Int J Environ Res Public Health. 2022 Nov 17;19(22):15174. doi: 10.3390/ijerph192215174.

ABSTRACT

OBJECTIVE: To identify and map the available evidence on the implementation of public health policies directed at individuals with rare diseases, and to compare the implementation of these health policies between Brazil and other countries.

METHOD: A scoping review guided by the PRISMA-ScR and JBI checklists. The search for articles was conducted in eight electronic databases, MEDLINE/Pubmed, Embase, Cochrane Library, Web of Science, Scopus, CINAHL, PsycINFO, and LILACS, using controlled descriptors, synonyms, and keywords combined with Boolean operators. All steps of this review were independently conducted by two researchers. The selected studies were classified by evidence hierarchy, and a generic quantitative tool was used for the assessment of the studies.

RESULTS: A total of 473 studies were identified, of which 13 which met all the inclusion criteria were selected and analyzed. Of these studies, 61.5% (n = 8) had final scores equal to or greater than 70%, i.e., they were classified by this tool as being well-reported. The comparative analysis of international rare diseases demonstrates that public authorities' priorities and recommendations regarding this topic also permeate and apply to the Brazilian context.

CONCLUSIONS: The evaluation and monitoring of public policies directed at rare disease patients are urgent and necessary to improve and implement such policies with less bureaucracy and more determination for this unique population that requires timely and high-quality care.

PMID:36429893 | DOI:10.3390/ijerph192215174

Cells. 2022 Nov 21;11(22):3702. doi: 10.3390/cells11223702.

ABSTRACT

Lysosome-related organelles (LROs) are a group of functionally diverse, cell type-specific compartments. LROs include melanosomes, alpha and dense granules, lytic granules, lamellar bodies and other compartments with distinct morphologies and functions allowing specialised and unique functions of their host cells. The formation, maturation and secretion of specific LROs are compromised in a number of hereditary rare multisystem disorders, including Hermansky-Pudlak syndromes, Griscelli syndrome and the Arthrogryposis, Renal dysfunction and Cholestasis syndrome. Each of these disorders impacts the function of several LROs, resulting in a variety of clinical features affecting systems such as immunity, neurophysiology and pigmentation. This has demonstrated the close relationship between LROs and led to the identification of conserved components required for LRO biogenesis and function. Here, we discuss aspects of this conserved machinery among LROs in relation to the heritable multisystem disorders they associate with, and present our current understanding of how dysfunctions in the proteins affected in the disease impact the formation, motility and ultimate secretion of LROs. Moreover, we have analysed the expression of the members of the CHEVI complex affected in Arthrogryposis, Renal dysfunction and Cholestasis syndrome, in different cell types, by collecting single cell RNA expression data from the human protein atlas. We propose a hypothesis describing how transcriptional regulation could constitute a mechanism that regulates the pleiotropic functions of proteins and their interacting partners in different LROs.

PMID:36429129 | DOI:10.3390/cells11223702

Pol Arch Intern Med. 2022 Nov 25;132(11):16363. doi: 10.20452/pamw.16363. Epub 2022 Nov 25.

NO ABSTRACT

PMID:36426771 | DOI:10.20452/pamw.16363

Sci Rep. 2022 Nov 24;12(1):20244. doi: 10.1038/s41598-022-24496-9.

ABSTRACT

Moyamoya disease (MMD) is a rare cerebrovascular disease endemic in East Asia. The p.R4810K mutation in RNF213 gene confers a risk of MMD, but other factors remain largely unknown. We tested the association of gut microbiota with MMD. Fecal samples were collected from 27 patients with MMD, 7 patients with non-moyamoya intracranial large artery disease (ICAD) and 15 control individuals with other disorders, and 16S rRNA were sequenced. Although there was no difference in alpha diversity or beta diversity between patients with MMD and controls, the cladogram showed Streptococcaceae was enriched in patient samples. The relative abundance analysis demonstrated that 23 species were differentially abundant between patients with MMD and controls. Among them, increased abundance of Ruminococcus gnavus > 0.003 and decreased abundance of Roseburia inulinivorans < 0.002 were associated with higher risks of MMD (odds ratio 9.6, P = 0.0024; odds ratio 11.1, P = 0.0051). Also, Ruminococcus gnavus was more abundant and Roseburia inulinivorans was less abundant in patients with ICAD than controls (P = 0.046, P = 0.012). The relative abundance of Ruminococcus gnavus or Roseburia inulinivorans was not different between the p.R4810K mutant and wildtype. Our data demonstrated that gut microbiota was associated with both MMD and ICAD.

PMID:36424438 | PMC:PMC9691692 | DOI:10.1038/s41598-022-24496-9

Genes (Basel). 2022 Nov 18;13(11):2154. doi: 10.3390/genes13112154.

ABSTRACT

TARP syndrome (Talipes equinovarus, Atrial septal defect, Robin sequence, and Persistence of the left superior vena cava) is a rare genetic condition, caused by developmental defects during embryogenesis. The phenotypic spectrum of TARP shows high clinical variability with patients either missing cardinal features or having additional clinical traits. Initially, TARP was considered a lethal syndrome, but patients with milder symptoms were recently described. The TARP-locus was mapped to the gene RNA-binding motif protein 10 (RBM10) on the human X-chromosome. We clinically and genetically described a six-year-old boy with a TARP-phenotype. Clinical heterogeneity of symptoms prompted us to sequence the entire exome of this patient. We identified a novel splice variant (NM_005676: c.17+1G&gt;C, p.?) in RBM10. A patient-derived cell line was used to verify the pathogenicity of the RBM10 splice variant by RNA analyses, Western blotting, and immunofluorescence staining. Our molecular genetic findings together with the analyses of progressing clinical symptoms confirmed the diagnosis of TARP. It seems essential to analyze correlations between genotype, phenotype, and molecular/cellular data to better understand RBM10-associated pathomechanisms, assist genetic counseling, and support development of therapeutic approaches.

PMID:36421828 | PMC:PMC9691016 | DOI:10.3390/genes13112154

Ann Afr Med. 2022 Oct-Dec;21(4):461-465. doi: 10.4103/aam.aam_130_21.

ABSTRACT

Eosinophilic gastroenteritis (EGE) is a rare disease with a myriad of presentations. In this case series of four patients from South India, we describe three classical manifestations of the disease (mucosal, muscular, and serosal). Two of them had obstructive jaundice as a presenting complaint due to duodenal obstruction, whereas one had massive upper gastrointestinal bleed. There are very few case series regarding this disease from India. Its presentation as hemetemesis and obstructive jaundice is also very rare,with only few such case reports reported till now.

PMID:36412352 | DOI:10.4103/aam.aam_130_21

Immunol Allergy Clin North Am. 2023 Feb;43(1):159-168. doi: 10.1016/j.iac.2022.07.003. Epub 2022 Oct 28.

ABSTRACT

Mastocytosis is a rare neoplastic disorder of the mast cell lineage resulting in unregulated proliferation and activation of mast cells. Symptoms worsen in about one-third of pregnant patients. Treatment focuses on management of symptoms with antimediator therapy (H1 & H2 antihistamines, glucocorticoids, and epinephrine, if required). Medication selection requires care during labor and delivery. Although it is generally considered safe to use a medication patient tolerated before, some common medications may need to be avoided or used with caution (eg, codeine, morphine, nonsteroidal antiinflammatory drugs, vancomycin) if the patient does not have any history of exposure to them.

PMID:36411001 | DOI:10.1016/j.iac.2022.07.003

Front Psychiatry. 2022 Nov 3;13:924956. doi: 10.3389/fpsyt.2022.924956. eCollection 2022.

ABSTRACT

16p13.11 copy number variants (CNVs) have been associated with autism, schizophrenia, psychosis, intellectual disability, and epilepsy. The majority of 16p13.11 deletions or duplications occur within three well-defined intervals, and despite growing knowledge of the functions of individual genes within these intervals, the molecular mechanisms that underlie commonly observed clinical phenotypes remain largely unknown. Patient-derived, induced pluripotent stem cells (iPSCs) provide a platform for investigating the morphological, electrophysiological, and gene-expression changes that result from 16p13.11 CNVs in human-derived neurons. Patient derived iPSCs with varying sizes of 16p13.11 deletions and familial controls were differentiated into cortical neurons for phenotypic analysis. High-content imaging and morphological analysis of patient-derived neurons demonstrated an increase in neurite branching in patients compared with controls. Whole-transcriptome sequencing revealed expression level changes in neuron development and synaptic-related gene families, suggesting a defect in synapse formation. Subsequent quantification of synapse number demonstrated increased numbers of synapses on neurons derived from early-onset patients compared to controls. The identification of common phenotypes among neurons derived from patients with overlapping 16p13.11 deletions will further assist in ascertaining common pathways and targets that could be utilized for screening drug candidates. These studies can help to improve future treatment options and clinical outcomes for 16p13.11 deletion patients.

PMID:36405918 | PMC:PMC9669751 | DOI:10.3389/fpsyt.2022.924956

Medicine (Baltimore). 2022 Nov 18;101(46):e31874. doi: 10.1097/MD.0000000000031874.

ABSTRACT

INTRODUCTION: Philadelphia chromosome (Ph) positive myelodysplastic syndrome (MDS) is a very rare disease. At present, the specific role of Ph in MDS is not clear, but such patients seem to have a poor prognosis, so the disease deserves attention. Here, we describe the history of a woman with Ph-positive MDS and perform a systematic review of related literature.

PATIENT CONCERNS AND DIAGNOSIS: We report a 38-year-old woman with Ph-positive MDS.

INTERVENTIONS AND OUTCOMES: She received chemotherapy with decitabine, cytarabine, aclarubicin, and granulocyte colony-stimulating factor (DCAG) combined with imatinib mesylate and achieved a bone marrow remission. She then underwent an allogeneic hematopoietic stem cell transplant. The condition is good and no recurrence of the disease has been observed.

CONCLUSION: Ph-positive MDS is a very rare disease. Ph may aid in the malignant progression of MDS leaving such patients with a very poor prognosis. Tyrosine kinase inhibitors (TKIs) plus chemotherapy followed by allogeneic hematopoietic stem cell transplantation has provided these patients with satisfactory outcomes.

PMID:36401464 | DOI:10.1097/MD.0000000000031874

Ann Ital Chir. 2022;93:566-570.

ABSTRACT

BACKGROUNDS: Low anterior resection syndrome (LARS) was defined with symptoms such as frequency, incontinence, urgency, and constipation in patients who underwent Sphincter-Sparing Rectum Surgery (SSRC). In this study, LARS rates and risk factors of the patients who underwent SSRC were Investigated.

MATERIAL METHOD: The medical records of patients with SSRC at general surgery department were examined retrospectively. Clinical characteristics, neo/adjuvant chemo-radiotherapies, distal resection levels, open/laparoscopic procedures, postoperative complications, and pathological outcomes were recorded. LARS scoring system defined by Emmertsen and Laurberg was used to calculate LARS scores.

RESULTS: The number of eligible patients was 129. The rectal resection was performed by either low anterior resection (LAR) or very low anterior resection (VLAR). VLAR was used to specify that had anastomosis <5cm to the anal verge. The median follow-up time was 12 (1-30) months. LARS were detected in 60 (%47) patients. LARS rates were significantly higher in the patients underwent VLAR (n: 35 9% vs. 48%<0,001). In univariate analysis, the level of distal resection, open surgeries, neoadjuvant RT, and diversion with temporary stoma were significantly different in LARS group. However, in multivariate analysis, distal resection level was the only significant risk factor for LARS.

CONCLUSION: Low anterior resection syndrome (LARS) was frequently seen in patients who underwent sphincter-sparing rectum surgery (SSRS). It was detected that distal resection levels were the most important risk factor for the development of LARS. This result showed that LARS should not be disregarded in patients underwent SSRS.

KEY WORDS: Bowel Disfunction, Cancer, Incontinence, LARS, Rectum.

PMID:36398766

Orphanet J Rare Dis. 2022 Nov 17;17(1):418. doi: 10.1186/s13023-022-02530-3.

ABSTRACT

BACKGROUND: According to the International Rare Diseases Research Consortium (IRDiRC), a known rare disease (RD) should be diagnosable within a year. This study sought: firstly, to ascertain how long it takes to obtain the diagnosis of a RD in Spain, along with its associated time trend; and secondly, to identify and measure diagnostic delay (defined by the IRDiRC as any period exceeding a year) by reference to the characteristics of RDs and the persons affected by them.

METHODS: Using data sourced from the Spanish Rare Diseases Patient Registry, we performed a descriptive analysis of the time elapsed between symptom onset and diagnosis of each RD, by sex, age and date of symptom onset, and type of RD. We analysed the time trend across the period 1960-2021 and possible change points, using a Joinpoint regression model and assuming a Poisson distribution. The multivariate analysis was completed with backward stepwise logistic regression.

RESULTS: Detailed information was obtained on 3304 persons with RDs: 56.4% had experienced delay in diagnosis of their RDs, with the mean time taken being 6.18 years (median = 2; IQR 0.2-7.5). Both the percentage of patients with diagnostic delay and the average time to diagnosis underwent a significant reduction across the study period (p < 0.001). There was a higher percentage of diagnostic delays: in women (OR 1.25; 95% CI 1.07-1.45); in cases with symptom onset at age 30-44 years (OR 1.48; 95% CI 1.19-1.84): and when analysed by type of RD, in mental and behavioural disorders (OR 4.21; 95% CI 2.26-7.85), followed by RDs of the nervous system (OR 1.39; 95% CI 1.02-1.88).

CONCLUSIONS: This is the first study to quantify time to diagnosis of RDs in Spain, based on data from a national registry open to any RD. Since over half of all persons affected by RDs experience delay in diagnosis, new studies are needed to ascertain the factors associated with this delay and the implications this has on the lives of patients and their families.

PMID:36397119 | PMC:PMC9670379 | DOI:10.1186/s13023-022-02530-3

Arab J Gastroenterol. 2022 Nov;23(4):290-293. doi: 10.1016/j.ajg.2022.10.007. Epub 2022 Nov 13.

NO ABSTRACT

PMID:36384942 | DOI:10.1016/j.ajg.2022.10.007

Arch Dis Child. 2022 Dec;107(12):1136. doi: 10.1136/archdischild-2022-325090.

NO ABSTRACT

PMID:36396169 | DOI:10.1136/archdischild-2022-325090

Med Ref Serv Q. 2022 Oct-Dec;41(4):389-394. doi: 10.1080/02763869.2022.2131143.

ABSTRACT

The Genetic and Rare Diseases Information Center (GARD) is a database dedicated to aiding anyone who may be seeking assistance and knowledge regarding rare diseases. This public health resource was put into motion by the Rare Diseases Act of 2002, and uses Translational Science to enhance research procedures. People can use this resource to find support, disease facts, ongoing research information, and available treatments. The GARD database is an excellent guide for anyone wanting to increase their knowledge of rare diseases and how to help those who have a rare disorder.

PMID:36394913 | DOI:10.1080/02763869.2022.2131143

Pediatr Rheumatol Online J. 2022 Nov 16;20(1):101. doi: 10.1186/s12969-022-00761-z.

ABSTRACT

BACKGROUND: Sjogren's syndrome (SS) is a rare chronic autoimmune disease involving exocrine glands presenting with sicca syndrome, recurrent parotitis and other extraglandular stigmata. SS is well characterized in the adult population with classification criteria; however, primary SS presenting in childhood is poorly defined and rare in males. Recurrent parotitis is the most common presenting symptom in children with primary SS; however, clinical phenotype in children appears more variable than in adults. The lungs are a common extraglandular location for manifestations of primary SS. However, interstitial lung disease (ILD) is rare in children with primary SS. There are only four published reports of ILD associated with primary SS in female children. Here, we present a very rare case of primary SS in a pediatric male with pulmonary manifestations and review of the literature on ILD in childhood-onset primary SS.

CASE PRESENTATION: A 14-year-old White male with a history of chronic severe asthma, recurrent parotitis and idiopathic intracranial hypertension was referred to pediatric rheumatology for evaluation of a positive ANA. In early childhood, he was diagnosed with persistent asthma recalcitrant to therapy. At age 8, he developed recurrent episodes of bilateral parotitis despite multiple treatments with sialoendoscopy. At age 14, respiratory symptoms significantly worsened prompting reevaluation. Lab workup was notable for positive ANA and Sjogren's Syndrome A and B antibodies. Pulmonary function tests showed only a mild obstructive process. Computed tomography of chest was significant for small airway disease, and lung biopsy was positive for mild interstitial lymphocytic inflammation presenting a conflicting picture for ILD. The constellation of findings led to the diagnosis of primary SS with associated pulmonary manifestations. He was treated with hydroxychloroquine, mycophenolate mofetil and oral corticosteroids with resolution of symptoms.

CONCLUSIONS: Primary SS is a rare disease in the pediatric population that is poorly characterized. This case is the very rare presentation of childhood-onset primary SS with pulmonary manifestations in a male patient. ILD associated with primary SS is also very rare with only four pediatric patients reported in the literature. Collaborative effort is needed to develop pediatric specific diagnostic and treatment guidelines in this rare condition.

PMID:36384806 | PMC:PMC9670561 | DOI:10.1186/s12969-022-00761-z

BMC Med Ethics. 2022 Nov 16;23(1):112. doi: 10.1186/s12910-022-00842-4.

ABSTRACT

BACKGROUND: As the use of AI becomes more pervasive, and computerised systems are used in clinical decision-making, the role of trust in, and the trustworthiness of, AI tools will need to be addressed. Using the case of computational phenotyping to support the diagnosis of rare disease in dysmorphology, this paper explores under what conditions we could place trust in medical AI tools, which employ machine learning.

METHODS: Semi-structured qualitative interviews (n = 20) with stakeholders (clinical geneticists, data scientists, bioinformaticians, industry and patient support group spokespersons) who design and/or work with computational phenotyping (CP) systems. The method of constant comparison was used to analyse the interview data.

RESULTS: Interviewees emphasized the importance of establishing trust in the use of CP technology in identifying rare diseases. Trust was formulated in two interrelated ways in these data. First, interviewees talked about the importance of using CP tools within the context of a trust relationship; arguing that patients will need to trust clinicians who use AI tools and that clinicians will need to trust AI developers, if they are to adopt this technology. Second, they described a need to establish trust in the technology itself, or in the knowledge it provides-epistemic trust. Interviewees suggested CP tools used for the diagnosis of rare diseases might be perceived as more trustworthy if the user is able to vouchsafe for the technology's reliability and accuracy and the person using/developing them is trusted.

CONCLUSION: This study suggests we need to take deliberate and meticulous steps to design reliable or confidence-worthy AI systems for use in healthcare. In addition, we need to devise reliable or confidence-worthy processes that would give rise to reliable systems; these could take the form of RCTs and/or systems of accountability transparency and responsibility that would signify the epistemic trustworthiness of these tools. words 294.

PMID:36384545 | PMC:PMC9670402 | DOI:10.1186/s12910-022-00842-4

BMC Bioinformatics. 2022 Nov 16;23(1):490. doi: 10.1186/s12859-022-05008-y.

ABSTRACT

BACKGROUND: Identification of deleterious genetic variants using DNA sequencing data relies on increasingly detailed filtering strategies to isolate the small subset of variants that are more likely to underlie a disease phenotype. Datasets reflecting population allele frequencies of different types of variants serve as powerful filtering tools, especially in the context of rare disease analysis. While such population-scale allele frequency datasets now exist for structural variants (SVs), it remains a challenge to match SV calls between multiple datasets, thereby complicating estimates of a putative SV's population allele frequency.

RESULTS: We introduce SVAFotate, a software tool that enables the annotation of SVs with variant allele frequency and related information from existing SV datasets. As a result, VCF files annotated by SVAFotate offer a variety of metrics to aid in the stratification of SVs as common or rare in the broader human population.

CONCLUSIONS: Here we demonstrate the use of SVAFotate in the classification of SVs with regards to their population frequency and illustrate how SVAFotate's annotations can be used to filter and prioritize SVs. Lastly, we detail how best to utilize these SV annotations in the analysis of genetic variation in studies of rare disease.

PMID:36384437 | PMC:PMC9670370 | DOI:10.1186/s12859-022-05008-y

Asian J Urol. 2022 Oct;9(4):451-459. doi: 10.1016/j.ajur.2022.08.001. Epub 2022 Sep 9.

ABSTRACT

OBJECTIVE: Extramammary Paget's disease (EMPD) is a rare cutaneous malignant disease. Due to its rarity, there is a paucity of data regarding best treatment strategy. EMPD primarily affects apocrine gland-bearing skin areas such as the vulva, scrotum, and penis. Our objective was to provide a present-day rationale for diagnosis, pathogenesis, and treatment of EMPD with a focus on recent progress in workup and management of the disease.

METHODS: Literature on EMPD until February 2022 was assessed through PubMed, MEDLINE databases, and Google scholar. A narrative review of the most relevant articles was provided.

RESULTS: EMPD usually presents with indolent growth while usually being diagnosed primarily as carcinoma in situ. The foundation of EMPD treatment centers around prompt and accurate diagnosis, wide local or Mohs micrographic surgical excision with proper management towards the margin status, and careful consideration for lymphadenectomy in patients with regionally positive disease. Conventional chemotherapies are alternative treatments modality for patients with distant metastases; however, they sometimes have suboptimal efficacy. At present, there is no agreement regarding adjuvant or systemic therapies, although recent studies have shown several insights into the molecular pathogenesis, tumor biology, and genomics of the development and advancement of EMPD, which may lead to novel and targeted treatment approaches for metastatic EMPD in the future.

CONCLUSION: Patients with EMPD should seek care from physicians with expertise in disease management and patient counseling. These patients should be surveilled with close follow-up to evaluate them for disease recurrence or progression. Global collaborations with groups such as the Global Society for Rare Genitourinary Tumors, and especially patient support groups are crucial in designing clinical trials to help elucidate more robust data in this orphan disease.

PMID:36381596 | PMC:PMC9643171 | DOI:10.1016/j.ajur.2022.08.001

BMJ Case Rep. 2022 Nov 15;15(11):e249391. doi: 10.1136/bcr-2022-249391.

ABSTRACT

We present an infant with persistent macrocephaly and developmental delay. There is a wide range of differential diagnoses for this presentation, including many rare genetic conditions. Here, a diagnosis of Malan syndrome was made-a rare overgrowth syndrome caused by haploinsufficiency of NFIX and features affecting the neurological and musculoskeletal systems. Improvements in genomic medicine technologies and clinical services have revolutionised the way clinicians diagnose rare diseases. We highlight the importance of early genetic testing, particularly if there are red flag features such as developmental delay, and the need for a coordinated strategy to improve the management of rare diseases like Malan syndrome.

PMID:36379624 | PMC:PMC9668004 | DOI:10.1136/bcr-2022-249391

JAMA. 2022 Nov 15;328(19):1898-1899. doi: 10.1001/jama.2022.18479.

NO ABSTRACT

PMID:36378219 | DOI:10.1001/jama.2022.18479