Oncol Res Treat. 2021 Apr 22:1-9. doi: 10.1159/000516262. Online ahead of print.

ABSTRACT

BACKGROUND: Data on institutional structures of sarcoma care in Germany are scarce. The utilization of an interdisciplinary tumor board (IDTB) is an essential part of modern cancer care. We investigated to which extent and when IDTB are used in sarcoma care. We hypothesized that IDTB before treatment initiation were used more often at certified cancer centers and at high-volume centers and that IDTB utilization increased over time.

METHODS: From 2017 to 2020 we conducted a prospective cohort study, undertaking major efforts to include the whole spectrum of sarcoma treatment facilities. To analyze potential predictors of IDTB utilization, we calculated multivariable logistic regressions.

RESULTS: Patients and survivors (n = 1,309) from 39 study centers (22 tertiary referral hospitals, 9 other hospitals, and 8 office-based practices) participated; 88.3% of the patients were discussed at some stage of their disease in an IDTB (56.1% before treatment, 78% after therapy, and 85.9% in metastatic disease). Hypotheses were confirmed regarding the utilization of IDTB in certified cancer centers (vs. all others: OR = 5.39; 95% CI 3.28-8.85) and the time of diagnosis (2018/2019 vs. until 2013: OR = 4.95; 95% CI 2.67-9.21).

CONCLUSION: Our study adds to the evidence regarding the institutional structures of sarcoma care in Germany. Utilization of a tumor board before therapy seems to be in an implementation process that is making progress but is far from complete. Certification is a possible tool to accelerate this development.

PMID:33887740 | DOI:10.1159/000516262

Acta Paediatr. 2021 Apr 18. doi: 10.1111/apa.15880. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is an orphan disease with increased morbidity and mortality, mainly due to chronic pulmonary infections. The symptoms and treatment are complex, and patients are followed at specialised CF centres. The exact treatment, and the segregation policies to avoid cross-infection from airway pathogens, vary between CF centres, including those in Scandinavian countries.

PMID:33866605 | DOI:10.1111/apa.15880

J Paediatr Child Health. 2021 Jun;57(6):778-781. doi: 10.1111/jpc.15507. Epub 2021 Apr 16.

ABSTRACT

Almost exactly 10 years after the publication of 'Call for a national plan for rare diseases' in this journal, the Federal Government launched the National Strategic Action Plan for Rare Diseases (the Action Plan) on the 26th of February 2020, in the lead up to Rare Disease Day on the 29th of February - a rare day for rare diseases. The Action Plan is the culmination of effective advocacy by Rare Voices Australia (RVA) and other stakeholders in the rare disease (RD) sector. RVA is the peak body for Australians living with a RD. The organisation works collaboratively with RD organisations, researchers and clinicians. Since the initial call for a RD plan, a number of health-care initiatives and policy changes have gathered apace including expanded antenatal and newborn screening, the increasing application of next generation sequencing and advances in gene and cell therapeutics. The development of new models of care, diagnostic and treatment pathways, and communities of practice have started to ease the considerable burden and inequitable access to care experienced by RD patients and their families. However, much work remains to be done. The Action Plan outlines the actions to bring about the best possible health and well-being outcomes for Australians living with RD. It is centred around three pillars - awareness and education, care and support, research and data - and will be delivered against the principles of person centredness, equity, and sustainable systems and workforce.

PMID:33861492 | DOI:10.1111/jpc.15507

Expert Rev Proteomics. 2021 Apr 16. doi: 10.1080/14789450.2021.1918549. Online ahead of print.

ABSTRACT

INTRODUCTION: The term "orphan diseases" includes conditions meeting prevalence-based or commercial viability criteria: they affect a small number of individuals and are considered an unviable market for drug development. Proteomics is an important technology to study them, providing information on mechanisms and evolution, biomarkers, and effects of therapeutic interventions.

AREAS COVERED: Herein, we review how proteomics and bioinformatic tools could be applied to the study of rare diseases and discuss pitfalls and potential.

EXPERT OPINION: Research in the field of rare diseases has to face many challenges, and implementation plans should foresee highly specialized collaborative consortia to create multidisciplinary frameworks for data sharing, advancing research, supporting clinical studies, and accelerating drug development. The integration of different technologies will allow better knowledge of disease pathophysiology, and the inclusion of proteomics and other omics technologies in this context will be pivotal to this aim.Several aspects of rare diseases, often perceived as limiting factors, might actually be advantages for a precision medicine approach: the limited number of patients, the collaboration with patient societies, and the availability of curated clinical registries could allow the development of homogeneous clinical databases and ultimately a better control over the data to be analysed.

PMID:33861161 | DOI:10.1080/14789450.2021.1918549

BMJ Case Rep. 2021 Apr 14;14(4):e239550. doi: 10.1136/bcr-2020-239550.

ABSTRACT

Eosinophilic granulomatosis with polyangiitis is an antineutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitis with cardiac involvement in more than 60% of cases. Authors describe the case of a 48-year-old woman who presented with progressively worsening asthenia, dyspnoea and macular, non-painful, non-itchy cutaneous lesions. She had signs of congestion on clinical examination and a history of asthma and nasal polyps. Blood tests showed eosinophilia (11.2%), positive troponin I (9698 μg/L), elevated B-type natriuretic peptide (2047 pg/mL) and positive C reactive protein (6.68 mg/dL). Echocardiogram displayed moderate left ventricular enlargement, left ventricular ejection fraction of 28% and mild pericardial effusion. Levosimendan relieved the congestion. Additional testing confirmed positive antinuclear antibodies with ANCA-negative autoimmune pattern. Cardiac magnetic resonance showed severely depressed systolic function due to diffuse hypokinesia. Cardiac biopsy had intercellular oedema and eosinophilic infiltrate. Treatment with prednisolone and cyclophosphamide was started. This is a case of a rare disease presenting with life-threatening cardiac involvement.

PMID:33853814 | PMC:PMC8054047 | DOI:10.1136/bcr-2020-239550

Clin Otolaryngol. 2021 Apr 13. doi: 10.1111/coa.13782. Online ahead of print.

ABSTRACT

OBJECTIVE: Identification of variations in tumor suppressor genes encoding the tetrameric succinate dehydrogenase (SDHx) mitochondrial enzyme complex may lead to personalized therapeutic concepts for the orphan disease, familial paraganglioma (PGL) type I. We undertook to determine the causative variation in a family suffering from idiopathic early-onset (22±2 years) head and neck PGL by PCR and Sanger sequencing.

DESIGN, SETTING AND PARTICIPANTS: In a prospective genetic study, twelve members of the family were recruited at a tertiary referral otolaryngology centre.

RESULTS: A novel heterozygous c.298delA frameshift variation in exon 3 of SDH subunit D (SDHD) was associated with a paternal transmission pattern of PGL in affected family members available to the study. Family history over five generations in adulthood indicated a variable penetrance for PGL inheritance in older generations. The c.298delA variant would cause translation of a 34-residue C-terminus distal to lysine residue 99 in the predicted transmembrane domain II of the full-length sequence p.(Thr100LeufsTer35) and would affect the translation products of all protein-coding SDHD isoforms containing transmembrane topologies required for positional integration in the inner mitochondrial membrane and complex formation.

CONCLUSIONS: A novel c.298delA variation in SDHD that causes paternally inherited PGL1 with an atypically low penetrance was identified. These results underly the importance of genetic screening for PGL also in cases of unclear inheritance and variation carriers should benefit from screening and lifelong follow-up.

PMID:33851515 | DOI:10.1111/coa.13782

Kyobu Geka. 2021 Apr;74(4):321-323.

ABSTRACT

Xiphodynia is a rare condition, and only a few reports of xiphoidectomy have been published. A 48-year-old male patient was admitted to our medical department because of xiphodynia induced by a severe asthma attack. Computed tomography showed that his xiphoid process protruded forward, with a xiphisternal angle of 160 degrees. It was suggested that the pain induced at severe asthma attack was caused by the prominent xiphoid process and we performed xiphoidectomy, The postoperative course was uneventful, and xiphodynia was dramatically improved.

PMID:33831895

Orphanet J Rare Dis. 2021 Apr 7;16(1):161. doi: 10.1186/s13023-021-01806-4.

ABSTRACT

Data silos are proliferating while research and development activity explode following genetic and immunological advances for many clinically described disorders with previously unknown etiologies. The latter event has inspired optimism in the patient, clinical, and research communities that disease-specific treatments are on the way. However, we fear the tendency of various stakeholders to balkanize databases in proprietary formats, driven by current economic and academic incentives, will inevitably fragment the expanding knowledge base and undermine current and future research efforts to develop much-needed treatments. The proliferation of proprietary databases, compounded by a paucity of meaningful outcome measures and/or good natural history data, slows our ability to generate scalable solutions to benefit chronically underserved patient populations in ways that would translate to more common diseases. The current research and development landscape sets too many projects up for unnecessary failure, particularly in the rare disease sphere, and does a grave disservice to highly vulnerable patients. This system also encourages the collection of redundant data in uncoordinated parallel studies and registries to ultimately delay or deny potential treatments for ostensibly tractable diseases; it also promotes the waste of precious time, energy, and resources. Groups at the National Institutes of Health and Food and Drug Administration have started programs to address these issues. However, we and many others feel there should be significantly more discussion of how to coordinate and scale registry efforts. Such discourse aims to reduce needless complexity and duplication of efforts, as well as promote a pre-competitive knowledge ecosystem for rare disease drug development that cultivates and accelerates innovation.

PMID:33827602 | DOI:10.1186/s13023-021-01806-4

Dermatology. 2021 Apr 7:1-8. doi: 10.1159/000514687. Online ahead of print.

ABSTRACT

BACKGROUND: Necrobiosis lipoidica (NL) is a rare granulomatous disorder of unknown aetiology. Randomized controlled studies are not available due to it being an orphan disease.

OBJECTIVES: We evaluated patients in 2 dermatological centres to cluster data about epidemiology, the therapeutic approaches for NL, and their efficacy.

MATERIALS AND METHODS: Comorbidity and the efficacy of the applied treatment was assessed for 98 patients.

RESULTS: We identified 54% of patients with concomitant diabetes and 19% with thyroidal disorders. Topical steroids (85.7%) were predominantly used followed by calcineurin inhibitors (31%) and phototherapy (41.8%). Systemically, fumaric acid esters were more frequently applied (26.8%) than steroids (24.4%) and dapsone (24.4%). Steroids, compression therapy, calcineurin inhibitors, phototherapy, fumaric acid esters, and dapsone showed remarkable efficacy.

CONCLUSION: Therapeutic options were chosen individually in accordance with the severity of NL and presence of ulceration. Topical calcineurin inhibitors, systemic application of fumaric acid esters, and dapsone represent effective alternatives to the use of steroids.

PMID:33827092 | DOI:10.1159/000514687

Hum Mol Genet. 2021 Apr 5:ddab093. doi: 10.1093/hmg/ddab093. Online ahead of print.

ABSTRACT

Mucolipidosis IV (MLIV) is an orphan disease leading to debilitating psychomotor deficits and vision loss. It is caused by loss-of-function mutations in the MCOLN1 gene that encodes the lysosomal transient receptor potential channel mucolipin1, or TRPML1. With no existing therapy, the unmet need in this disease is very high. Here we showed that AAV-mediated CNS-targeted gene transfer of the human MCOLN1 gene rescued motor function and alleviated brain pathology in the MLIV mouse model. Using the AAV-PHP.b vector in symptomatic mice, we showed long-term reversal of declined motor function and significant delay of paralysis. Next, using self-complementary AAV9 clinical candidate vector, we showed that its intracerebroventricular administration in post-natal day 1 mice significantly improved motor function, myelination and reduced lysosomal storage load in the MLIV mouse brain. Based on our data and general advancements in the gene therapy field, we propose scAAV9-mediated CSF-targeted MCOLN1 gene transfer as a therapeutic strategy in MLIV.

PMID:33822942 | DOI:10.1093/hmg/ddab093

Int J Environ Res Public Health. 2021 Mar 21;18(6):3234. doi: 10.3390/ijerph18063234.

ABSTRACT

Scientific knowledge on depression and anxiety in patients with rare diseases during the COVID-19 pandemic is scarce; however, it is essential to perform comprehensive management of these patients. The aim of this study was to research how the situation caused by the SARS-CoV-2 pandemic has influenced the lives of patients with rare diseases regarding depression and anxiety. This Spanish study considered a heterogeneous population sample of 86 patients with confirmed diagnosis of different rare diseases. Participants took part in a cross-sectional online study by completing specific questionnaires on the study topic. Depression was measured using the Patient Health Questionnaire (PHQ-9), and the General Anxiety Disorder Scale (GAD-7) was used for evaluating anxiety. Data collection through an online questionnaire allowed for a greater population scope and therefore the inclusion patients of other nationalities in the study sample. Finally, as a general result, this study found that, in the face of the pandemic, anxiety and depression remained at a higher level in this group than in the general population, making these patients a vulnerable population group.

PMID:33800980 | PMC:PMC8003983 | DOI:10.3390/ijerph18063234

J Clin Med. 2021 Mar 3;10(5):1034. doi: 10.3390/jcm10051034.

ABSTRACT

Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy that most commonly affects the pleural lining of the lungs. It has a strong association with exposure to biopersistent fibers, mainly asbestos (80% of cases) and-in specific geographic regions-erionite, zeolites, ophiolites, and fluoro-edenite. Individuals with a chronic exposure to asbestos generally have a long latency with no or few symptoms. Then, when patients do become symptomatic, they present with advanced disease and a worse overall survival (about 13/15 months). The fibers from industrial production not only pose a substantial risk to workers, but also to their relatives and to the surrounding community. Modern targeted therapies that have shown benefit in other human tumors have thus far failed in MPM. Overall, MPM has been listed as orphan disease by the European Union. However, molecular high-throughput profiling is currently unveiling novel biomarkers and actionable targets. We here discuss the natural evolution, mainly focusing on the novel concept of molecular epidemiology. The application of innovative endpoints, quantification of genetic damages, and definition of genetic susceptibility are reviewed, with the ultimate goal to point out new tools for screening of exposed subject and for designing more efficient diagnostic and therapeutic strategies.

PMID:33802313 | DOI:10.3390/jcm10051034

Int J Mol Sci. 2021 Mar 7;22(5):2692. doi: 10.3390/ijms22052692.

ABSTRACT

microRNAs (miRNAs) regulate messenger RNA (mRNA) abundance and translation during key developmental processes including muscle differentiation. Assessment of miRNA targets can provide insight into muscle biology and gene expression profiles altered by disease. mRNA and miRNA libraries were generated from C2C12 myoblasts during differentiation, and predicted miRNA targets were identified based on presence of miRNA binding sites and reciprocal expression. Seventeen miRNAs were differentially expressed at all time intervals (comparing days 0, 2, and 5) of differentiation. mRNA targets of differentially expressed miRNAs were enriched for functions related to calcium signaling and sarcomere formation. To evaluate this relationship in a disease state, we evaluated the miRNAs differentially expressed in human congenital myotonic dystrophy (CMD) myoblasts and compared with normal control. Seventy-four miRNAs were differentially expressed during healthy human myocyte maturation, of which only 12 were also up- or downregulated in CMD patient cells. The 62 miRNAs that were only differentially expressed in healthy cells were compared with differentiating C2C12 cells. Eighteen of the 62 were conserved in mouse and up- or down-regulated during mouse myoblast differentiation, and their C2C12 targets were enriched for functions related to muscle differentiation and contraction.

PMID:33799993 | DOI:10.3390/ijms22052692

Wien Med Wochenschr. 2021 Apr;171(5-6):85. doi: 10.1007/s10354-021-00822-0. Epub 2021 Apr 1.

NO ABSTRACT

PMID:33796966 | DOI:10.1007/s10354-021-00822-0

Circ Genom Precis Med. 2021 Apr 2:CIRCGEN120003310. doi: 10.1161/CIRCGEN.120.003310. Online ahead of print.

NO ABSTRACT

PMID:33794647 | DOI:10.1161/CIRCGEN.120.003310

Genome Biol. 2021 Mar 29;22(1):92. doi: 10.1186/s13059-021-02285-3.

ABSTRACT

BACKGROUND: Post-zygotic mutations incurred during DNA replication, DNA repair, and other cellular processes lead to somatic mosaicism. Somatic mosaicism is an established cause of various diseases, including cancers. However, detecting mosaic variants in DNA from non-cancerous somatic tissues poses significant challenges, particularly if the variants only are present in a small fraction of cells.

RESULTS: Here, the Brain Somatic Mosaicism Network conducts a coordinated, multi-institutional study to examine the ability of existing methods to detect simulated somatic single-nucleotide variants (SNVs) in DNA mixing experiments, generate multiple replicates of whole-genome sequencing data from the dorsolateral prefrontal cortex, other brain regions, dura mater, and dural fibroblasts of a single neurotypical individual, devise strategies to discover somatic SNVs, and apply various approaches to validate somatic SNVs. These efforts lead to the identification of 43 bona fide somatic SNVs that range in variant allele fractions from ~ 0.005 to ~ 0.28. Guided by these results, we devise best practices for calling mosaic SNVs from 250× whole-genome sequencing data in the accessible portion of the human genome that achieve 90% specificity and sensitivity. Finally, we demonstrate that analysis of multiple bulk DNA samples from a single individual allows the reconstruction of early developmental cell lineage trees.

CONCLUSIONS: This study provides a unified set of best practices to detect somatic SNVs in non-cancerous tissues. The data and methods are freely available to the scientific community and should serve as a guide to assess the contributions of somatic SNVs to neuropsychiatric diseases.

PMID:33781308 | DOI:10.1186/s13059-021-02285-3

Internist (Berl). 2021 May;62(5):486-495. doi: 10.1007/s00108-021-00995-1. Epub 2021 Mar 29.

ABSTRACT

Delineating the genetic background and the underlying pathophysiology of rare skeletal dysplasias enables a broader understanding of these disorders as well as novel perspectives regarding differential diagnosis and targeted development of therapeutic approaches. Hypophosphatasia (HPP) due to genetically determined Alkaline Phosphatase deficiency exemplifies this development. While an enzyme replacement therapy could be established for severe HPP with the prevailing bone manifestation, the clinical impact of not immediately bone-related manifestations just being successively understood. Correspondingly, the elucidation of the pathophysiology underlying renal phosphate wasting expanded our knowledge regarding phosphate metabolism and bone health and facilitated the development of an anti-FGF-23 Antibody for targeted treatment of X‑linked Hypophosphatemia (XLH). Evolutions regarding the nosology of osteogenesis imperfecta (OI) along with the identification of further causative genes also detected in the context of genetically determined osteoporosis illustrate the pathophysiologic interrelation between monogenetic bone dysplasias and multifactorial osteoporosis. While current therapeutic strategies for OI follow osteoporosis treatment, the expanding knowledge about OI forms the fundament for establishing improved treatment strategies-for both OI and osteoporosis. Similar developments are emerging regarding rare skeletal disorders like Achondroplasia, Fibrodysplasia ossificans progressive and Morbus Morquio (Mukopolysaccharidosis Type IV).

PMID:33779789 | DOI:10.1007/s00108-021-00995-1

Genet Med. 2021 Mar 26. doi: 10.1038/s41436-021-01146-5. Online ahead of print.

ABSTRACT

PURPOSE: Newborn screening (NBS) is performed to identify neonates at risk for actionable, severe, early-onset disorders, many of which are genetic. The BabySeq Project randomized neonates to receive conventional NBS or NBS plus exome sequencing (ES) capable of detecting sequence variants that may also diagnose monogenic disease or indicate genetic disease risk. We therefore evaluated how ES and conventional NBS results differ in this population.

METHODS: We compared results of NBS (including hearing screens) and ES for 159 infants in the BabySeq Project. Infants were considered "NBS positive" if any abnormal result was found indicating disease risk and "ES positive" if ES identified a monogenic disease risk or a genetic diagnosis.

RESULTS: Most infants (132/159, 84%) were NBS and ES negative. Only one infant was positive for the same disorder by both modalities. Nine infants were NBS positive/ES negative, though seven of these were subsequently determined to be false positives. Fifteen infants were ES positive/NBS negative, all of which represented risk of genetic conditions that are not included in NBS programs. No genetic explanation was identified for eight infants referred on the hearing screen.

CONCLUSION: These differences highlight the complementarity of information that may be gleaned from NBS and ES in the newborn period.

PMID:33772220 | DOI:10.1038/s41436-021-01146-5

Mol Genet Metab Rep. 2021 Mar 13;27:100742. doi: 10.1016/j.ymgmr.2021.100742. eCollection 2021 Jun.

ABSTRACT

Adult-onset non-cirrhotic hyperammonemia (NCH) is a rare, but often fatal condition that can result in both reversible and irreversible neurological defects. Here we present five cases of adult-onset non-cirrhotic hyperammonemia wherein brain magnetic resonance spectroscopy (MRS) scans for cerebral glutamine (Gln) and myo-inositol (mI) levels helped guide clinical management. Specifically, we demonstrate that when combined with traditional brain magnetic resonance imaging (MRI) scans, cerebral Gln and mI MRS can help disentangle the reversible from irreversible neurological defects associated with hyperammonemic crisis. Specifically, we demonstrate that whereas an elevated brain MRS Gln level is associated with reversible neurological defects, markedly low mI levels are associated with a risk for irreversible neurological defects such as central pontine myelinolysis. Overall, our findings indicate the utility of brain MRS in guiding clinical care and prognosis in patients with adult-onset non-cirrhotic hyperammonemia.

PMID:33763331 | PMC:PMC7973242 | DOI:10.1016/j.ymgmr.2021.100742

J Bronchology Interv Pulmonol. 2021 Apr 1;28(2):e31-e33. doi: 10.1097/LBR.0000000000000720.

NO ABSTRACT

PMID:33753709 | DOI:10.1097/LBR.0000000000000720