Nervenarzt. 2024 Jun;95(6):564-572. doi: 10.1007/s00115-024-01674-w. Epub 2024 Jun 6.

ABSTRACT

Reversible cerebral vasoconstriction syndrome (RCVS) is a complex and etiologically diverse neurovascular disorder that typically presents with severe thunderclap headaches (TCH) as the primary symptom, accompanied by reversible vasoconstriction of the cerebral arteries. The clinical course may include focal neurological deficits or epileptic seizures. There are two types: idiopathic RCVS and secondary RCVS, the latter triggered by various substances, medical interventions, or diseases. In clinical practice, various medical specialists may initially encounter this condition, underscoring the importance of accurate recognition and diagnosis of RCVS. The clinical course often appears monophasic and self-limiting, with recurrences reported in only 1.7% of cases annually. Complications such as cerebral hemorrhages and cerebral ischemia can lead to death in 5-10% of cases. This article utilizes a case study to explore RCVS, its complications, and the diagnostic procedures involved.

PMID:38842549 | DOI:10.1007/s00115-024-01674-w

Endocr Connect. 2024 Jun 1:EC-24-0091. doi: 10.1530/EC-24-0091. Online ahead of print.

ABSTRACT

Prader Willi syndrome (PWS) is a rare orphan disease and complex genetic neurodevelopmental disorder, with a birth incidence of approximately 1 in 10,000-30,000. Management of people with PWS requires a multi-disciplinary approach, ideally through a multi-disciplinary team (MDT) clinic with community support. Hypotonia, poor feeding and faltering growth are characteristic features in the neonatal period, followed by hyperphagia and risk of rapid weight gain later in childhood. Children and adolescents (CA) with PWS usually display developmental delay and mild learning disability, and can develop endocrinopathies, scoliosis, respiratory difficulties (both central and obstructive sleep apnoea), challenging behaviours, skin picking, and mental health issues especially into adulthood. This consensus statement is intended to be a reference document for clinicians managing children and adolescents (up to 18 years of age) with PWS. It considers the bio-psycho-social domains of diagnosis, clinical assessment, and management in the paediatric setting as well as during and after transition to adult services. The guidance has been developed from information gathered from peer-reviewed scientific reports and from the expertise of a range of experienced clinicians in the United Kingdom and Ireland involved in the care of patients with PWS.

PMID:38838713 | DOI:10.1530/EC-24-0091

N Engl J Med. 2024 Jun 6;390(21):1985-1997. doi: 10.1056/NEJMoa2314761.

ABSTRACT

BACKGROUND: Genetic variants that cause rare disorders may remain elusive even after expansive testing, such as exome sequencing. The diagnostic yield of genome sequencing, particularly after a negative evaluation, remains poorly defined.

METHODS: We sequenced and analyzed the genomes of families with diverse phenotypes who were suspected to have a rare monogenic disease and for whom genetic testing had not revealed a diagnosis, as well as the genomes of a replication cohort at an independent clinical center.

RESULTS: We sequenced the genomes of 822 families (744 in the initial cohort and 78 in the replication cohort) and made a molecular diagnosis in 218 of 744 families (29.3%). Of the 218 families, 61 (28.0%) - 8.2% of families in the initial cohort - had variants that required genome sequencing for identification, including coding variants, intronic variants, small structural variants, copy-neutral inversions, complex rearrangements, and tandem repeat expansions. Most families in which a molecular diagnosis was made after previous nondiagnostic exome sequencing (63.5%) had variants that could be detected by reanalysis of the exome-sequence data (53.4%) or by additional analytic methods, such as copy-number variant calling, to exome-sequence data (10.8%). We obtained similar results in the replication cohort: in 33% of the families in which a molecular diagnosis was made, or 8% of the cohort, genome sequencing was required, which showed the applicability of these findings to both research and clinical environments.

CONCLUSIONS: The diagnostic yield of genome sequencing in a large, diverse research cohort and in a small clinical cohort of persons who had previously undergone genetic testing was approximately 8% and included several types of pathogenic variation that had not previously been detected by means of exome sequencing or other techniques. (Funded by the National Human Genome Research Institute and others.).

PMID:38838312 | DOI:10.1056/NEJMoa2314761

BMC Med Res Methodol. 2024 Jun 4;24(1):128. doi: 10.1186/s12874-024-02239-w.

ABSTRACT

BACKGROUND: Clinical prediction models can help identify high-risk patients and facilitate timely interventions. However, developing such models for rare diseases presents challenges due to the scarcity of affected patients for developing and calibrating models. Methods that pool information from multiple sources can help with these challenges.

METHODS: We compared three approaches for developing clinical prediction models for population screening based on an example of discriminating a rare form of diabetes (Maturity-Onset Diabetes of the Young - MODY) in insulin-treated patients from the more common Type 1 diabetes (T1D). Two datasets were used: a case-control dataset (278 T1D, 177 MODY) and a population-representative dataset (1418 patients, 96 MODY tested with biomarker testing, 7 MODY positive). To build a population-level prediction model, we compared three methods for recalibrating models developed in case-control data. These were prevalence adjustment ("offset"), shrinkage recalibration in the population-level dataset ("recalibration"), and a refitting of the model to the population-level dataset ("re-estimation"). We then developed a Bayesian hierarchical mixture model combining shrinkage recalibration with additional informative biomarker information only available in the population-representative dataset. We developed a method for dealing with missing biomarker and outcome information using prior information from the literature and other data sources to ensure the clinical validity of predictions for certain biomarker combinations.

RESULTS: The offset, re-estimation, and recalibration methods showed good calibration in the population-representative dataset. The offset and recalibration methods displayed the lowest predictive uncertainty due to borrowing information from the fitted case-control model. We demonstrate the potential of a mixture model for incorporating informative biomarkers, which significantly enhanced the model's predictive accuracy, reduced uncertainty, and showed higher stability in all ranges of predictive outcome probabilities.

CONCLUSION: We have compared several approaches that could be used to develop prediction models for rare diseases. Our findings highlight the recalibration mixture model as the optimal strategy if a population-level dataset is available. This approach offers the flexibility to incorporate additional predictors and informed prior probabilities, contributing to enhanced prediction accuracy for rare diseases. It also allows predictions without these additional tests, providing additional information on whether a patient should undergo further biomarker testing before genetic testing.

PMID:38834992 | DOI:10.1186/s12874-024-02239-w

Brain. 2024 Jun 4:awae175. doi: 10.1093/brain/awae175. Online ahead of print.

ABSTRACT

Congenital hydrocephalus (CH), characterized by cerebral ventriculomegaly, is one of the most common reasons for pediatric brain surgery. Recent studies have implicated lin-41 (lineage variant 41)/TRIM71 (tripartite motif 71) as a candidate CH risk gene, however, TRIM71 variants have not been systematically examined in a large patient cohort or conclusively linked with an OMIM syndrome. Through cross-sectional analysis of the largest assembled cohort of patients with cerebral ventriculomegaly, including neurosurgically-treated CH (totaling 2,697 parent-proband trios and 8,091 total exomes), we identified 13 protein-altering de novo variants (DNVs) in TRIM71 in unrelated children exhibiting variable ventriculomegaly, CH, developmental delay, dysmorphic features, and other structural brain defects including corpus callosum dysgenesis and white matter hypoplasia. Eight unrelated patients were found to harbor arginine variants, including two recurrent missense DNVs, at homologous positions in RPXGV motifs of different NHL domains. Seven additional patients with rare, damaging, unphased or transmitted variants of uncertain significance were also identified. NHL-domain variants of TRIM71 exhibited impaired binding to the canonical TRIM71 target CDKN1A; other variants failed to direct the subcellular localization of TRIM71 to processing bodies. Single-cell transcriptomic analysis of human embryos revealed expression of TRIM71 in early first-trimester neural stem cells of the brain. These data show TRIM71 is essential for human brain morphogenesis and that TRIM71 mutations cause a novel neurodevelopmental syndrome featuring ventriculomegaly and CH.

PMID:38833623 | DOI:10.1093/brain/awae175

Eur J Med Genet. 2023 Dec;66(12):104871. doi: 10.1016/j.ejmg.2023.104871. Epub 2023 Oct 29.

ABSTRACT

Rare diseases encompass a diverse group of genetic disorders that affect a small proportion of the population. Identifying the underlying genetic causes of these conditions presents significant challenges due to their genetic heterogeneity and complexity. Conventional short-read sequencing (SRS) techniques have been widely used in diagnosing and investigating of rare diseases, with limitations due to the nature of short-read lengths. In recent years, long read sequencing (LRS) technologies have emerged as a valuable tool in overcoming these limitations. This minireview provides a concise overview of the applications of LRS in rare disease research and diagnosis, including the identification of disease-causing tandem repeat expansions, structural variations, and comprehensive analysis of pathogenic variants with LRS.

PMID:38832911 | DOI:10.1016/j.ejmg.2023.104871

Eur J Med Genet. 2023 Dec;66(12):104868. doi: 10.1016/j.ejmg.2023.104868. Epub 2023 Oct 30.

ABSTRACT

BACKGROUND: knowledge on the natural history of rare diseases is necessary to improve outcomes. Disease registries may play a key role in covering these unmet needs in the rare bone and mineral community.

OBJECTIVE: to map existing bone and mineral conditions registries in Europe and their characteristics.

METHODS: online survey about the use of registries/databases and their characteristics. This survey was disseminated among members of the European Reference Network on Rare Bone Diseases (ERN BOND) and non-ERN experts in the field of bone and mineral conditions as well as patient organisations.

RESULTS: sixty-three responses from health care providers (HCPs) and 10 responses from patient groups (PGs) were collected. The response rate for ERN BOND members was 55%. Of 63 HCPs, 37 declared using a registry. Osteogenesis imperfecta (OI) was the most registered condition. We mapped 3 international registries, all were disease-specific.

CONCLUSIONS: There is a need for developing a common high-quality platform for registering rare bone and mineral conditions.

PMID:38832910 | DOI:10.1016/j.ejmg.2023.104868

bioRxiv [Preprint]. 2024 May 22:2024.05.22.595175. doi: 10.1101/2024.05.22.595175.

ABSTRACT

Recurrent copy number variation represents one of the most well-established genetic drivers in neurodevelopmental disorders, including autism spectrum disorder (ASD). Duplication of 15q11.2-13.1 (dup15q) is a well-described neurodevelopmental syndrome that increases the risk of ASD by over 40-fold. However, the effects of this duplication on gene expression and chromatin accessibility in specific cell types in the human brain remain unknown. To identify the cell-type-specific transcriptional and epigenetic effects of dup15q in the human frontal cortex we conducted single-nucleus RNA-sequencing and multi-omic sequencing on dup15q cases (n=6) as well as non-dup15q ASD (n=7) and neurotypical controls (n=7). Cell-type-specific differential expression analysis identified significantly regulated genes, critical biological pathways, and differentially accessible genomic regions. Although there was overall increased gene expression across the duplicated genomic region, cellular identity represented an important factor mediating gene expression changes. Neuronal subtypes, showed greater upregulation of gene expression across a critical region within the duplication as compared to other cell types. Genes within the duplicated region that had high baseline expression in control individuals showed only modest changes in dup15q, regardless of cell type. Of note, dup15q and ASD had largely distinct signatures of chromatin accessibility, but shared the majority of transcriptional regulatory motifs, suggesting convergent biological pathways. However, the transcriptional binding factor motifs implicated in each condition implicated distinct biological mechanisms; neuronal JUN/FOS networks in ASD vs. an inflammatory transcriptional network in dup15q microglia. This work provides a cell-type-specific analysis of how dup15q changes gene expression and chromatin accessibility in the human brain and finds evidence of marked cell-type-specific effects of this genetic driver. These findings have implications for guiding therapeutic development in dup15q syndrome, as well as understanding the functional effects CNVs more broadly in neurodevelopmental disorders.

PMID:38826276 | PMC:PMC11142199 | DOI:10.1101/2024.05.22.595175

Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2023 Dec 23;39:e20230008. doi: 10.62958/j.cjap.2023.008.

ABSTRACT

In the United States, cancer is one of the major causes of death. In 2010 alone, over 1.5 million fresh instances were recorded and over 0.5 billion died. After the completion of human genome sequence, significant progress in characterizing human epigenomes, proteomes and metabolomes has been made; a stronger knowledge of pharmacogenomics has been established and the capacity for individual personalization of health care has grown considerably. Personalized medicine has recently been primarily used to systematically select or optimize the prevention and therapeutic care of the patient through genetic or other data about the particular patient. Molecular profiling in healthy samples and cancer patients can allow for more personalized medications than is currently available. Patient protein, genetic and metabolic information may be used for adapting medical attention to the needs of that individual. The development of complementary diagnostics is a key attribute of this medicinal model. Molecular tests measuring the level of proteins, genes or specific mutations are used to provide a specific treatment for a particular individual by stratify the status of a disease, selecting the right drugs and tailoring dosages to the particular needs of the patient. These methods are also available for assessing risk factors for a patient for a number of conditions and for tailoring individual preventive therapies. Recent advances of personalized cancer medicine, challenges and futures perspectives are discussed.

PMID:38830754 | DOI:10.62958/j.cjap.2023.008

Cancer Discov. 2024 Jun 3;14(6):909-914. doi: 10.1158/2159-8290.CD-24-0368.

ABSTRACT

Advances in cancer biology and diagnostics have led to the recognition of a multitude of rare cancer subtypes, emphasizing the pressing need for strategies to accelerate drug development for patients with these cancers. This paper addresses the unique challenges of dose finding in trials that accrue small numbers of patients with rare cancers; strategies for dose optimization are proposed, in line with evolving approaches to dose determination in the age of the US Food and Drug Administration's Project Optimus.

PMID:38826101 | DOI:10.1158/2159-8290.CD-24-0368

Lancet Glob Health. 2024 Jul;12(7):e1092. doi: 10.1016/S2214-109X(24)00219-5. Epub 2024 May 29.

NO ABSTRACT

PMID:38823408 | DOI:10.1016/S2214-109X(24)00219-5

Science. 2024 May 31;384(6699):943-944. doi: 10.1126/science.adq7356. Epub 2024 May 30.

ABSTRACT

Five drugs are now approved or in trials for genetic condition that triggers misplaced bone growth.

PMID:38815021 | DOI:10.1126/science.adq7356

Transplant Proc. 2024 May;56(4):907-909. doi: 10.1016/j.transproceed.2024.01.064. Epub 2024 May 28.

ABSTRACT

For many rare disease (RD) patients, allogenic transplantation represents an effective therapy, improving overall survival rates and quality of life (QoL). Globally, ∼1% of liver transplants are performed for RDs and rare indications. However, patients and carers report unmet needs on their pathway toward treatment-in education and therapeutic measures, oftentimes shouldering expertise-building responsibility themselves. These issues are exacerbated in child patients. Estimates indicate that 6% to 8% of Poland's population (2.3-3 million persons) are burdened by RDs and potentially face such issues. This work aims to identify shortcomings of Polish policy in the field of educational and therapeutic measures for RD transplant candidates and recipients. Based on solutions introduced by pioneers, recommendations are formulated regarding priority actions. An analysis of national, transnational, and individual-center programs, directed at patients during their path from diagnosis to life post-transplant, was conducted. The investigation uncovered measure gaps not addressed by the National Plan for Rare Diseases-in fields of patient and stakeholder education (pre- and post-transplant), psychological care provision, specialized center creation, integration of data scattered among registries with the national insurer's database, and artificial intelligence (AI) tool implementation to support both early diagnostic efforts and tailoring of patient treatment. Programs directed at RD transplant candidates and recipients must aim to ensure that a satisfactory psychosomatic condition of the patient is maintained before and following the procedure, therefore lending credence to success. This necessitates early diagnosis schemes, and personalized medicine, multidisciplinary approaches to the individual, achievable only through big data system creation and AI introduction.

PMID:38811302 | DOI:10.1016/j.transproceed.2024.01.064

Lancet Glob Health. 2024 Jul;12(7):e1091. doi: 10.1016/S2214-109X(24)00189-X. Epub 2024 May 24.

NO ABSTRACT

PMID:38801829 | DOI:10.1016/S2214-109X(24)00189-X

Adv Exp Med Biol. 2024;1451:355-368. doi: 10.1007/978-3-031-57165-7_23.

ABSTRACT

Monkeypox (mpox), a zoonotic disease caused by the monkeypox virus (MPXV), poses a significant public health threat with the potential for global dissemination beyond its endemic regions in Central and West Africa. This study explores the multifaceted aspects of monkeypox, covering its epidemiology, genomics, travel-related spread, mass gathering implications, and economic consequences. Epidemiologically, mpox exhibits distinct patterns, with variations in age and gender susceptibility. Severe cases can arise in immunocompromised individuals, underscoring the importance of understanding the factors contributing to its transmission. Genomic analysis of MPXV highlights its evolutionary relationship with the variola virus and vaccinia virus. Different MPXV clades exhibit varying levels of virulence and transmission potential, with Clade I associated with higher mortality rates. Moreover, the role of recombination in MPXV evolution remains a subject of interest, with implications for understanding its genetic diversity. Travel and mass gatherings play a pivotal role in the spread of monkeypox. The ease of international travel and increasing globalization have led to outbreaks beyond African borders. The economic ramifications of mpox outbreaks extend beyond public health. Direct treatment costs, productivity losses, and resource-intensive control efforts can strain healthcare systems and economies. While vaccination and mitigation strategies have proven effective, the cost-effectiveness of routine vaccination in non-endemic countries remains a subject of debate. This study emphasizes the role of travel, mass gatherings, and genomics in its spread and underscores the economic impacts on affected regions. Enhancing surveillance, vaccination strategies, and public health measures are essential in controlling this emerging infectious disease.

PMID:38801590 | DOI:10.1007/978-3-031-57165-7_23

Probl Endokrinol (Mosk). 2023 Oct 8;70(2):86-93. doi: 10.14341/probl13369.

ABSTRACT

Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) is an ultra-orphan disease from the group of premature aging syndromes with an autosomal recessive type of inheritance associated with mutations in the POLR3A, POLR3B, and POLR3GL genes encoding RNA polymerase III. The incidence of the disease is currently unknown. We present the first clinical description in Russian Federation of a patient 7 years 6 months old with Wiedemann-Rautenstrauch syndrome (compound heterozygous mutations in POLR3A gene) with progeroid features, adentia, growth retardation (height SDS -3,41, height velocity SDS -2,47), underweight (BMI SDS -6,20), and generalized lipodystrophy. The article presents the observation of the patient for 1.5 years, the world experience of dynamic follow-up of patients with neonatal progeroid syndrome, differential diagnosis, as well as recommendations for the management of patients with this syndrome. Given the lack of specific treatment to date, patients are observed by a multidisciplinary team of physicians.

PMID:38796765 | DOI:10.14341/probl13369

Lancet Haematol. 2024 Jun;11(6):e403. doi: 10.1016/S2352-3026(24)00110-8.

NO ABSTRACT

PMID:38796191 | DOI:10.1016/S2352-3026(24)00110-8

Int J Environ Res Public Health. 2024 May 13;21(5):616. doi: 10.3390/ijerph21050616.

ABSTRACT

The National Institute for Health and Care Excellence (NICE) in England uses quality-adjusted life years (QALYs) to assess the cost-effectiveness of treatments. A QALY is a measure that combines the size of the clinical benefit of a treatment with the time the patient benefits from it, i.e., the time horizon. We wanted to know how consistently QALY gains are calculated at NICE. Therefore, we have analysed information on the time horizons used for the QALY calculations of the concluded evaluations conducted under the Highly Specialised Technologies programme for treatments of very rare diseases at NICE. For treatments with final guidance published by December 2023 (n = 29), a time horizon of median 97.5 years (range: 35 to 125 years) was used to calculate the QALY gains. For most QALY calculations, the accepted time horizon was longer than either the expected treatment duration or the estimated life expectancy. In contrast, for the only technology with a final negative funding decision, i.e., afamelanotide for treating the lifelong chronic disease erythropoietic protoporphyria, a time horizon that was shorter than the expected treatment duration was used. The fairness and consistency of the evaluation process of treatments for very rare diseases at NICE should be reviewed.

PMID:38791830 | DOI:10.3390/ijerph21050616

Int J Environ Res Public Health. 2024 May 13;21(5):615. doi: 10.3390/ijerph21050615.

ABSTRACT

Congenital facial weakness (CFW) encompasses a heterogenous set of rare disorders presenting with decreased facial movement from birth, secondary to impaired function of the facial musculature. The aim of the present study is to provide an analysis of subject-reported oral health-related quality of life (OHRQoL) in congenital facial weakness (CFW) disorders. Forty-four subjects with CFW and age- and sex- matched controls were enrolled in an Institutional Review Board (IRB)-approved study. Demographic data, medical and surgical history, comprehensive oral examination, and the Oral Health Impact Profile (OHIP-14) were obtained. Compared to unaffected controls, subjects with CFW had higher OHIP-14 scores overall (mean ± SD: 13.11 ± 8.11 vs. 4.46 ± 4.98, p < 0.0001) and within five of seven oral health domains, indicating decreased OHRQoL. Although subjects with Moebius syndrome (MBS) were noted to have higher OHIP-14 scores than those with Hereditary Congenital Facial Paresis (HCFP), there was no significant correlation in OHIP-14 score to age, sex, or specific diagnosis. An increase in OHIP-14 scores in subjects was detected in those who had undergone reanimation surgery. In conclusion, subjects with CFW had poorer OHRQoL compared to controls, and subjects with MBS had poorer OHRQoL than subjects with HCFP. This study provides better understanding of oral health care needs and quality of life in a CFW cohort and suggests that guidelines for dental treatment are required.

PMID:38791829 | DOI:10.3390/ijerph21050615

Expert Rev Pharmacoecon Outcomes Res. 2024 Jul;24(6):713-721. doi: 10.1080/14737167.2024.2360201. Epub 2024 Jun 7.

ABSTRACT

INTRODUCTION: Preserving function and independence to perform activities of daily living (ADL) is critical for patients and carers to manage the burden of care and improve quality of life. In children living with rare diseases, video recording ADLs offer the opportunity to collect the patients' experience in a real-life setting and accurately reflect treatment effectiveness on outcomes that matter to patients and families.

AREAS COVERED: We reviewed the measurement of ADL in pediatric rare diseases and the use of video to develop at-home electronic clinical outcome assessments (eCOA) by leveraging smartphone apps and artificial intelligence-based analysis. We broadly searched PubMed using Boolean combinations of the following MeSH terms 'Rare Diseases,' 'Quality of Life,' 'Activities of Daily Living,' 'Child,' 'Video Recording,' 'Outcome Assessment, Healthcare,' 'Intellectual disability,' and 'Genetic Diseases, Inborn.' Non-controlled vocabulary was used to include human pose estimation in movement analysis.

EXPERT OPINION: Broad uptake of video eCOA in drug development is linked to the generation of technical and clinical validation evidence to confidently assess a patient's functional abilities. Software platforms handling video data must align with quality regulations to ensure data integrity, security, and privacy. Regulatory flexibility and optimized validation processes should facilitate video eCOA to support benefit/risk drug assessment.

PMID:38789406 | DOI:10.1080/14737167.2024.2360201