Orphanet J Rare Dis. 2022 Mar 4;17(1):113. doi: 10.1186/s13023-022-02260-6.

ABSTRACT

BACKGROUND: The Canadian government has committed to developing a national strategy for drugs for rare diseases starting in 2022. Considering this announcement, we conducted a comparative analysis to examine patient access to therapies for rare disease in Canada relative to Europe and the U.S.

METHODS: Given its similarity to the Canadian health care system, we used Europe as the reference point to analyze all of the therapies with an orphan drug designation approved by the European Medicine Agency (EMA) from 1 January 2015 to 31 March 2020. We then contrasted access to these drugs in Canada (Health Canada) and the U.S. (Food and Drug Administration, FDA). We focused on: (1) the number of therapies for rare diseases entering the Canadian market; (2) the percentage of these therapies that are publicly available to Canadians; and (3) the timelines for patients to access these therapies in Canada.

RESULTS: Sixty-three approved therapies with an orphan drug designation from the EMA were identified. Fifty-three (84%) of these drugs had also been submitted to the FDA for approval, and 41 (65%) were submitted to Health Canada for approval. In Europe, Germany, Denmark, and the U.K. had the highest percentage of publicly reimbursed orphan drugs (84%, 70%, 68%, respectively). In comparison, Ontario (32%), Quebec (25%), and Alberta (25%) had the highest percentage of drugs reimbursed among the Canadian provinces. The shortest median duration (in months) from EMA approval to jurisdictional decision on reimbursement was in Austria (3.2), followed by Germany (4.1), and Finland (6.0). In Canada, the shortest median duration (in months) from regulatory approval to reimbursement was in British Columbia (17.3), Quebec (19.6) and Manitoba (19.6), while the longest duration was in P.E.I (38.5), followed by Nova Scotia (25.9), and Newfoundland (25.1).

CONCLUSIONS: Our comparative analysis found that relative to the EU Canadians had less frequent and timely access to therapies for rare diseases. This highlights the need for a rare disease strategy in Canada that allows for clear identification and transparent tracking of the pathway for rare disease drugs, and ultimately optimizes the number of patients with access to these therapies.

PMID:35246200 | PMC:PMC8895096 | DOI:10.1186/s13023-022-02260-6

Orphanet J Rare Dis. 2022 Mar 4;17(1):108. doi: 10.1186/s13023-022-02240-w.

ABSTRACT

Rett syndrome is associated with severe functional impairments and many comorbidities, each in urgent need of treatments. Mutations in the MECP2 gene were identified as causing Rett syndrome in 1999. Over the past 20 years there has been an abundance of preclinical research with some studies leading to human clinical trials. Despite this, few viable therapeutic options have emerged from this investment of effort. Reasons for this lack of success as they relate both to preclinical research and the clinical trial landscape are discussed. Considering what needs to be done to promote further success in the field, we take a positive and constructive approach and introduce the concept of clinical trial readiness and its necessary ingredients for Rett syndrome. These include: listening to the needs of families; support from advocacy groups; optimising use of existing clinic infrastructures and available natural history data; and, finally, the validation of existing outcome measures and/or the development and validation of new measures. We conclude by reiterating the need for a collaborative and coordinated approach amongst the many different stakeholder groups and the need to engage in new types of trial design which could be much more efficient, less costly and much less burdensome on families.

PMID:35246185 | PMC:PMC8894842 | DOI:10.1186/s13023-022-02240-w

Orphanet J Rare Dis. 2022 Mar 2;17(1):89. doi: 10.1186/s13023-022-02209-9.

ABSTRACT

BACKGROUND: Since it first started operating in 2017, the European Reference Network for Rare Neurological Diseases (ERN-RND) implemented a multi-channel communication strategy to effectively reach its target audience: healthcare professionals, patients, researchers, industry representatives and the general public. We first created a website containing useful and up to date information, followed by social media accounts. Here, the analytical data collected about the ERN-RND website and social media channels was compared (Twitter, Facebook, YouTube) during two periods: October 2018 to September 2019, and the year after the ERN-RND free educational webinars were launched: from October 2019 to September 2020. This allowed us to quantify the impact of offering a tangible product (webinars) on the communication strategy.

RESULTS: The analytical data obtained from October 2018 to September 2019 and from October 2019 to September 2020 clearly shows a significant increase in traffic and followers since the launch of the ERN-RND webinars in November 2019. We also created a communication survey which was disseminated between February and June 2021. We collected responses from 61 people: 38 healthcare professionals, 11 scientists, 10 patients (advocates), 2 industry representatives, 1 patient association, 1 charity representative, 1 resident and 1 master student. Most respondents answered "webinars" as the number one reason when asked about which content they look for on the ERN-RND website.

CONCLUSIONS: Offering a tangible product-such as the webinars presented in this report-to a specific target group (healthcare professionals) supported our communication strategy by driving traffic to ERN-RND communication channels. It has also successfully tackled ERN-RND's general aim: by enabling the flow of knowledge on rare neurological and movement disorders to the medical community in hospitals treating patients with these rare and complex conditions, patients ultimately benefit from improved and faster diagnosis, care, and treatment. We aim to set up similar strategies to effectively reach other or the same target groups. For healthcare professionals, organising eConsultations via the Clinical Patient Management System or disseminating standards of care such as diagnostic and therapeutic algorithms as well as clinical practice guidelines might offer potential. For the patient community, organising customised and multilingual webinars could also work.

PMID:35236389 | PMC:PMC8889675 | DOI:10.1186/s13023-022-02209-9

Clin Chest Med. 2022 Mar;43(1):1-6. doi: 10.1016/j.ccm.2021.12.001.

ABSTRACT

The previous issue of Clinics in Chest Medicine was published in 2012 and described the state of the art in the disease at that time. In the intervening years, bronchiectasis has experienced something of a renaissance, leaving behind the label of an "orphan disease." Major developments in the past 10 years including a deeper understanding of epidemiology include the development of international registries. An exponential increase in randomized clinical trials in bronchiectasis has strengthened the evidence base for treatments but much work remains to translate the increasing global interest in the disease into a better understanding of the condition and improved patient outcomes.

PMID:35236552 | DOI:10.1016/j.ccm.2021.12.001

J Int Med Res. 2022 Feb;50(2):3000605221082882. doi: 10.1177/03000605221082882.

ABSTRACT

Coronary artery-left ventricular multiple microfistulas (CALVMMFs) are a very rare type of coronary artery fistula. Because of their special anatomical structure and hemodynamics, CALVMMFs often result in no obvious symptoms and signs. Most patients are diagnosed by coronary angiography; however, as a routine noninvasive screening method, Doppler echocardiography is a potential first-choice diagnostic technique for patients with CALVMMFs. Although satisfactory results of CALVMMF closure are difficult to achieve, the clinical symptoms of these patients are not obvious, and drug therapy has a clear therapeutic effect on most patients. We herein introduce seven cases of CALVMMFs confirmed by our hospital and briefly review the related literature.

PMID:35225046 | DOI:10.1177/03000605221082882

J Thromb Haemost. 2022 Mar;20(3):783-784. doi: 10.1111/jth.15634.

NO ABSTRACT

PMID:35220655 | DOI:10.1111/jth.15634

J Thromb Haemost. 2022 Mar;20(3):781-783. doi: 10.1111/jth.15632.

NO ABSTRACT

PMID:35220653 | DOI:10.1111/jth.15632

J Nephrol. 2022 Apr;35(3):841-850. doi: 10.1007/s40620-022-01258-4. Epub 2022 Feb 26.

ABSTRACT

BACKGROUND: Primary hyperoxalurias (PHs) are rare autosomal recessive diseases of the glyoxylate metabolism; PH1 is caused by mutations in the AGXT gene, PH2 in GRHPR and PH3 in HOGA1.

METHODS: Here we report the first large multi-center cohort of Italian PH patients collected over 30 years (1992-2020 median follow-up time 8.5 years). Complete genotype was available for 94/95 PH1 patients and for all PH2 (n = 3) and PH3 (n = 5) patients. Symptoms at onset were mainly nephrolithiasis (46.3%) and nephrocalcinosis (33.7%). Median age at onset of symptoms and diagnosis were 4.0 years and 9.9 years, respectively.

RESULTS: Fifty-four patients (56.8%) were diagnosed after chronic kidney disease. Sixty-three patients (66.3%) developed end stage kidney disease (median age 14.0 years). Twenty-one patients had a kidney-only transplant and, among them, seven had a second kidney transplant combined with liver transplant. A combined kidney-liver transplant was carried out in 29 patients and a sequential kidney-liver transplant was performed in two. In five cases a preemptive liver transplant was performed. Those receiving a liver-only transplant tended to have lower kidney function at last follow-up.

CONCLUSION: Our study of PHs in Italy underlines a considerable diagnostic delay, which has only slightly decreased in recent years. Therefore, we suggest a more extensive use of both metabolic screening among patients with recurrent kidney stones and genotyping, including unambiguous assignment of minor/major allele status in order to promptly begin appropriate treatment. This will be fundamental in order to have access to the new therapies, which are mainly focused on substrate reduction for the oxalate-producing enzymes using RNA-interference.

PMID:35218550 | DOI:10.1007/s40620-022-01258-4

Cold Spring Harb Mol Case Stud. 2022 Mar 24;8(2):a006205. doi: 10.1101/mcs.a006205. Print 2022 Feb.

ABSTRACT

My underlying diagnosis since birth was congenital muscular dystrophy not otherwise specified Being born in 1970 meant that there were no genetic testing, no standards of care, and no true understanding of the pathology that separates one congenital-onset neuromuscular disorder from the next. Two muscle biopsies described histological abnormalities of small type 1 fibers and were among the first of M.H. Brooke's cases described as congenital fiber-type disproportion (Brooke, Experta Medica 295: 147 [1973]).

PMID:35217566 | PMC:PMC8958917 | DOI:10.1101/mcs.a006205

Cold Spring Harb Mol Case Stud. 2022 Mar 24;8(2):a006198. doi: 10.1101/mcs.a006198. Print 2022 Feb.

ABSTRACT

In the past 5 years transcriptome or RNA-sequencing (RNA-seq) has steadily emerged as a complementary assay for rare disease diagnosis and discovery. In this perspective, we summarize several recent developments and challenges in the use of RNA-seq for rare disease investigation. Using an accessible patient sample, such as blood, skin, or muscle, RNA-seq enables the assay of expressed RNA transcripts. Analysis of RNA-seq allows the identification of aberrant or outlier gene expression and alternative splicing as functional evidence to support rare disease study and diagnosis. Further, many types of variant effects can be profiled beyond coding variants, as the consequences of noncoding variants that impact gene expression and splicing can be directly observed. This is particularly apparent for structural variants that disproportionately underlie outlier gene expression and for splicing variants in which RNA-seq can both measure aberrant canonical splicing and detect deep intronic effects. However, a major potential limitation of RNA-seq in rare disease investigation is the developmental and cell type specificity of gene expression as a pathogenic variant's effect may be limited to a specific spatiotemporal context and access to a patient's tissue sample from the relevant tissue and timing of disease expression may not be possible. We speculate that as advances in computational methods and emerging experimental techniques overcome both developmental and cell type specificity, there will be broadening use of RNA sequencing and multiomics in rare disease diagnosis and delivery of precision health.

PMID:35217565 | PMC:PMC8958920 | DOI:10.1101/mcs.a006198

Cold Spring Harb Mol Case Stud. 2022 Mar 24;8(2):a006204. doi: 10.1101/mcs.a006204. Print 2022 Feb.

ABSTRACT

The start of 2022 is an inflection point in the development of diagnostics and treatments for rare genetic diseases in prenatal, pediatric, and adult individuals-the theme of this special issue. Here I briefly review recent developments in two pivotal aspects of genetic disease diagnostics and treatments: education and equitable implementation.

PMID:35217563 | PMC:PMC8958907 | DOI:10.1101/mcs.a006204

Int J Mol Sci. 2022 Feb 21;23(4):2373. doi: 10.3390/ijms23042373.

ABSTRACT

The circadian clock, which drives a wide range of bodily rhythms in synchrony with the day-night cycle, is based on a molecular oscillator that ticks with a period of approximately 24 h. Timed proteasomal degradation of clock components is central to the fine-tuning of the oscillator's period. FBXL3 is a protein that functions as a substrate-recognition factor in the E3 ubiquitin ligase complex, and was originally shown in mice to mediate degradation of CRY proteins and thus contribute to the mammalian circadian clock mechanism. By exome sequencing, we have identified a FBXL3 mutation in patients with syndromic developmental delay accompanied by morphological abnormalities and intellectual disability, albeit with a normal sleep pattern. We have investigated the function of FBXL3 in the zebrafish, an excellent model to study both vertebrate development and circadian clock function and, like humans, a diurnal species. Loss of fbxl3a function in zebrafish led to disruption of circadian rhythms of promoter activity and mRNA expression as well as locomotor activity and sleep-wake cycles. However, unlike humans, no morphological effects were evident. These findings point to an evolutionary conserved role for FBXL3 in the circadian clock system across vertebrates and to the acquisition of developmental roles in humans.

PMID:35216494 | PMC:PMC8875760 | DOI:10.3390/ijms23042373

BMJ Case Rep. 2022 Feb 24;15(2):e244732. doi: 10.1136/bcr-2021-244732.

ABSTRACT

A 34-year-old man presented to our hospital with a 5-day history of progressive abdominal pain and fever. A CT scan identified extensive mesenteric lymphadenopathy. Initial diagnostic tests were inconclusive. Abdominal lymph node biopsy showed histiocytic necrotising lymphadenitis, compatible with Kikuchi-Fujimoto disease (KFD). This benign and self-limiting disease generally resolves following supportive treatment. In this case, remission occurred within 3 weeks of initial presentation. KFD is a very uncommon cause of lymphadenopathy, and selective mesenteric involvement is rare. Definitive diagnosis often requires lymph node biopsy. It is important to exclude more common and serious differential diagnoses associated with mesenteric lymphadenopathy, while maintaining a minimally invasive diagnostic approach, before progressing to nodal biopsy.

PMID:35210223 | DOI:10.1136/bcr-2021-244732

Curr Oncol. 2022 Feb 10;29(2):956-968. doi: 10.3390/curroncol29020081.

ABSTRACT

Diffuse large B-cell lymphoma (DLBCL) represents the most frequent type of non-Hodgkin lymphoma. Globally, DLBCL is an aggressive disease, requiring an accurate diagnosis and prompt treatment. The diagnosis is often made on biopsy samples of a nodal mass, however, approximately 40% of DLBCL cases arise at extranodal sites. The most common extranodal site is the gastrointestinal tract, however any extranodal area may be primarily involved. Primary urinary bladder lymphoma represents only 0.2% of extranodal non-Hodgkin lymphomas, whereas secondary involvement of the urinary bladder by a systemic lymphoma is a more common event. Despite being rare, DLBCL is considered to represent the predominant primary urinary bladder lymphoma. The majority of cases reported in the bladder belong to the DLBCL, NOS group, and there are only rare cases of EBV-positive DLBCL, NOS. In this review, we summarize the current knowledge on DLBCL primarily occurring in the urinary bladder, with the aim of increasing clinician and pathologist awareness on this aggressive lymphoma rarely arising in the urinary bladder. Additionally, we focus on those entities which should be taken into consideration in the differential diagnosis, highlighting potential diagnostic pitfalls.

PMID:35200580 | PMC:PMC8870454 | DOI:10.3390/curroncol29020081

Am J Hum Genet. 2022 Feb 17:S0002-9297(22)00054-4. doi: 10.1016/j.ajhg.2022.02.003. Online ahead of print.

ABSTRACT

Chromatin is essentially an array of nucleosomes, each of which consists of the DNA double-stranded fiber wrapped around a histone octamer. This organization supports cellular processes such as DNA replication, DNA transcription, and DNA repair in all eukaryotes. Human histone H4 is encoded by fourteen canonical histone H4 genes, all differing at the nucleotide level but encoding an invariant protein. Here, we present a cohort of 29 subjects with de novo missense variants in six H4 genes (H4C3, H4C4, H4C5, H4C6, H4C9, and H4C11) identified by whole-exome sequencing and matchmaking. All individuals present with neurodevelopmental features of intellectual disability and motor and/or gross developmental delay, while non-neurological features are more variable. Ten amino acids are affected, six recurrently, and are all located within the H4 core or C-terminal tail. These variants cluster to specific regions of the core H4 globular domain, where protein-protein interactions occur with either other histone subunits or histone chaperones. Functional consequences of the identified variants were evaluated in zebrafish embryos, which displayed abnormal general development, defective head organs, and reduced body axis length, providing compelling evidence for the causality of the reported disorder(s). While multiple developmental syndromes have been linked to chromatin-associated factors, missense-bearing histone variants (e.g., H3 oncohistones) are only recently emerging as a major cause of pathogenicity. Our findings establish a broader involvement of H4 variants in developmental syndromes.

PMID:35202563 | DOI:10.1016/j.ajhg.2022.02.003

Curr Oncol. 2022 Feb 17;29(2):1223-1236. doi: 10.3390/curroncol29020104.

ABSTRACT

Small bowel adenocarcinoma (SBA) is a rare malignancy, with a rising incidence in recent decades, and accounts for roughly 40% of all cancers of the small bowel. The majority of SBAs arise in the duodenum and are associated with a dismal prognosis. Surgery remains the mainstay of treatment for localized disease, while systemic treatments parallel those used in colorectal cancer (CRC), both in the adjuvant and palliative setting. In fact, owing to the lack of prospective data supporting its optimal management, SBA has historically been treated in the same way as CRC. However, recent genetic and molecular data suggest a distinct profile from other gastrointestinal malignancies and support a more nuanced approach to its management. Herein, we briefly review the state-of-the-art in the clinical management of early-stage and advanced disease and recent discoveries of potentially actionable genetic alterations or pathways along with the most promising ongoing clinical trials, which will hopefully revolutionize the treatment landscape of this orphan disease in the foreseeable future.

PMID:35200603 | DOI:10.3390/curroncol29020104

Zool Res. 2022 Mar 18;43(2):234-236. doi: 10.24272/j.issn.2095-8137.2022.068.

NO ABSTRACT

PMID:35194981 | DOI:10.24272/j.issn.2095-8137.2022.068

Ann Surg Oncol. 2022 May;29(5):2805-2811. doi: 10.1245/s10434-022-11416-4. Epub 2022 Feb 21.

ABSTRACT

It is unknown whether the survival of patients cured of esophageal cancer differs from that of the corresponding background population. This nationwide and population-based cohort study included all patients who survived for at least 5 years after surgery for esophageal cancer in Sweden between 1987 and 2015, with follow-up throughout 2020. Relative survival rates with 95% confidence intervals (95% CI) were calculated by dividing the observed with the expected survival. The expected survival was assessed from the entire Swedish population of the corresponding age, sex, and calendar year. Yearly relative survival rates were calculated between 6 and 10 years postoperatively. Among all 762 participants, the relative survival was initially similar to the background population (96.1%, 95% CI 94.3-97.9%), but decreased each following postoperative year to 83.5% (95% CI 79.5-87.6%) by year 10. The drop in relative survival between 6 and 10 years was more pronounced in participants with a history of squamous cell carcinoma [from 94.5% (95% CI 91.2-97.8%) to 70.8% (95% CI 64.0-77.6%)] than in those with adenocarcinoma [from 96.9% (95% CI 94.8-99.0%) to 91.5% (95% CI 86.6-96.3%)], and in men [from 96.0% (95% CI 93.8-98.1%) to 81.8% (95% CI 76.8-86.8%)] than in women [from 96.4% (95% CI 93.4-99.5%) to 88.1% (95% CI 81.5-94.8%)]. No major differences were found between age groups. In conclusion, esophageal cancer survivors had a decline in survival between 6 and 10 years after surgery compared with the corresponding general population, particularly those with a history of squamous cell carcinoma of the esophagus and male sex.

PMID:35190948 | DOI:10.1245/s10434-022-11416-4

Brain. 2021 Nov 23:awab327. doi: 10.1093/brain/awab327. Online ahead of print.

ABSTRACT

Disease-causing variants in STXBP1 are among the most common genetic causes of neurodevelopmental disorders. However, the phenotypic spectrum in STXBP1-related disorders is wide and clear correlations between variant type and clinical features have not been observed so far. Here, we harmonized clinical data across 534 individuals with STXBP1-related disorders and analysed 19 973 derived phenotypic terms, including phenotypes of 253 individuals previously unreported in the scientific literature. The overall phenotypic landscape in STXBP1-related disorders is characterized by neurodevelopmental abnormalities in 95% and seizures in 89% of individuals, including focal-onset seizures as the most common seizure type (47%). More than 88% of individuals with STXBP1-related disorders have seizure onset in the first year of life, including neonatal seizure onset in 47%. Individuals with protein-truncating variants and deletions in STXBP1 (n = 261) were almost twice as likely to present with West syndrome and were more phenotypically similar than expected by chance. Five genetic hotspots with recurrent variants were identified in more than 10 individuals, including p.Arg406Cys/His (n = 40), p.Arg292Cys/His/Leu/Pro (n = 30), p.Arg551Cys/Gly/His/Leu (n = 24), p.Pro139Leu (n = 12), and p.Arg190Trp (n = 11). None of the recurrent variants were significantly associated with distinct electroclinical syndromes, single phenotypic features, or showed overall clinical similarity, indicating that the baseline variability in STXBP1-related disorders is too high for discrete phenotypic subgroups to emerge. We then reconstructed the seizure history in 62 individuals with STXBP1-related disorders in detail, retrospectively assigning seizure type and seizure frequency monthly across 4433 time intervals, and retrieved 251 anti-seizure medication prescriptions from the electronic medical records. We demonstrate a dynamic pattern of seizure control and complex interplay with response to specific medications particularly in the first year of life when seizures in STXBP1-related disorders are the most prominent. Adrenocorticotropic hormone and phenobarbital were more likely to initially reduce seizure frequency in infantile spasms and focal seizures compared to other treatment options, while the ketogenic diet was most effective in maintaining seizure freedom. In summary, we demonstrate how the multidimensional spectrum of phenotypic features in STXBP1-related disorders can be assessed using a computational phenotype framework to facilitate the development of future precision-medicine approaches.

PMID:35190816 | DOI:10.1093/brain/awab327

Front Immunol. 2022 Feb 4;13:785231. doi: 10.3389/fimmu.2022.785231. eCollection 2022.

ABSTRACT

Uveal melanoma (UM) is an orphan disease with a mortality of 80% within one year upon the development of metastatic disease. UM does hardly respond to chemotherapy and kinase inhibitors and is largely resistant to checkpoint inhibition. Hence, further therapy approaches are urgently needed. To improve clinical outcome, we designed a trial employing the 3rd generation personalized IKKβ-matured RNA-transfected dendritic cell (DC) vaccine which primes T cells and in addition activates NK cells. This ongoing phase I trial [NCT04335890 (www.clinicaltrials.gov), Eudract: 2018-004390-28 (www.clinicaltrialsregister.eu)] investigates patients with treatment-naive metastatic UM. Monocytes are isolated by leukapheresis, differentiated to immature DCs, matured with a cytokine cocktail, and activated via the NF-κB pathway by electroporation with RNA encoding a constitutively active mutant of IKKβ. Three types of antigen-RNA are co-electroporated: i) amplified mRNA of the tumor representing the whole transcriptome, ii) RNA encoding driver mutations identified by exome sequencing, and iii) overexpressed non-mutated tumor antigens detected by transcriptome sequencing. This highly personalized DC vaccine is applied by 9 intravenous infusions in a staggered schedule over one year. Parallel to the vaccination, standard therapy, usually an immune checkpoint blockade (ICB) as mono (anti-PD-1) or combined (anti-CTLA4 and anti-PD-1) regimen is initiated. The coordinated vaccine-induced immune response encompassing tumor-specific T cells and innate NK cells should synergize with ICB, perhaps resulting in measurable clinical responses in this resistant tumor entity. Primary outcome measures of this trial are safety, tolerability and toxicity; secondary outcome measures comprise overall survival and induction of antigen-specific T cells.

PMID:35185883 | PMC:PMC8854646 | DOI:10.3389/fimmu.2022.785231