154S variant is not sufficient to produce ALS-like pathology in vivo.

PMID:36689813 | DOI:10.1016/j.bbrc.2023.01.032