Medicina (Kaunas). 2023 Jan 30;59(2):266. doi: 10.3390/medicina59020266.

ABSTRACT

Background and Objectives: Rare diseases (RDs) are life-threatening or chronically impairing conditions that affect about 6% of the world's population. RDs are often called 'orphan' diseases, since people suffering from them attract little support from national health systems. Aim: The aim of this study is to describe the clinical characteristics of, and the available laboratory examinations for, patients who were hospitalized in a tertiary referral center and finally received a diagnosis associated with a Rare Neurological Disease (RND). Materials and Methods: Patients that were hospitalized in our clinic from 1 January 2014 to 31 March 2022 and were finally diagnosed with an RND were consecutively included. The RND classification was performed according to the ORPHAcode system. Results: A total of 342 out of 11.850 (2.9%) adult patients admitted to our department during this period received a diagnosis associated with an RND. The most common diagnosis (N = 80, 23%) involved an RND presenting with dementia, followed by a motor neuron disease spectrum disorder (N = 64, 18.7%). Family history indicative of an RND was present in only 21 patients (6.1%). Fifty-five (16%) people had previously been misdiagnosed with another neurological condition. The mean time delay between disease onset and diagnosis was 4.24 ± 0.41 years. Conclusions: Our data indicate that a broad spectrum of RNDs may reach a tertiary Neurological Center after a significant delay. Moreover, our data underline the need for a network of reference centers, both at a national and international level, expected to support research on the diagnosis and treatment of RND.

PMID:36837468 | DOI:10.3390/medicina59020266

Genes (Basel). 2023 Jan 26;14(2):324. doi: 10.3390/genes14020324.

ABSTRACT

Pseudohypoparathyroidism (PHP) is a heterogeneous orphan disease characterized by multihormonal resistance and several phenotypic features. In some cases, PHP is caused by a mutation in the GNAS that encodes the alpha subunit of the G protein, one of the key transmitters of intracellular signals. A correlation between the genotype and phenotype of patients with GNAS mutations has not yet been described. This often makes diagnosis, drug prescription, and timely diagnosis difficult. Information about GNAS functioning and the impact of specific mutations on the clinical course of the disease is limited. Establishing of the pathogenicity by newly identified GNAS mutations will expand the understanding of this gene functioning in the cAMP signaling pathway and may become the basis for personalized treatment. This paper provides a clinical description of a patient with the Ia PHP phenotype caused by a previously unknown mutation in GNAS (NC_000020.11(NM_000516.7)): c.719-29_719-13delinsACCAAAGAGAGCAAAGCCAAG in the heterozygous state. Verification of the pathogenicity of the detected mutation is also described.

PMID:36833251 | DOI:10.3390/genes14020324

Medicine (Baltimore). 2023 Feb 22;102(8):e33084. doi: 10.1097/MD.0000000000033084.

ABSTRACT

RATIONALE: Cholesterol granuloma of the breast is a rare disease defined as chronic reactive inflammation of cholesterol crystals and foreign body giant cells. This disease can mimic breast cancer in the clinic as painless palpable hard nodules, and imaging shows irregular hypoechoic nodules with unclear boundaries. Therefore, the uncommon lesions can be easily misdiagnosed as breast cancer. Meanwhile, it can be easily neglected by clinicians because of poor understanding.

PATIENT CONCERNS: In this report, we present a rare case of multiple cholesterol granulomas of the breast, which was analyzed retrospectively and combined with all 11 relevant available studies in the last 50 years.

INTERVENTIONS: The patient had undergone multiple breast imaging inspections for breast nodules and had the local resection of nodules.

DIAGNOSES: The patient was confirmed to have a final diagnosis of benign cholesterol granulomas but was initially considered as breast cancer.

OUTCOMES: The patient did not complain of discomfort after surgery, and ultrasound reexamination 5 months after surgery showed no recurrence.

LESSONS: By retrospective analysis, dynamic contrast-enhanced magnetic resonance imaging and core needle biopsy can synergistically help clinicians distinguish it from other breast disease. To raise awareness of such a rare disease and reduce related misdiagnoses, we summarize the characteristics of cholesterol granulomas and recommend appropriate novel diagnosis and treatment regimens for patients with cholesterol granulomas.

PMID:36827045 | DOI:10.1097/MD.0000000000033084

MMW Fortschr Med. 2023 Mar;165(4):20. doi: 10.1007/s15006-023-2431-0.

NO ABSTRACT

PMID:36826644 | DOI:10.1007/s15006-023-2431-0

Orphanet J Rare Dis. 2023 Feb 24;18(1):41. doi: 10.1186/s13023-023-02635-3.

ABSTRACT

BACKGROUND: In recent years, significant advances have been made in the field of rare diseases (RDs). However, there is a large number of RDs without specific treatment and half of these treatments have public funding in Spain. The aim of the FINEERR project was to carry out a multidisciplinary strategic discussion on the challenge of funding and access to RD-targeted drugs in Spain, in order to agree on specific proposals for medium-term improvement and hence support decision-making in the Spanish National Healthcare System (SNHS).

RESULTS: The FINEERR Project was organized around a CORE Advisory Committee, which provided an overview, agreed on the design and scope of the project, and selected the members within each of four working groups (WG). Overall, 40 experts discussed and reached a consensus on different relevant aspects, such as conditioning factors for initial funding and access, evaluation and access to RD-targeted therapies, funding of these therapies, and implementation of a new funding and access model. From these meetings, 50 proposals were defined and classified by their level of relevance according to the experts. A descriptive analysis of responses was performed for each proposal. Thereafter, experts completed another questionnaire where they ranked the 25 most relevant proposals according to their level of feasibility of being implemented in the SNHS. The most relevant and feasible proposals were to improve: process of referral of patients with RDs, control over monitoring mechanisms, and communication between healthcare professionals and patients.

CONCLUSIONS: The FINEERR project may provide a starting point for stakeholders involved in the process of funding and access to RD-targeted therapies in Spain to provide the necessary resources and implement measures to improve both the quality of life and life expectancy of patients with RDs.

PMID:36823598 | PMC:PMC9950008 | DOI:10.1186/s13023-023-02635-3

Lancet Diabetes Endocrinol. 2023 Mar;11(3):139. doi: 10.1016/S2213-8587(23)00042-6.

NO ABSTRACT

PMID:36822740 | DOI:10.1016/S2213-8587(23)00042-6

Front Cell Dev Biol. 2023 Feb 2;11:1105565. doi: 10.3389/fcell.2023.1105565. eCollection 2023.

ABSTRACT

Pulmonary arterial hypertension (PAH) is an orphan disease of the cardiopulmonary unit that reflects an obstructive pulmonary vasculopathy and presents with hypertrophy, inflammation, fibrosis, and ultimately failure of the right ventricle (RVF). Despite treatment using pulmonary hypertension (PH)-targeted therapies, persistent functional impairment reduces the quality of life for people with PAH and death from RVF occurs in approximately 40% of patients within 5 years of diagnosis. PH-targeted therapeutics are primarily vasodilators and none, alone or in combination, are curative. This highlights a need to therapeutically explore molecular targets in other pathways that are involved in the pathogenesis of PAH. Several candidate pathways in PAH involve acquired mitochondrial dysfunction. These mitochondrial disorders include: 1) a shift in metabolism related to increased expression of pyruvate dehydrogenase kinase and pyruvate kinase, which together increase uncoupled glycolysis (Warburg metabolism); 2) disruption of oxygen-sensing related to increased expression of hypoxia-inducible factor 1α, resulting in a state of pseudohypoxia; 3) altered mitochondrial calcium homeostasis related to impaired function of the mitochondrial calcium uniporter complex, which elevates cytosolic calcium and reduces intramitochondrial calcium; and 4) abnormal mitochondrial dynamics related to increased expression of dynamin-related protein 1 and its binding partners, such as mitochondrial dynamics proteins of 49 kDa and 51 kDa, and depressed expression of mitofusin 2, resulting in increased mitotic fission. These acquired mitochondrial abnormalities increase proliferation and impair apoptosis in most pulmonary vascular cells (including endothelial cells, smooth muscle cells and fibroblasts). In the RV, Warburg metabolism and induction of glutaminolysis impairs bioenergetics and promotes hypokinesis, hypertrophy, and fibrosis. This review will explore our current knowledge of the causes and consequences of disordered mitochondrial function in PAH.

PMID:36819102 | PMC:PMC9933518 | DOI:10.3389/fcell.2023.1105565

Probl Sotsialnoi Gig Zdravookhranenniiai Istor Med. 2023 Jan 15;31(1):33-43. doi: 10.32687/0869-866X-2023-31-1-33-43.

ABSTRACT

In Russia, the orphan diseases for many years are the object of intent attention both of the national legislation and health care system. The lower prevalence of these diseases in population causes predicaments to timely diagnosis, drug provision and medical care. Besides, absence of integrated approach to issues of diagnosis and treatment of rare diseases contribute nothing to fast solving of actual problems in this field. Frequently, impossibility to get necessary course of treatment forces patients with orphan diseases to seek for alternative sources. The article assesses current situation with medications support of patients suffering from diseases included in the list of life-threatening and chronic progressive rare (orphan) diseases that result in shortening life-span or disability and diseases included in the Federal Program "The 14 high-cost nosologies". The issues of keeping record of patients and financing medications purchase are touched upon. The study results identified problems of organization of medication support of patients with orphan diseases associated with complexity of accounting their number and absence of integral system of preferential medication support.

PMID:36801872 | DOI:10.32687/0869-866X-2023-31-1-33-43

Probl Sotsialnoi Gig Zdravookhranenniiai Istor Med. 2023 Jan 15;31(1):16-19. doi: 10.32687/0869-866X-2023-31-1-16-19.

ABSTRACT

The rare diseases are characterized both by relatively small prevalence in population and complexity of medical care support of patients. In this particular case, the legal regulation of medical care takes its particular placement in health care. The uniqueness of rare diseases requires development of special normative legal acts, definitions and treating approaches. One of such approaches are orphan drugs that also are unique, complicated in development and require special legislative regulation. The article presents corresponding legislative terminology in modern Russian health care, actual listings of rare diseases and orphan drugs. The directions to improve current terminology and normative legal regulation are proposed.

PMID:36801869 | DOI:10.32687/0869-866X-2023-31-1-16-19

Lab Invest. 2023 Jan 18;103(5):100062. doi: 10.1016/j.labinv.2023.100062. Online ahead of print.

ABSTRACT

Tissue microarrays (TMA) have become an important tool in high-throughput molecular profiling of tissue samples in the translational research setting. Unfortunately, high-throughput profiling in small biopsy specimens or rare tumor samples (eg, orphan diseases or unusual tumors) is often precluded owing to limited amounts of tissue. To overcome these challenges, we devised a method that allows tissue transfer and construction of TMAs from individual 2- to 5-μm sections for subsequent molecular profiling. We named the technique slide-to-slide (STS) transfer, and it requires a series of chemical exposures (so-called xylene-methacrylate exchange) in combination with rehydrated lifting, microdissection of donor tissues into multiple small tissue fragments (methacrylate-tissue tiles), and subsequent remounting on separate recipient slides (STS array slide). We developed the STS technique by assessing the efficacy and analytical performance using the following key metrics: (a) dropout rate, (b) transfer efficacy, (c) success rates using different antigen-retrieval methods, (d) success rates of immunohistochemical stains, (e) fluorescent in situ hybridization success rates, and (f) DNA and (g) RNA extraction yields from single slides, which all functioned appropriately. The dropout rate ranged from 0.7% to 6.2%; however, we applied the same STS technique successfully to fill these dropouts ("rescue" transfer). Hematoxylin and eosin assessment of donor slides confirmed a transfer efficacy of >93%, depending on the size of the tissue (range, 76%-100%). Fluorescent in situ hybridization success rates and nucleic acid yields were comparable with those of traditional workflows. In this study, we present a quick, reliable, and cost-effective method that offers the key advantages of TMAs and other molecular techniques-even when tissue is sparse. The perspectives of this technology in biomedical sciences and clinical practice are promising, given that it allows laboratories to create more data with less tissue.

PMID:36801639 | DOI:10.1016/j.labinv.2023.100062

Cell Calcium. 2023 Mar;110:102702. doi: 10.1016/j.ceca.2023.102702. Epub 2023 Feb 5.

ABSTRACT

Deafness is a highly heterogeneous disorder which stems, for 50%, from genetic origins. Sensory transduction relies mainly on sensory hair cells of the cochlea, in the inner ear. Calcium is key for the function of these cells and acts as a fundamental signal transduction. Its homeostasis depends on three factors: the calcium influx, through the mechanotransduction channel at the apical pole of the hair cell as well as the voltage-gated calcium channel at the base of the cells; the calcium buffering via Ca2+-binding proteins in the cytoplasm, but also in organelles such as mitochondria and the reticulum endoplasmic mitochondria-associated membranes with specialized proteins; and the calcium extrusion through the Ca-ATPase pump, located all over the plasma membrane. In addition, the synaptic transmission to the central nervous system is also controlled by calcium. Genetic studies of inherited deafness have tremendously helped understand the underlying molecular pathways of calcium signaling. In this review, we discuss these different factors in light of the associated genetic diseases (syndromic and non-syndromic deafness) and the causative genes.

PMID:36791536 | DOI:10.1016/j.ceca.2023.102702

Arq Bras Cardiol. 2023 Jan;120(1):e20220147. doi: 10.36660/abc.20220147.

NO ABSTRACT

PMID:36790305 | DOI:10.36660/abc.20220147

Proc Natl Acad Sci U S A. 2023 Feb 21;120(8):e2206878120. doi: 10.1073/pnas.2206878120. Epub 2023 Feb 15.

ABSTRACT

SET is a multifunctional histone-binding oncoprotein that regulates transcription by an unclear mechanism. Here we show that SET enhances estrogen-dependent transcription. SET knockdown abrogates transcription of estrogen-responsive genes and their enhancer RNAs. In response to 17β-estradiol (E2), SET binds to the estrogen receptor α (ERα) and is recruited to ERα-bound enhancers and promoters at estrogen response elements (EREs). SET functions as a histone H2 chaperone that dynamically associates with H2A.Z via its acidic C-terminal domain and promotes H2A.Z incorporation, ERα, MLL1, and KDM3A loading and modulates histone methylation at EREs. SET depletion diminishes recruitment of condensin complexes to EREs and impairs E2-dependent enhancer-promoter looping. Thus, SET boosts E2-induced gene expression by establishing an active chromatin structure at ERα-bound enhancers and promoters, which is essential for transcriptional activation.

PMID:36791099 | DOI:10.1073/pnas.2206878120

Int J Environ Res Public Health. 2023 Jan 30;20(3):2483. doi: 10.3390/ijerph20032483.

ABSTRACT

The article deals with one of the effects of health inequalities and gaps in access to treatments for rare diseases, namely health-driven emigration. The purpose of the paper is to systematize knowledge about the phenomenon of health emigration observed among families affected by rare diseases, for which reimbursed treatment is available, but only in selected countries. The topic proved to be niche; the issue of "health emigration in rare diseases" is an area for exploration. Therefore, the further analysis used text mining and machine learning methods based on a database selected based on keywords related to this issue. The results made it possible to systematize the guesses made by researchers in management and economic fields, to identify the most common keywords and thematic clusters around the perspective of the patient, drug manufacturer and treatment reimbursement decision-maker, and the perspective integrating all the others. Since the topic of health emigration was not directly addressed in the selected sources, the authors attempted to define the related concepts and discussed the importance of this phenomenon in managing the support system in rare diseases. Thus, they indicated directions for further research in this area.

PMID:36767849 | PMC:PMC9915846 | DOI:10.3390/ijerph20032483

Cells. 2023 Jan 30;12(3):449. doi: 10.3390/cells12030449.

ABSTRACT

Rare diseases affect less than 1 in 2000 people and are characterized by a serious, chronic, and progressive course. Among the described diseases, a mutation in a single gene caused mastocytosis, thrombotic thrombocytopenic purpura, Gaucher disease, and paroxysmal nocturnal hemoglobinuria (KIT, ADAMTS13, GBA1, and PIG-A genes, respectively). In Castleman disease, improper ETS1, PTPN6, TGFBR2, DNMT3A, and PDGFRB genes cause the appearance of symptoms. In histiocytosis, several mutation variants are described: BRAF, MAP2K1, MAP3K1, ARAF, ERBB3, NRAS, KRAS, PICK1, PIK3R2, and PIK3CA. Genes like HPLH1, PRF1, UNC13D, STX11, STXBP2, SH2D1A, BIRC4, ITK, CD27, MAGT1, LYST, AP3B1, and RAB27A are possible reasons for hemophagocytic lymphohistiocytosis. Among novel molecular medicines, tyrosine kinase inhibitors, mTOR inhibitors, BRAF inhibitors, interleukin 1 or 6 receptor antagonists, monoclonal antibodies, and JAK inhibitors are examples of drugs expanding therapeutic possibilities. An explanation of the molecular basis of rare diseases might lead to a better understanding of the pathogenesis and prognosis of the disease and may allow for the development of new molecularly targeted therapies.

PMID:36766791 | PMC:PMC9913931 | DOI:10.3390/cells12030449

Pediatr Rheumatol Online J. 2023 Feb 10;21(1):15. doi: 10.1186/s12969-023-00795-x.

ABSTRACT

BACKGROUND: Cryopyrin-associated periodic syndrome (CAPS), a rare genetic autoimmune disease, is composed of familial cold autoinflammatory syndrome (FCAs), Muckle-Wells syndrome (MWS), and neonatal onset multisystem inflammatory disease (NOMID). MWS is caused by dominantly inherited or de novo gain-of-function mutations in the NOD-like receptor 3 (NLRP3) gene. At present, there is no report about the variation of R262W in China.

CASE PRESENTATION: We reported a 3-year-old Chinese boy who had recurrent fever without obvious inducement, bilateral conjunctival congestion, and urticarial-like rash. Laboratory examination showed elevation in leukocyte count, neutrophil count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) and serum amyloid protein (SAA) levels. Whole exome sequencing identified a missense variation c.784-786delinsTGG (p.R262W) in the coding region of the NLRP3 gene.

CONCLUSION: A classical variant of the NLRP3 gene in a patient with MWS was first reported in China.

PMID:36765385 | PMC:PMC9918341 | DOI:10.1186/s12969-023-00795-x

J Perinatol. 2023 Feb 11. doi: 10.1038/s41372-023-01630-7. Online ahead of print.

ABSTRACT

Genetic disorders are a leading cause of morbidity and mortality in infants admitted to neonatal intensive care units. This population has immense potential to benefit from genomic medicine, as early precision diagnosis is critical to early personalized management. However, the implementation of genomic medicine in neonatology thus far has arguably worsened health inequities, and strategies are urgently needed to achieve equitable access to genomics in neonatal care. In this perspective, we demonstrate the utility of genomic sequencing in critically ill infants and highlight three key recommendations to advance equitable access: recruitment of underrepresented populations, education of non-genetics providers to empower practice of genomic medicine, and development of innovative infrastructure to implement genomic medicine across diverse settings.

PMID:36774516 | DOI:10.1038/s41372-023-01630-7

Clin Lab Med. 2023 Mar;43(1):127-143. doi: 10.1016/j.cll.2022.09.023.

NO ABSTRACT

PMID:36764805 | DOI:10.1016/j.cll.2022.09.023

J Allergy Clin Immunol. 2023 Feb 7:S0091-6749(23)00151-3. doi: 10.1016/j.jaci.2023.01.023. Online ahead of print.

ABSTRACT

BACKGROUND: Inborn errors of immunity (IEI) have been implicated in causing immune dysregulation, including allergic diseases. The signal transducer and activator of transcription 6 (STAT6) is a key regulator of allergic responses.

OBJECTIVE: We sought to characterize a novel gain-of-function (GOF) STAT6 mutation identified in a child with severe allergic manifestations.

METHODS: We performed whole-exome and targeted gene sequencing, lymphocyte characterization, and molecular and functional analyses of mutated STAT6.

RESULTS: We report a child with a missense mutation in the DNA binding domain of STAT6 (c.1114G>A, p.E372K) who presented with severe atopic dermatitis, eosinophilia and elevated IgE. Naive lymphocytes from the affected patient displayed increased TH2 and suppressed TH1 and TH17 cell responses. The mutation augmented both basal and cytokine-induced STAT6 phosphorylation without affecting dephosphorylation kinetics. Treatment with the Janus kinase 1/2 inhibitor ruxolitinib reversed STAT6 hyperresponsiveness to IL-4, normalized TH1, and TH17, suppressed the eosinophilia and improved the patient's atopic dermatitis.

CONCLUSIONS: We identified a novel IEI due to STAT6 GOF mutation that gave rise to severe allergic dysregulation. Janus kinase inhibitor therapy could represent an effective targeted treatment for this disorder.

PMID:36758835 | DOI:10.1016/j.jaci.2023.01.023

Brain. 2023 Feb 9:awad039. doi: 10.1093/brain/awad039. Online ahead of print.

ABSTRACT

In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated to torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with TOR1A-AMC5 have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with fetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71% with higher mortality in males. Death occurred at a median age of 1.2 months (1 week - 9 years) due to respiratory failure, cardiac arrest, or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival.

PMID:36757831 | DOI:10.1093/brain/awad039