Nat Rev Dis Primers. 2024 Feb 29;10(1):13. doi: 10.1038/s41572-024-00505-1.

NO ABSTRACT

PMID:38424095 | DOI:10.1038/s41572-024-00505-1

Laeknabladid. 2024 mars;110(3):133. doi: 10.17992/lbl.2024.03.783.

NO ABSTRACT

PMID:38420957 | DOI:10.17992/lbl.2024.03.783

Nat Commun. 2024 Feb 28;15(1):1227. doi: 10.1038/s41467-024-45099-0.

ABSTRACT

Exploring the molecular basis of disease severity in rare disease scenarios is a challenging task provided the limitations on data availability. Causative genes have been described for Congenital Myasthenic Syndromes (CMS), a group of diverse minority neuromuscular junction (NMJ) disorders; yet a molecular explanation for the phenotypic severity differences remains unclear. Here, we present a workflow to explore the functional relationships between CMS causal genes and altered genes from each patient, based on multilayer network community detection analysis of complementary biomedical information provided by relevant data sources, namely protein-protein interactions, pathways and metabolomics. Our results show that CMS severity can be ascribed to the personalized impairment of extracellular matrix components and postsynaptic modulators of acetylcholine receptor (AChR) clustering. This work showcases how coupling multilayer network analysis with personalized -omics information provides molecular explanations to the varying severity of rare diseases; paving the way for sorting out similar cases in other rare diseases.

PMID:38418480 | PMC:PMC10902324 | DOI:10.1038/s41467-024-45099-0

J Breast Imaging. 2023 Sep 22;5(5):585-590. doi: 10.1093/jbi/wbad033.

ABSTRACT

Diabetic fibrous mastopathy (DFM) is a rare benign fibrotic disease of the breast that develops in patients with longstanding and often uncontrolled diabetes mellitus. Clinically, patients may present with an irregular, firm, palpable mass, which may be solitary or multiple, occurring in one or both breasts. Diabetic fibrous mastopathy occurs most often in premenopausal women with heterogeneously or extremely dense breasts; mammography may show focal asymmetry or, less often, a noncalcified mass with indistinct or obscured margins, but there are usually no discrete findings. On US, DFM may have marked hypoechogenicity and posterior shadowing secondary to extensive fibrosis. Diabetic fibrous mastopathy features on contrast-enhanced MRI are also nonspecific, with gradual persistent nonmass enhancement reported. Because the clinical presentation and US features of DFM overlap with those of breast cancer, histopathologic correlation is needed to confirm diagnosis and exclude malignancy. These findings include collagenous stroma often with keloidal features and chronic perilobular and perivascular inflammation. Histopathologic findings of lymphocytic lobulitis and perivascular inflammation are common to other autoimmune conditions.

PMID:38416913 | DOI:10.1093/jbi/wbad033

Rev Med Suisse. 2024 Feb 28;20(863):430-435. doi: 10.53738/REVMED.2024.20.863.430.

ABSTRACT

Antiphospholipid syndrome (APS) is a rare autoimmune disease characterized by recurrent arterial and venous thromboembolic events. Renal complications occur in 3 % of patients. Renal artery stenosis is the most common, and APS-related nephropathy is the predominant microvascular complication. APS nephropathy has heterogeneous manifestations ranging from hematuria and non-nephrotic range proteinuria to hypertension and multi-organ failure caused by catastrophic antiphospholipid antibody syndrome. Anticoagulation and thromboprophylaxis are key to management. Immunosuppression has been used with some success but lacks randomized controlled trial validation for their use.

PMID:38415729 | DOI:10.53738/REVMED.2024.20.863.430

Hong Kong Med J. 2024 Feb;30 Suppl 1(1):23-26.

NO ABSTRACT

PMID:38413208

Orphanet J Rare Dis. 2024 Feb 27;19(1):91. doi: 10.1186/s13023-024-03095-z.

ABSTRACT

BACKGROUND: Over the last twenty years of orphan drug regulation in Europe, the regulatory framework has increased its complexity, with different regulatory paths and tools engineered to facilitate the innovation and accelerate approvals. Recently, the proposal of the new Pharmaceutical Legislation for the European Union, which will replace at least three Regulations and one Directive, was released and its new framework is raising many questions. The aim of this study was to present a characterisation of the Orphan Medicinal Products (OMPs) authorised by the European Commission (EC), between 2010 and 2022, looking into eighteen variables, contributing to the ongoing discussion on the proposal and implementation of the new Pharmaceutical Legislation proposed.

METHODS: Data of the OMPs identified and approved between 2010 and 2022 were extracted from the European Public Assessment Reports (EPARs) produced by the European Medicines Agency. Information regarding legal basis of the application, applicant, protocol assistance received, type of authorization, registration status, type of molecule, ATC code, therapeutic area, target age, disease prevalence, number of pivotal clinical trials supporting the application, clinical trial designs, respective efficacy endpoints and number of patients enrolled in the pivotal clinical trials were extracted. A descriptive statistical analysis was applied.

RESULTS: We identified 192 OMPs approved in the period between 2010 and 2022. 89% of the OMPs have legal basis of "full application". 86% of the sponsors received protocol assistance whereas 64% of the MAA benefited from the accelerated assessment. 53% of the active substances are small molecules; about 1 in 5 molecules are repurposed. 40% of the OMPs have oncological therapeutic indications and 56% of the OMPs are intended to treat only adults. 71% of the products were approved based on a single pivotal trial.

CONCLUSIONS: This analysis of OMPs approved between 2010 and 2022 shows that a shift has occurred in the rare disease medicine development space. Through the period studied we observe an increase of non-small molecules approved, accelerated assessment received and non-standard MA's granted.

PMID:38413985 | PMC:PMC10900541 | DOI:10.1186/s13023-024-03095-z

Orphanet J Rare Dis. 2024 Feb 26;19(1):37. doi: 10.1186/s13023-024-03050-y.

ABSTRACT

Rare diseases present immense challenges to physicians, patients, and the healthcare system at large due to a scarcity of research and knowledge in the field. This contributes to uncertainty surrounding rare diseases, which can hinder the management of these chronic conditions. An analysis of my family's experience battling my mother's ameloblastic carcinoma highlights the difficulties in communicating the uncertainty around rare diseases and their damaging effects on our family's well-being. Here, we will recognize the importance of acknowledging uncertainty during diagnoses and advocating for enhanced detection strategies. The goal of this article is to emphasize that effective medical communication around rare diseases, accessibility to accurate information, proper services, and a shift toward a culture that prioritizes patient well-being are critical for improving health outcomes for rare disease patients.

PMID:38403651 | PMC:PMC10895854 | DOI:10.1186/s13023-024-03050-y

Orphanet J Rare Dis. 2024 Feb 25;19(1):86. doi: 10.1186/s13023-024-03097-x.

ABSTRACT

BACKGROUND: The Rare Pediatric Disease (RPD) Priority Review Voucher (PRV) Program was enacted in 2012 to support the development of new products for children. Prior to requesting a voucher, applicants can request RPD designation, which confirms their product treats or prevents a rare disease in which the serious manifestations primarily affect children. This study describes the trends and characteristics of these designations. Details of RPD designations are not publicly disclosable; this research represents the first analysis of the RPD designation component of the program.

RESULTS: We used an internal US Food and Drug Administration database to analyze all RPD designations between 2013 and 2022. Multiple characteristics were analyzed, including the diseases targeted by RPD designation, whether the product targeted a neonatal disease, product type (drug/biologic), and the level of evidence (preclinical/clinical) to support designation. There were 569 RPD designations during the study period. The top therapeutic areas were neurology (26%, n = 149), metabolism (23%, n = 131), oncology (18%, n = 105). The top diseases targeted by RPD designation were Duchenne muscular dystrophy, neuroblastoma, and sickle cell disease. Neonatology products represented 6% (n = 33), over half were for drug products and 38% were supported by clinical data.

CONCLUSIONS: The RPD PRV program was created to encourage development of new products for children. The results of this study establish that a wide range of diseases have seen development-from rare pediatric cancers to rare genetic disorders. Continued support of product development for children with rare diseases is needed to find treatments for all children with unmet needs.

PMID:38403586 | PMC:PMC10895788 | DOI:10.1186/s13023-024-03097-x

Biomolecules. 2024 Feb 11;14(2):211. doi: 10.3390/biom14020211.

ABSTRACT

Niemann-Pick Disease (NPD) is a rare autosomal recessive disease belonging to lysosomal storage disorders. Three types of NPD have been described: NPD type A, B, and C. NPD type A and B are caused by mutations in the gene SMPD1 coding for sphingomyelin phosphodiesterase 1, with a consequent lack of acid sphingomyelinase activity. These diseases have been thus classified as acid sphingomyelinase deficiencies (ASMDs). NPD type C is a neurologic disorder due to mutations in the genes NPC1 or NPC2, causing a defect of cholesterol trafficking and esterification. Although all three types of NPD can manifest with pulmonary involvement, lung disease occurs more frequently in NPD type B, typically with interstitial lung disease, recurrent pulmonary infections, and respiratory failure. In this sense, bronchoscopy with broncho-alveolar lavage or biopsy together with high-resolution computed tomography are fundamental diagnostic tools. Although several efforts have been made to find an effective therapy for NPD, to date, only limited therapeutic options are available. Enzyme replacement therapy with Olipudase α is the first and only approved disease-modifying therapy for patients with ASMD. A lung transplant and hematopoietic stem cell transplantation are also described for ASMD in the literature. The only approved disease-modifying therapy in NPD type C is miglustat, a substrate-reduction treatment. The aim of this review was to delineate a state of the art on the genetic basis and lung involvement in NPD, focusing on clinical manifestations, radiologic and histopathologic characteristics of the disease, and available therapeutic options, with a gaze on future therapeutic strategies.

PMID:38397448 | PMC:PMC10886890 | DOI:10.3390/biom14020211

J Med Case Rep. 2024 Feb 24;18(1):108. doi: 10.1186/s13256-024-04434-1.

ABSTRACT

INTRODUCTION: Primary Thyroid Lymphoma (PTL) is defined as lymphoma involving the thyroid gland alone or the thyroid gland and adjacent neck lymph nodes without contiguous spread or distant metastases at the time of diagnosis. Most thyroid lymphomas are B cell lymphomas, and 98% of all PTL cases are non-Hodgkin's lymphoma. It is a rare disease accounting for around 5% of the thyroid neoplasms and 2% of extranodal lymphomas. If properly diagnosed and treated, the prognosis is favorable.

CASE PRESENTATION: Five cases (three men and two women) of PTL were diagnosed and treated in our institute between January 2005 and September 2019. These are 5 cases of Caucasian origin. The mean age was 76.2 (range: 63-95 years); one patient had associated hypothyroid. One patient had a medical history of breast cancer; one was hypothyroid, and four were euthyroid at the diagnosis. In 4 of these patients, PTL started with compressive symptoms. No patients underwent fine needle aspiration cytology (FNAC) or biopsy for the diagnostic only. In sonography, two cases showed bilateral nodules with goiter; in the three cases it showed nodules in the lobe and isthmus. Technetium-99m scintigraphy was performed on only two patients. Bone Marrow Biopsy (BMB) showed normal cellularity in 4 cases and only one case showed tumor cells. LDH levels were increased in all cases. The extension was evaluated in all patients with cervical and thoracic CT scans, Bone Marrow Biopsy (BMB), beta-2 microglobulin, and serum lactate dehydrogenase (LDH) levels. Three cases were staged as IE and two cases as IIE. Three patients underwent total thyroidectomy; two of them underwent cervical lymph node dissection. Two patients underwent lobectomy. All were diagnosed with lymphoma postoperatively and all were diffuse large B cell lymphoma (DLBCL). One patient completed treatment with R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), and two cases received adjuvant chemo-radiotherapy (30 Gy). Two patients died immediately after surgery.

CONCLUSION: PTL is a rare disease whose diagnosis should be considered in cases of rapidly growing goitres. Timely needle biopsy in suspected cases can avoid unnecessary surgery. Systemic treatment is required, depending on the stage of the tumour.

PMID:38395921 | PMC:PMC10893725 | DOI:10.1186/s13256-024-04434-1

Am J Bioeth. 2024 Mar;24(3):106-108. doi: 10.1080/15265161.2024.2303152. Epub 2024 Feb 23.

NO ABSTRACT

PMID:38394024 | DOI:10.1080/15265161.2024.2303152

J Biosci. 2024;49:34.

ABSTRACT

Rare genetic diseases are rare by themselves with prevalence of 1 in 25,000, but collectively they are a significant cause of morbidity and mortality. Till date, collectively there are more than 9,000 rare diseases documented, which impose a devastating impact on patients, their families, and the healthcare system, including enormous societal burden. Obtaining a conclusive diagnosis for a patient with a rare genetic disease can be long and gruelling. For some patients it takes months or years to receive a definite diagnosis, and around 50% of the patients remain undiagnosed even with expert clinical and advanced high-end laboratory investigations. Owing to the large population and practice of consanguinity the Indian population is a pool of indigenous variants and unreported phenotypes or diseases. A mission program on pediatric rare diseases is an unparalleled initiative to study unique clinical conditions via the use of latest state-of-art technologies and with the combination of a mulit-omics approach. Our initiative will not only provide diagnosis to patients with rare disease but also build a platform for translational research for rare disease screening, management, and treatment.

PMID:38383979

J Biosci. 2024;49:33.

ABSTRACT

The medical emergency of COVID-19 brought to the forefront mRNA vaccine technology where the mRNA vaccine candidates mRNA-1273 and BNT162b2 displayed superlative and more than 90% efficacy in protecting against SARS-CoV2 infections. Rare genetic disorders are rare individually, but collectively they are common and represent a medical emergency. In mRNA biotherapeutic technology, administration of a therapeutic protein-encoding mRNA-nanoparticle formulation allows for in vivo production of therapeutic proteins to functionally complement the protein functions lacking in rare disease patients. The platform nature of mRNA biotherapeutic technology propels rare disease drug discovery and, owing to the scalable and synthetic nature of mRNA manufacturing, empowers parallel product development using a universal production pipeline. This review focuses on the advantages of mRNA biotherapeutic technology over current therapies for rare diseases and provides summaries for the proof-of-concept preclinical studies performed to demonstrate the potential of mRNA biotherapeutic technology. Apart from preclinical studies, this review also spotlights the clinical trials currently being conducted for mRNA biotherapeutic candidates. Currently, seven mRNA biotherapeutic candidates have entered clinical trials for rare diseases, and of them, 3 candidates entered in the year 2023 alone. The rapid pace of clinical development promises a future where, as with mRNA vaccines for COVID-19, mRNA biotherapeutic technology would combat an emergency of rare genetic disorders.

PMID:38383978

J Biosci. 2024;49:31.

ABSTRACT

Rare diseases (RD) pose significant challenges for healthcare systems globally, necessitating the establishment of disease registries to facilitate research, diagnosis, and treatment. This article explores the development of a comprehensive national RD registry for India, informed by insights gained through interactions with experts from India and the Asia-Pacific Economic Cooperation (APEC) region. The social and technological challenges involved in creating and maintaining a national RDs registry are highlighted. Moreover, the roles and responsibilities of different stakeholders are discussed. Additionally, the RD-RAP (Registry and Analytics Platform) framework is also discussed, which is an analytics-based RD registry model with multi-stakeholder end-user utility. Although developed for the APEC region, the RD-RAP framework holds promise in the Indian context. This article discusses the key features of the RD-RAP framework that are relevant and applicable to the Indian setting. By leveraging these insights, this research aimed to provide valuable guidance for the development and operation of a comprehensive national RD registry in India.

PMID:38383976

J Biosci. 2024;49:30.

ABSTRACT

Rare diseases, also known as orphan diseases, are diseases with low occurrence in the population. Developing orphan drugs is challenging because of inadequate financial and scientific resources and insufficient subjects to run clinical trials. With advances in genome sequencing technologies, emergence of cell and gene therapies, and the latest developments in regulatory pathways, some orphan drugs that have curative potential have been approved. In India, due to its large population and resource crunch, developing orphan drugs is phenomenally challenging. After adopting the Orphan Drug Act, the US-FDA has continuously made advances in regulatory pathways for orphan drugs. Particularly, n-of-one clinical trials have been successful in some cases. India has recently adopted policies that have impacted the long-neglected rare-disease ecosystem; however, there is no clear regulatory path for orphan drug development in India. We have proposed a multi-pronged approach involving close collaboration between the government, regulatory bodies, industries, and patient advocacy groups to boost orphan drug development in India. We believe that rapidly evolving technologies and business models can enable better and faster development of novel orphan drugs in India and other resource-constrained countries.

PMID:38383975

J Biosci. 2024;49:28.

ABSTRACT

Rare genetic diseases are a group of life-threatening disorders affecting significant populations worldwide and posing substantial challenges to healthcare systems globally. India, with its vast population, is also no exception. The country harbors millions of individuals affected by these fatal disorders, which often result from mutations in a single gene. The emergence of CRISPR-Cas9 technology, however, has ushered in a new era of hope in genetic therapies. CRISPR-based treatments hold the potential to precisely edit and correct diseasecausing mutations, offering tailored solutions for rare genetic diseases in India. This review explores the landscape of rare genetic diseases in India along with national policies and major challenges, and examines the implications of CRISPR-based therapies for potential cure. It delves into the potential of this technology in providing personalized and effective treatments. However, alongside these promising prospects, some ethical considerations, regulatory challenges, and concerns about the accessibility of CRISPR therapies are also discussed since addressing these issues is crucial for harnessing the full power of CRISPR in tackling rare genetic diseases in India. By taking a multidisciplinary approach that combines scientific advancements, ethical principles, and regulatory frameworks, these complexities can be reconciled, paving the way for innovative and impactful healthcare solutions for rare diseases in India.

PMID:38383973

J Biosci. 2024;49:27.

ABSTRACT

Rare muscular disorders (RMDs) are disorders that affect a small percentage of the population. The disorders which are attributed to genetic mutations often manifest in the form of progressive weakness and atrophy of skeletal and heart muscles. RMDs includes disorders such as Duchenne muscular dystrophy (DMD), GNE myopathy, spinal muscular atrophy (SMA), limb girdle muscular dystrophy, and so on. Due to the infrequent occurrence of these disorders, development of therapeutic approaches elicits less attention compared with other more prevalent diseases. However, in recent times, improved understanding of pathogenesis has led to greater advances in developing therapeutic options to treat such diseases. Exon skipping, gene augmentation, and gene editing have taken the spotlight in drug development for rare neuromuscular disorders. The recent innovation in targeting and repairing mutations with the advent of CRISPR technology has in fact opened new possibilities in the development of gene therapy approaches for these disorders. Although these treatments show satisfactory therapeutic effects, the susceptibility to degradation, instability, and toxicity limits their application. So, an appropriate delivery vector is required for the delivery of these cargoes. Viral vectors are considered potential delivery systems for gene therapy; however, the associated concurrent immunogenic response and other limitations have paved the way for the applications of other non-viral systems like lipids, polymers, cellpenetrating peptides (CPPs), and other organic and inorganic materials. This review will focus on non-viral vectors for the delivery of therapeutic cargoes in order to treat muscular dystrophies.

PMID:38383972

J Biosci. 2024;49:26.

ABSTRACT

Diseases of the human nervous system are an important cause of morbidity and mortality worldwide. These disorders arise out of multiple aetiologies of which rare genetic mutations in genes vital to nervous system development and function are an important cause. The diagnosis of such rare disorders is challenging due to the close overlap of clinical presentations with other diseases that are not of genetic origin. Further, understanding the mechanisms by which mutations lead to altered brain structure and function is also challenging, given that the brain is not readily accessible for tissue biopsy. However, recent developments in modern technologies have opened up new opportunities for the analysis of rare genetic disorders of the brain. In this review, we discuss these developments and strategies by which they can be applied effectively for better understanding of rare diseases of the brain. This will lead to the development of new clinical strategies to manage brain disorders.

PMID:38383971

J Biosci. 2024;49:25.

ABSTRACT

I am writing this piece as the parent of a son diagnosed with Duchenne muscular dystrophy, a severely debilitating disease that not only impairs skeletal muscles of the limbs but is also life-threatening due to progressive weakening of the cardiac and diaphragm muscles. I have traversed the harrowing diagnostic, treatment, and management odyssey of a typical rare disease (RD) patient in India.

PMID:38383970