BMC Bioinformatics. 2022 Nov 14;23(1):482. doi: 10.1186/s12859-022-05041-x.

ABSTRACT

BACKGROUND: Despite numerous molecular and computational advances, roughly half of patients with a rare disease remain undiagnosed after exome or genome sequencing. A particularly challenging barrier to diagnosis is identifying variants that cause deleterious alternative splicing at intronic or exonic loci outside of canonical donor or acceptor splice sites.

RESULTS: Several existing tools predict the likelihood that a genetic variant causes alternative splicing. We sought to extend such methods by developing a new metric that aids in discerning whether a genetic variant leads to deleterious alternative splicing. Our metric combines genetic variation in the Genome Aggregate Database with alternative splicing predictions from SpliceAI to compare observed and expected levels of splice-altering genetic variation. We infer genic regions with significantly less splice-altering variation than expected to be constrained. The resulting model of regional splicing constraint captures differential splicing constraint across gene and exon categories, and the most constrained genic regions are enriched for pathogenic splice-altering variants. Building from this model, we developed ConSpliceML. This ensemble machine learning approach combines regional splicing constraint with multiple per-nucleotide alternative splicing scores to guide the prediction of deleterious splicing variants in protein-coding genes. ConSpliceML more accurately distinguishes deleterious and benign splicing variants than state-of-the-art splicing prediction methods, especially in "cryptic" splicing regions beyond canonical donor or acceptor splice sites.

CONCLUSION: Integrating a model of genetic constraint with annotations from existing alternative splicing tools allows ConSpliceML to prioritize potentially deleterious splice-altering variants in studies of rare human diseases.

PMID:36376793 | DOI:10.1186/s12859-022-05041-x

Med Anthropol. 2022 Nov-Dec;41(8):866-878. doi: 10.1080/01459740.2022.2141630. Epub 2022 Nov 14.

ABSTRACT

Treatment of a child diagnosed with an inherited metabolic disease is a demanding task both for the clinicians and for the parents. The metabolic pediatricians and dietitians have to deal with scarce and dispersed clinical knowledge, while the parents must actively participate in its treatment, the bulk of which consists of a stringent diet and managing the risk of metabolic decompensation or intoxication. In this article, I characterize the medical epistemologies of a particular kind of "metabolic living," discussing differences and similarities between the clinical/expert knowledge of metabolic specialists, and the lay knowledge of parents of affected children.

PMID:36375091 | DOI:10.1080/01459740.2022.2141630

Orphanet J Rare Dis. 2022 Nov 12;17(1):415. doi: 10.1186/s13023-022-02568-3.

ABSTRACT

BACKGROUND: Individuals with Friedreich ataxia (FRDA) can find it difficult to access specialized clinical care. To facilitate best practice in delivering healthcare for FRDA, clinical management guidelines (CMGs) were developed in 2014. However, the lack of high-certainty evidence and the inadequacy of accepted metrics to measure health status continues to present challenges in FRDA and other rare diseases. To overcome these challenges, the Grading of Recommendations Assessment and Evaluation (GRADE) framework for rare diseases developed by the RARE-Bestpractices Working Group was adopted to update the clinical guidelines for FRDA. This approach incorporates additional strategies to the GRADE framework to support the strength of recommendations, such as review of literature in similar conditions, the systematic collection of expert opinion and patient perceptions, and use of natural history data.

METHODS: A panel representing international clinical experts, stakeholders and consumer groups provided oversight to guideline development within the GRADE framework. Invited expert authors generated the Patient, Intervention, Comparison, Outcome (PICO) questions to guide the literature search (2014 to June 2020). Evidence profiles in tandem with feedback from individuals living with FRDA, natural history registry data and expert clinical observations contributed to the final recommendations. Authors also developed best practice statements for clinical care points that were considered self-evident or were not amenable to the GRADE process.

RESULTS: Seventy clinical experts contributed to fifteen topic-specific chapters with clinical recommendations and/or best practice statements. New topics since 2014 include emergency medicine, digital and assistive technologies and a stand-alone section on mental health. Evidence was evaluated according to GRADE criteria and 130 new recommendations and 95 best practice statements were generated.

DISCUSSION AND CONCLUSION: Evidence-based CMGs are required to ensure the best clinical care for people with FRDA. Adopting the GRADE rare-disease framework enabled the development of higher quality CMGs for FRDA and allows individual topics to be updated as new evidence emerges. While the primary goal of these guidelines is better outcomes for people living with FRDA, the process of developing the guidelines may also help inform the development of clinical guidelines in other rare diseases.

PMID:36371255 | DOI:10.1186/s13023-022-02568-3

Fish Shellfish Immunol. 2022 Nov 9:S1050-4648(22)00743-4. doi: 10.1016/j.fsi.2022.10.067. Online ahead of print.

ABSTRACT

Spring viremia of carp (SVC) remains as a vaccine orphan disease mostly affecting juvenile specimens. Young fish are especially difficult to vaccinate and oral administration of vaccine combined with food would be the election system to minimise stress and the vaccination costs associated to injection. However, administration of prophylactics with food pellets faces off several drawbacks mainly related with vaccine degradation and weak protection correlates of oral vaccines. Here we present a platform based on recombinant proteins (subunit vaccines) manufactured as highly resistant nanostructured materials, and providing excellent levels of protection against SVC virus in a preliminar i.p injection challenge. The G3 domain of SVCV glycoprotein G was overexpressed in E. coli together with IFNγ and the modular protein was purified from bacterial aggregates (inclusion bodies) as highly organised nanostructured biomaterial (nanopellets, NP). These SVCV-IFNNP were taken up by zebrafish cells leading to the enhanced expression of different antiviral and IFN markers (e.g vig1, mx, lmp2 or infgr1 among others) in zebrafish liver cells (ZFL). To monitor if SVCVNP and SVCV-IFNNP can be taken up by intestinal epithelia and can induce antiviral response we performed experiments with SVCVNP and SVCV-IFNNP in 3 days post fertilization (dpf) zebrafish larvae. Both, SVCVNP and SVCV-IFNNP were taken up and accumulated in the intestine without signs of toxicity. The antiviral response in larvae showed a different induction pattern: SVCV-IFNNP did not induce an antiviral response while SVCVNP showed a good antiviral induction. Interestingly ZF4, an embryonic derived cell line, showed an antiviral response like ZFL cells, although the lmp2 and infgr (markers of the IFNγ response) were not overexpressed. Experiments with adult zebrafish indicated an excellent level of protection against a SVCV model infection where SVCV-IFNNP vaccinated fish reached 20% cumulative mortality while control fish reached over 80% cumulative mortality.

PMID:36371050 | DOI:10.1016/j.fsi.2022.10.067

Neurol Sci. 2022 Nov 11. doi: 10.1007/s10072-022-06487-w. Online ahead of print.

ABSTRACT

BACKGROUND: Hereditary spastic paraplegia (HSP) include various sporadic and hereditary neurodegenerative disorders, characterized by progressive spasticity and weakness of lower limbs, possibly associated to additional features.

CASE PRESENTATION: We report a male HPS patient in his 40 s, showing mental retardation associated with language impairment, dysarthria, and increased urinary frequency. Three months after treatment with electric chronic high-frequency cervical spinal cord stimulation (HF-SCS), he showed an amelioration of motor symptoms (lower limbs spasticity and gait), dysarthria, cognitive functioning (language and constructive praxic abilities), and urinary symptoms (decreased urinary frequency). Single-photon emission computed tomography (SPECT) showed a postoperative increase of cerebral perfusion in right frontal cortex and temporal cortex bilaterally.

CONCLUSION: In our patient, HF-SCS might have induced an activation of ascending neural pathways, resulting in changes in activity in various cortical areas (including sensory-motor cortical areas), which may give rise to a modulation of activity in spared descending motor pathways and in neural networks involved in cognitive functions, including language. Although further studies in patients with HPS are needed to clarify whether HF-SCS can be a suitable treatment option in HSP, our observation suggests that HF-SCS, a minimally invasive neurosurgical procedure, might induce beneficial effects of on various symptoms of such orphan disease.

PMID:36369309 | DOI:10.1007/s10072-022-06487-w

Int J Environ Res Public Health. 2022 Oct 28;19(21):14103. doi: 10.3390/ijerph192114103.

ABSTRACT

The context of a school may play a fundamental role in students' academic and personal progress. In this study, we focus on two contextual variables, the school type and school location or setting. The study used a questionnaire to assess teachers' knowledge and thoughts about rare diseases based on these variables, with the participation of 574 school teachers. To broaden the research perspective, another questionnaire was administered to members of 152 rare disease patient advocacy groups to ask about their participation in educational processes and analyse their results according to one of the contextual variables: the setting or location of each association. The results indicated statistically significant differences according to the variables examined, which were larger for the type of school variable. In short, numerous variables that influence the teaching and learning processes need to be considered in educational praxis; in this study, we looked at those of a contextual nature (for example, the geographic characteristics of schools and associations), and this is essential for increasingly heterogeneous educational locations that demand multidimensional approaches.

PMID:36360981 | DOI:10.3390/ijerph192114103

Pharmaceutics. 2022 Oct 29;14(11):2335. doi: 10.3390/pharmaceutics14112335.

ABSTRACT

To date, there is no approved local therapeutic agent for the treatment of epistaxis due to hereditary hemorrhagic telangiectasia (HHT). Several case reports suggest the topical use of timolol. This monocentric, prospective, randomized, placebo-controlled, double-blinded, cross-over study investigated whether the effectiveness of the standard treatment with a pulsed diode laser can be increased by also using timolol nasal spray. The primary outcome was severity of epistaxis after three months, while the main secondary outcome was severity of epistaxis and subjective satisfaction after one month. Twenty patients were allocated and treated, of which 18 patients completed both 3-month treatment sequences. Timolol was well tolerated by all patients. Epistaxis Severity Score after three months, the primary outcome measure, showed a beneficial, but statistically nonsignificant (p = 0.084), effect of additional timolol application. Epistaxis Severity Score (p = 0.010) and patients' satisfaction with their nosebleeds after one month (p = 0.050) showed statistically significant benefits. This placebo-controlled, randomized trial provides some evidence that timolol nasal spray positively impacts epistaxis severity and subjective satisfaction in HHT patients when additively applied to standard laser therapy after one month. However, the effect of timolol was observed to diminish over time. Trials with larger sample sizes are warranted to confirm these findings.

PMID:36365152 | DOI:10.3390/pharmaceutics14112335

Cancers (Basel). 2022 Oct 28;14(21):5313. doi: 10.3390/cancers14215313.

ABSTRACT

Over the last several decades, an improved understanding of von Hippel-Lindau disease and its underlying biology has informed the successful development of numerous anti-cancer agents, particularly for the treatment of advanced renal cell carcinoma. Most recently, this has culminated in the first regulatory approval for a systemic therapy for VHL disease-associated neoplasms. This review will trace the clinical development of systemic therapies for VHL disease and additionally highlight anticipated challenges and opportunities for future VHL systemic therapy.

PMID:36358730 | DOI:10.3390/cancers14215313

Nat Biotechnol. 2022 Nov;40(11):1539-1541. doi: 10.1038/s41587-022-01545-2.

NO ABSTRACT

PMID:36347981 | DOI:10.1038/s41587-022-01545-2

Orphanet J Rare Dis. 2022 Nov 8;17(1):408. doi: 10.1186/s13023-022-02526-z.

ABSTRACT

BACKGROUND: Extremely high prices facilitate drug development for ultra-rare diseases (ultra-orphan drugs). However, various problems arise in terms of healthcare financing and fairness, and the status of ultra-orphan drug pricing remains ambiguous. In this study, we investigated ultra-orphan drug prices in Japan relative to that of other drugs. We examined the relationship between annual expected drug prices and expected sales, and the expected number of patients, for 393 drugs containing new active ingredients for therapeutic use that were listed on the National Health Insurance drug price list in Japan between April 16, 2010 and August 26, 2020. In addition, we compared prices, the drug price calculation method, and price calculation adjustment factors for ultra-orphan and other drugs.

RESULTS: Drug prices tended to increase as the expected number of patients to whom the drug was administered decreased; however, this trend diminished when the expected number of patients was less than 1000. On the other hand, the expected sales tended to decrease as the number of expected patients decreased, and this tendency was reinforced when the expected number of patients was less than 1000. The cost accounting method tended to be used for the price calculation of ultra-orphan drugs, but there were no price differences based on the drug price calculation method. Regarding the price calculation adjustment factors, the premium for usefulness tended to be higher for ultra-orphan drugs. The premium for marketability was higher for non-orphan drugs but did not differ from that for orphan drugs, except for ultra-orphan drugs.

CONCLUSIONS: The status of drug prices and expected sales differed beyond a threshold of 1000 expected patients, indicating that recovering the development cost for ultra-orphan drugs is difficult. In addition, the higher premium for usefulness for ultra-orphan drugs reflects the largely unmet need of the associated diseases. Scarcity among orphan drugs is not considered for marketability, highlighting the need for a new framework to promote the development of ultra-orphan drugs.

PMID:36348359 | DOI:10.1186/s13023-022-02526-z

BMC Pediatr. 2022 Nov 8;22(1):650. doi: 10.1186/s12887-022-03722-3.

ABSTRACT

BACKGROUND: Primary generalized glucocorticoid hypersensitivity (PGGH) is a very rare disease caused by terminal organ hypersensitivity to glucocorticoids for which the aetiology is unknown. The incidence of PGGH is extremely rare, especially in children. To date, the literatures about the etiology, prognosis and treatment of PGGH are scarce. Aim of the study is describing the cases of two Chinese children with infantile-onset PGGH in one family, one of whom died and one who was treated with mifepristone. They are the two youngest children with PGGH reported in the literature.

CASE PRESENTATION: Two siblings with infantile-onset PGGH were affected in this family. The main manifestations of patient 1 were typical Cushing's syndrome-like manifestations, significantly aggravated symptoms after physiological doses of glucocorticoids and very low levels of serum cortisol and adrenocorticotropin hormone (ACTH) during attacks. After being diagnosed with PGGH, he was given guidance to avoid glucocorticoids and took mifepristone therapy for 5 months, and his symptoms improved. Patient 2 was the younger brother of patient 1, with similar manifestations to his brother at the age of 4 months. Patient 2 ultimately died at the age of 9 months.

CONCLUSION: PGGH is a very rare disease that can lead to death if not diagnosed and treated in a timely manner. This article describes the cases of the two youngest children with PGGH reported in the literature, one of whom improved after mifepristone treatment, and increases the knowledge of the clinical manifestations of and the treatment experience in PGGH.

PMID:36348308 | DOI:10.1186/s12887-022-03722-3

Nat Commun. 2022 Nov 7;13(1):6324. doi: 10.1038/s41467-022-32908-7.

ABSTRACT

Diagnostic whole genome sequencing (WGS) is increasingly used in rare diseases. However, standard, semi-automated WGS analysis may overlook diagnoses in complex disorders. Here, we show that specialist multidisciplinary analysis of WGS, following an initial 'no primary findings' (NPF) report, improves diagnostic rates and alters management. We undertook WGS in 102 adults with diagnostically challenging primary mitochondrial disease phenotypes. NPF cases were reviewed by a genomic medicine team, thus enabling bespoke informatic approaches, co-ordinated phenotypic validation, and functional work. We enhanced the diagnostic rate from 16.7% to 31.4%, with management implications for all new diagnoses, and detected strong candidate disease-causing variants in a further 3.9% of patients. This approach presents a standardised model of care that supports mainstream clinicians and enhances diagnostic equity for complex disorders, thereby facilitating access to the potential benefits of genomic healthcare. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project: http://www.genomicsengland.co.uk .

PMID:36344503 | DOI:10.1038/s41467-022-32908-7

Front Public Health. 2022 Oct 18;10:1028545. doi: 10.3389/fpubh.2022.1028545. eCollection 2022.

ABSTRACT

The genomics revolution over the past three decades has led to great strides in rare disease (RD) research, which presents a major shift in global policy landscape. While RDs are individually rare, there are common challenges and unmet medical and social needs experienced by the RD population globally. The various disabilities arising from RDs as well as diagnostic and treatment uncertainty were demonstrated to have detrimental influence on the health, psychosocial, and economic aspects of RD families. Despite the collective large number of patients and families affected by RDs internationally, the general lack of public awareness and expertise constraints have neglected and marginalized the RD population in health systems and in health- and social-care policies. The current Coronavirus Disease of 2019 (COVID-19) pandemic has exposed the long-standing and fundamental challenges of the RD population, and has reminded us of the critical need of addressing the systemic inequalities and widespread disparities across populations and jurisdictions. Owing to the commonality in goals between RD movements and universal health coverage targets, the United Nations (UN) has highlighted the importance of recognizing RDs in policies, and has recently adopted the UN Resolution to promote greater integration of RDs in the UN agenda, advancing UN's commitment in achieving the 2030 Sustainable Development Goals of "leav[ing] no one behind." Governments have also started to launch Genome Projects in their respective jurisdictions, aiming to integrate genomic medicine into mainstream healthcare. In this paper, we review the challenges experienced by the RD population, the establishment and adoption of RD policies, and the state of evidence in addressing these challenges from a global perspective. The Hong Kong Genome Project was illustrated as a case study to highlight the role of Genome Projects in enhancing clinical application of genomic medicine for personalized medicine and in improving equity of access and return in global genomics. Through reviewing what has been achieved to date, this paper will provide future directions as RD emerges as a global public health priority, in hopes of moving a step toward a more equitable and inclusive community for the RD population in times of pandemics and beyond.

PMID:36339196 | PMC:PMC9632971 | DOI:10.3389/fpubh.2022.1028545

Joint Bone Spine. 2022 Nov 4:105480. doi: 10.1016/j.jbspin.2022.105480. Online ahead of print.

NO ABSTRACT

PMID:36343878 | DOI:10.1016/j.jbspin.2022.105480

Am J Hum Genet. 2022 Nov 3;109(11):1947-1959. doi: 10.1016/j.ajhg.2022.10.002.

ABSTRACT

The past decade has witnessed a rapid evolution in rare disease (RD) research, fueled by the availability of genome-wide (exome and genome) sequencing. In 2011, as this transformative technology was introduced to the research community, the Care4Rare Canada Consortium was launched: initially as FORGE, followed by Care4Rare, and Care4Rare SOLVE. Over what amounted to three eras of diagnosis and discovery, the Care4Rare Consortium used exome sequencing and, more recently, genome and other 'omic technologies to identify the molecular cause of unsolved RDs. We achieved a diagnostic yield of 34% (623/1,806 of participating families), including the discovery of deleterious variants in 121 genes not previously associated with disease, and we continue to study candidate variants in novel genes for 145 families. The Consortium has made significant contributions to RD research, including development of platforms for data collection and sharing and instigating a Canadian network to catalyze functional characterization research of novel genes. The Consortium was instrumental to implementing genome-wide sequencing as a publicly funded test for RD diagnosis in Canada. Despite the successes of the past decade, the challenge of solving all RDs remains enormous, and the work is far from over. We must leverage clinical and 'omic data for secondary use, develop tools and policies to support safe data sharing, continue to explore the utility of new and emerging technologies, and optimize research protocols to delineate complex disease mechanisms. Successful approaches in each of these realms is required to offer diagnostic clarity to all families with RDs.

PMID:36332610 | DOI:10.1016/j.ajhg.2022.10.002

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2022 Nov;65(11):1117-1118. doi: 10.1007/s00103-022-03604-0. Epub 2022 Nov 4.

NO ABSTRACT

PMID:36331592 | PMC:PMC9636115 | DOI:10.1007/s00103-022-03604-0

Syst Rev. 2022 Nov 3;11(1):235. doi: 10.1186/s13643-022-02105-0.

ABSTRACT

BACKGROUND: Rare liver lesions and diseases have seldomly aroused major interest of researchers. For most guidelines, presumably similar clinical conditions are pooled without detailed investigations of singularities that they present.

MAIN TEXT: A multidisciplinary project aiming to establish evidence-based therapies for rare liver diseases has been founded. A series of systematic reviews and meta-analyses will be the starting point for a structured development of guidelines for rare conditions of the liver affecting pediatric and adult populations. The novel approach will be focusing on case reports and small patient series with distinct rare liver diseases without pooling several presumably acceptably similar conditions. Thus, a vital resource of information will be utilized, which has been largely neglected hitherto.

CONCLUSION: Highly specific recommendations based on highest available evidence will therefore be developed for specific conditions, advancing the individualized medicine approach for the afflicted patients.

PMID:36329524 | PMC:PMC9635082 | DOI:10.1186/s13643-022-02105-0

Neurol Genet. 2022 Oct 25;8(6):e200027. doi: 10.1212/NXG.0000000000200027. eCollection 2022 Dec.

ABSTRACT

BACKGROUND AND OBJECTIVES: Centronuclear myopathy (CNM) due to mutations in the dynamin 2 gene, DNM2, is a rare neuromuscular disease about which little is known. The objective of this study was to describe the range of clinical presentations and subsequent natural history of DNM2-related CNM.

METHODS: Pediatric and adult patients with suspicion for a CNM diagnosis and confirmed heterozygous pathogenic variants in DNM2 were ascertained between December 8, 2000, and May 1, 2019. Data were collected through a retrospective review of genetic testing results, clinical records, and pathology slides combined with patient-reported clinical findings via questionnaires.

RESULTS: Forty-two patients with DNM2-related CNM, whose ages ranged from 0.95 to 75.76 years at most recent contact, were enrolled from 34 families in North or South America and Europe. There were 8 different DNM2 pathogenic variants within the cohort. Of the 32 biopsied patients, all had histologic features of CNM. The disease onset was in infancy or childhood in 81% of the cohort, and more than half of the patients had high arched palates, indicative of weakness in utero. Ambulation was affected in nearly all (92%) the patients, and while the rapidity of progression was variable, most (67%) reported a "deteriorating course." Ptosis, ophthalmoparesis, facial weakness, dysphagia, and respiratory insufficiency were commonly reported. One-third of the patients experienced restricted jaw mobility. Certain pathogenic variants appear to correlate with a more severe phenotype.

DISCUSSION: DNM2-related CNM has a predominantly early-onset, often congenital, myopathy resulting in progressive difficulty with ambulation and occasionally bulbar and respiratory dysfunction. This detailed characterization of the phenotype provides important information to support clinical trial readiness for future disease-modifying therapies.

PMID:36324371 | PMC:PMC9621335 | DOI:10.1212/NXG.0000000000200027

Aliment Pharmacol Ther. 2022 Nov 2. doi: 10.1111/apt.17251. Online ahead of print.

ABSTRACT

BACKGROUND: Primary sclerosing cholangitis (PSC) is a progressive liver disease with poor prognosis and no effective therapies to prevent progression. An aetiopathological link between PSC and gastrointestinal microbial dysbiosis has been suggested.

AIM: To evaluate all potential medical therapies which may exert their effect in PSC by modulation of the gut-liver axis.

METHODS: We conducted a comprehensive scoping review of PubMed and Cochrane Library, including all articles evaluating an intervention aimed at manipulating the gastrointestinal microbiome in PSC.

RESULTS: A wide range of therapies proposed altering the gastrointestinal microbiome for the treatment of PSC. In particular, these considered antibiotics including vancomycin, metronidazole, rifaximin, minocycline and azithromycin. However, few therapies have been investigated in randomised, placebo-controlled trials. Vancomycin has been the most widely studied antibiotic, with improvement in alkaline phosphatase reported in two randomised controlled trials, but with no data on disease progression. Unlike antibiotics, strategies such as faecal microbiota transplantation and dietary therapy can improve microbial diversity. However, since these have only been tested in small numbers of patients, robust efficacy data are currently lacking.

CONCLUSIONS: The gut-liver axis is increasingly considered a potential target for the treatment of PSC. However, no therapies have been demonstrated to improve transplant-free survival. Innovative and well-designed clinical trials of microbiome-targeted therapies with long-term follow-up are required for this orphan disease.

PMID:36324251 | DOI:10.1111/apt.17251

Zhonghua Zhong Liu Za Zhi. 2022 Oct 23;44(10):1003-1010. doi: 10.3760/cma.j.cn112152-20220803-00531.

NO ABSTRACT

PMID:36319447 | DOI:10.3760/cma.j.cn112152-20220803-00531