Rare Disease Research Articles

A Case Report of a New Variant Associated with Vici Syndrome in a Turkish Infant; EPG5 Frameshift Variant

Introduction: Vici syndrome is a congenital multisystem disorder characterized primarily by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency, and oculocutaneous hypopigmentation, along with additional newly recognized findings. Autosomal recessive variants in the EPG5 gene, which encodes ectopic P-granules autophagy protein 5 (EPG5), a key regulator of autophagy, are known genetic causes of this syndrome. The aim of this case report is to present a novel disease-causing variant identified through EPG5 gene sequence analysis. Case Presentation: We report on a 2-month-old Turkish girl who presented with developmental delay, bilateral congenital cataracts, microcephaly, hypotonia, hypertrophic cardiomyopathy, hypopigmented skin lesions, and agenesis of the corpus callosum. Genetic analysis revealed a homozygous c.7504delC (p.Gln2502Argfs*4) frameshift variant in the EPG5 gene, which has not been previously documented. Conclusions: Adding a new variant to the literature is crucial, as it highlights the feasibility of reaching an accurate diagnosis through well-conducted physical examination findings in patients with early developmental delay. This case also raises awareness about such rare diseases. Moreover, recognizing new mutations is critical for understanding atypical findings, prognosis, treatment responses, and the genetic risks for other family members.

Case report: orthostatic hypotension as the first presentation of progressive encephalomyelitis with rigidity and myoclonus (PERM) with multiple autoimmune antibodies

IntroductionStiff person syndrome (SPS) is a rare disease characterized by axial and lower-extremity muscle rigidity, muscle spasm, and pain. Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a variant of SPS. This case is particularly notable for its uncommon initial symptom: orthostatic hypotension, coupled with the presence of multiple antibodies. Such a presentation is a rarity in the context of PERM, thus providing a fresh and unique angle for both diagnosis and treatment.Case presentationThis case presents a 71-year-old man who was ultimately diagnosed with progressive encephalomyelitis with rigidity and myoclonus (PERM). His initial symptom was orthostatic hypotension, and we detected multiple antibodies such as GlyR antibody, GAD antibody, GM1-IgG and GQ1b-IgG in his serum. The patient showed partial response to glucocorticoid and immunoglobulin therapies, but as the disease recurred and progressed, plasma exchange, rituximab, and cyclophosphamide immunosuppressive therapy was administered, the prognosis remained poor. During follow-up after treatment, the patient developed pulmonary embolism and cardiac arrest, and died.ConclusionPERM exhibits diverse manifestation and pathogenic mechanisms. Immune heterogeneity affects clinical symptoms and prognosis. Cases of PERM combined with orthostatic hypotension and various antibodies have rarely been reported, the incidence and the specific mechanism is unknown, underscoring the need for further research. This case report underscores the importance of recognizing the diverse clinical presentations of PERM and the challenges in its diagnosis and management. It highlights autonomic dysfunction may be as the initial symptom of PERM. Moreover, it emphasizes the limitations of current treatment modalities and the necessity for further research to elucidate the underlying mechanisms and optimize therapeutic approaches for this debilitating autoimmune condition.

Syringocysadenoma Papilliferum Vulve – Tumor with Very Rare Localization on the Vulva

Syringocystadenoma papilliferum is a benign cutaneous adnexal tumor of eccrine and apocrine glands, with a warty appearance that is usually found on the scalp, neck and face, much less frequently appears in the chest or abdomen and extremely rarely on the female genital organs, i.e. the vulva. We present a case of Syringocystadenoma papilliferum on the vulva of a 64-year-old woman. This case illustrates the atypical location of this rare disease and adds to the differential diagnosis of lesions on the vulva.

Pediatric Bone Tumors: Location and Age Distribution of 420 Cases

Background/Objectives: One of the most important diagnostic tools in bone tumors is X-rays. Preliminary and, in the case of some benign lesions, definitive diagnoses are formed using this basic tool. Part of the decision making in this stage is based on statistical probability using the patient’s age, as well as the incidence and predilection sites of different entities. The information used today is based on older and fragmented data. To verify the underlying principles, we retrospectively evaluated all bone tumors in children and adolescents treated by our tertiary center in the last 20 years. Methods: For this retrospective study, patients under the age of 18 years suffering from histopathologically verified bone tumors were evaluated. Data were retrieved from our local musculoskeletal tumor database. Results: We were able to include 420 children treated for bone tumors in our tertiary center. The cohort consisted of 335 benign and 85 malignant lesions. The most common lesions were 137 osteochondromas; the malignant tumors consisted mainly of osteosarcomas (53) and Ewing’s sarcomas (28). The primary predilection sites were the metaphyses of long bones. Conclusions: We were able to confirm and supplement the fragmentary data of these rare diseases using our own cohort.

Rare atypical type a thymoma: a case report and literature review

BackgroundAn atypical type A thymoma variant was recently added to the World Health Organization classification of type A thymoma in 2015. This novel form of type A thymoma presents with hypercellularity, increased mitotic activity, and necrosis. In particular, necrosis seems to be related to postoperative recurrence and metastasis, but the clinical significance of these changes still needs to be studied.Case presentationA 76-year-old man underwent thoracoscopic surgery for tumour resection due to an anterior mediastinal mass. Pathological examination revealed that the tumour invaded the surrounding thymic tissue. Cells were arranged in nest-like and whirl-like patterns, accompanied by prominent comedo-like necrosis, increased cell density, mild atypia, and a mitotic count of 4–6 per 10 high-power fields. Immunohistochemistry revealed positive expression of cytokeratin 19 and P63 in the tumour cells. Lymphocytes in the background were positive for CD3 and CD5, did not express terminal deoxynucleotide transferase, CD20, or CD117, and had an MIB-1 labelling index(LI) value of 15%. On the basis of these findings, the tumour was finally diagnosed as an atypical type A thymoma variant.ConclusionsWe report a case of atypical type A thymoma and review the literature to enhance our understanding of and provide accumulated pathological data on this rare disease.

DUPILUMAB: A NEW ALLY FOR THE TREATMENT OF EOSINOPHILIC ESOPHAGITIS?

INTRODUCTION: Eosinophilic esophagitis is a chronic, immune-mediated disease of the gastrointestinal tract, resulting from the interaction between genetic, environmental and immunological factors of the affected patient. The clinical picture is characterized by esophageal dysfunction, which may present as dysphagia, precordial pain, upper abdominal pain or food impaction. Treatment aims to improve clinical symptoms and prevent disease progression and subsequent complications. In this context, immunobiologicals are emerging and promising therapies, with Dupilumab being the first specific treatment approved by the FDA. It is an IgG4 monoclonal antibody that targets IL-4R alpha and, from there, reduces protein transphorylation, transcription and the T helper 2-regulated response. The objective of this systematic review is to evaluate the efficacy of this drug in the treatment of eosinophilic esophagitis, in comparison with the options already available on the market. METHOD: PubMed searches were performed using the keywords “eosinophilic esophagitis dupilumab” and “dupilumab treatment esophagitis eosinophilic”. Initially, 60 results were obtained, but after exclusion by title, abstract and full text, 14 articles were included. RESULT: all articles analyzed demonstrated improvement in patients using Dupilumab, with 13 of them indicating a reduction in eosinophil counts, 8 showing clinical improvement in symptoms, 8 indicating histological improvement, 7 indicating improvement in the endoscopic pattern, according to the Endoscopic Reference for Eosinophilic Esophagitis, and 4 indicating a reduction in the Dysphagia Symptom Questionnaire (DQQ) score. DISCUSSION: eosinophilic esophagitis is a rare disease, but with potential for progression, negatively interfering with the patient's quality of life. Therefore, since current drug therapy is nonspecific, the use of Dupilumab presents itself as an innovative and optimistic solution for the future, because it changes the understanding of disease management, expands therapeutic options and improves prognosis. CONCLUSION: the use of Dupilumab in the treatment of eosinophilic esophagitis has proven to be effective. However, for the treatment to be well established with regard to the doses used, frequency of administration and longitudinal monitoring, further studies are still required.

Expediting treatments in the 21st century: orphan drugs and accelerated approvals

BackgroundIn response to activated patient communities’ catalyzation, two significant efforts by the FDA to expedite treatments have now been in place for multiple decades. In 1983, the United States Congress passed the Orphan Drug Act to provide financial incentives for development of drugs for rare diseases. In 1992, partly in response to the HIV epidemic, the FDA implemented Accelerated Approval (AA) to expedite access to promising new therapies to treat serious conditions with unmet medical need based on surrogate marker efficacy while additional clinical data is confirmed.The uses of these regulatory approaches over time are assessed in this study.MethodsThe following U.S. FDA CDER published lists were used in this analysis: 1. all orphan designations and approvals; 2. all AA and their details updated through December 31, 2022; new molecular entities (NMEs).ResultsOrphan drug designations and approvals have increased several-fold over the past four decades. The largest increase recently has been in therapies targeting oncological diseases (comprised of both oncology and malignant hematology).Although orphan drug approvals based on NMEs are the minority of orphan drug designations, the count of approved orphan drug NMEs has increased in recent years.The characteristics of orphan drug approvals show notable differences by disease area with rare diseases and medical genetics (49%) having a relatively large fraction of orphan drug approvals with NMEs compared to the oncological diseases (32%).Similar to the use of orphan drug designation, oncological disease therapies have been the largest utilizers of AA. Many therapies targeting these diseases address unmet medical need and can leverage surrogate markers that have previously been used in similar trials.The timings of conversion of AA (confirmed or withdrawn) were assessed and found to be consistent across decades and to have some dependency upon the broad disease area (when assessed by three large groups: HIV conversions were fastest; followed by oncology; followed by all others). By the end of 2022, 98% of the first 105 (approved in 2010 or earlier) AA had been converted to confirmed or withdrawn.ConclusionsAlthough the typical timings for AA to be confirmed or withdrawn has not changed significantly over the decades, the disease areas utilizing orphan drug designation and AA have changed significantly over time. Both programs have had increases in their use for therapies targeting oncological diseases.The re-use of surrogate markers for oncological diseases has been an advantage in a way that may not be scientifically feasible in many other disease areas that have greater differentiation across disease etiology. For non-oncological diseases, applicability of AA is, in part, dependent upon greater focus on characterization and acceptance of novel surrogate markers.

Floating ascending aortic thrombus with antiphospholipid syndrome: a case report

BackgroundAscending aortic thrombus is a rare disease that can cause fatal thromboembolism. The treatment for the disease is not well defined and depends on the clinical experience of surgeons. Most reports of thrombosis in antiphospholipid syndrome (APS) are associated with venous or peripheral arterial thrombosis, and there are almost no reports of thrombosis of the aorta.Case presentationA 74-year-old male was referred to our department with claudication of the left leg lasting 3 months. A computed tomography angiography (CTA) and a transthoracic echocardiography demonstrated that a floating and pedunculated mass associated with APS was located at ascending aortic lumen and an embolism in the left superficial femoral artery. Under deep hypothermic circulatory arrest, we resected a floating mass without the graft replacement. CTA 1 year after surgery showed no recurrence of thrombus.ConclusionWe experienced a rare case of floating ascending aortic thrombi. As in this case, we consider that a floating ascending aortic thrombus with embolic events should be performed by surgical intervention.

Granulomatous mastitis forming a well-defined large mass diagnosed by surgical excision: a case report

BackgroundGranulomatous mastitis is a relatively rare benign inflammatory disease of the breast, but it is sometimes difficult to distinguish from breast cancer by imaging. We experienced a case that was definitively diagnosed as granulomatous mastitis from the surgical specimen. The mass appeared as a large cystic lesion on imaging, which is unusual for granulomatous mastitis, and was initially suspected to be an encapsulated papillary carcinoma.Case presentationA 43-year-old woman presented with a painful mass in her right breast. Ultrasonography revealed a cystic mass lesion with internal solid components, with partially indistinct cyst walls and abundant blood flow. Additionally, lymphadenopathy of one axillary lymph node was observed. Magnetic resonance imaging findings showed irregularly spreading enhanced nodules within the cystic lesion, raising the suspicion of encapsulated papillary carcinoma. Although the histological findings from a needle biopsy were consistent with granulomatous mastitis, the possibility of malignancy could not be ruled out based on imaging, prompting a diagnostic probe lumpectomy. However, the surgical specimens did not reveal any tumorous lesions, and we reached a final diagnosis of granulomatous mastitis. Postoperatively, the patient was followed-up without steroid therapy and has been free from recurrence of mastitis for 22 months after surgery.ConclusionsWe report a case of granulomatous mastitis that was detected as a large cystic lesion with a well-defined border on imaging and a definitive diagnosis was made from a surgical specimen.

Robust and Explainable Stage Prediction in Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is one of the life-threatening rare genetic disease affecting millions of male minors across the globe. Given its progressive nature, we can demarcate the various stages of DMD through the loss of muscular movements, ambulation, respiratory difficulties, and cardiac dysfunction. In this work, we employ machine learning models for understanding the progression of DMD through the prediction of its stages. Our attempts to predict the stages of DMD on the data collected by Molecular Diagnostics, Counseling, Care and Research Center (MDCRC) from 223 visits of 90 subjects demonstrate more than 80% accuracy with the state-of-the-art methods. We further study the biological/physiological importance of features in characterizing the stages of DMD.

A Retrospective Review of Clinical Characteristics and Risk Factors of Dysphagia in Patients with Dermatomyositis.

Dermatomyositis is a rare autoimmune-mediated disease characterised by distinctive rash and progressive muscle weakness. Patients with dermatomyositis may develop swallowing disorders (dysphagia) due to the inflammation of muscles involved in swallowing which may lead to serious health consequences. However, to date, the clinical characteristics of and risk factors for dysphagia in dermatomyositis remain poorly understood. This retrospective study aimed to identify the characteristics and risk factors for dysphagia in dermatomyositis. All patients with clinical diagnosis of dermatomyositis (ICD-9-CM 701.3) were identified and retrieved retrospectively via hospital electronic record over a 10-year period for review. A total of 231 patients were identified with 149 fulfilled the inclusion criteria (median age [range] = 54.5 [3-92] years; 51 males) were recruited. The incidence of dysphagia was 18.8%, with predominantly pharyngeal phase impairments. Six patients had silent aspiration. Dysphagia was positively correlated with the age of diagnosis (r[148] = 0.187, p = 0.023), mortality (r[149] = 0.186, p = 0.023), presence of underlying malignancy (r[149] = 0.222, p = 0.007), methylprednisolone use (r[149] = 0.166, p = 0.042) and intravenous immunoglobulin (IVIg; r[149] = 0.217, p = 0.008), and negatively correlated with disease duration (r[147]=-0.273, p < 0.001). Moreover, it was more likely to have symptomatic dysphagia in patients prescribing systemic corticosteroid (OR[95%CI] = 4.43[1.02, 19.27], p = 0.047) and IVIg (OR[95%CI] = 6.39[1.14, 35.68], p = 0.035). Dysphagia was associated with advanced age, increased mortality and malignancy in patients with dermatomyositis. Routine screening of dysphagia is recommended at initial diagnosis and severe disease activity requiring high dose systemic steroid and IVIg use.

Enhanced Gαq Signaling in TSC2-deficient Cells Is Required for Their Neoplastic Behavior.

Inherited or sporadic loss of the TSC2 gene can lead to pulmonary lymphangioleiomyomatosis (LAM), a rare cystic lung disease caused by protease-secreting interstitial tumor nodules. The nodules arise by metastasis of cells that exhibit features of neural crest and smooth muscle lineage ('LAM cells'). Their aberrant growth is attributed to increased activity of 'mechanistic target of rapamycin complex 1' (mTORC1), an anabolic protein kinase that is normally suppressed by the TSC1-TSC2 protein complex. The mTORC1 inhibitor rapamycin slows the progression of LAM, but fails to eradicate disease, indicating a role for mTORC1-independent mechanisms in LAM pathogenesis. Our previous studies revealed G-protein coupled urotensin-II receptor (UT) signaling as a candidate mechanism, but how it promotes oncogenic signaling in TSC2-deficient cells remained unknown. Using a human pluripotent stem cell-derived in vitro model of LAM, we now show hyperactivation of UT, which was required for their enhanced migration and pro-neoplastic signaling in a rapamycin-insensitive mechanism that required heterotrimeric Gαq/11 (Gαq). Bioluminescence resonance energy transfer assays in HEK 293T cells lacking TSC2 demonstrated selective and enhanced activation of Gαq and its RhoA-associated effectors compared to wild-type control cells. By immunoprecipitation, recombinant UT was physically associated with Gαq and TSC2. The augmented Gαq signaling in TSC2-deleted cells was independent of mTOR activity, and associated with increased endosomal targeting of p63RhoGEF, a known RhoA-activating effector of Gαq. These studies identify potential mTORC1-independent pro-neoplastic mechanisms that can be targeted for prevention or eradication of pulmonary and extrapulmonary LAM tumors.

What are Juvenile-onset systemic sclerosis providers thoughts, experiences, and reasons for autologous stem cell transplant? Result of a multinational survey.

Juvenile-onset systemic sclerosis (jSSc) is a rare and life-threatening disease with no formal studies evaluating the indications for, access to, or benefits of autologous stem cell transplantation (ASCT). As a first step toward understanding pediatric jSSc specialist thoughts and experiences with ASCT, we conducted a multinational survey. An electronic survey was developed and distributed in November 2023 to members of the Pediatric Rheumatology European Society (PRES) and/or Childhood Arthritis and Rheumatology Research Alliance (CARRA) pediatric scleroderma workgroups. Twenty-nine (69%) jSSc specialists completed the survey. All participants have considered or would consider ASCT referral for a jSSc patient. Nearly all respondents indicated disease-modifying anti-rheumatic drugs (DMARDs) should be trialed prior to ASCT referral, with most indicating two to four DMARDs. The most common reasons selected for referral were rapidly progressive disease (despite DMARD) (90%), followed by severe disease status (83%), and significant impact on quality of life (83%). All respondents selected pulmonary disease as an indication for referral, followed by cardiac (93%), gastrointestinal (72%), and skin disease (66%). While pulmonary and cardiac involvement were considered individually sufficient for referral for ASCT, only a minority considered musculoskeletal involvement (28%) sufficient on its own. This survey is the first explore thoughts and experience with ASCT for jSSc. Results indicate pediatric rheumatologists were aware of and would consider ASCT for their patients. Our results indicate there is likely some variability in clinical practice regarding who is referred for ASCT, and further research is needed to guide development of evidence-based clinical care guidelines.

Lymphocytic Esophagitis—A Novel Clinicopathologic Variant of Chronic Esophagitis: A Review Paper

Background/Objectives: Lymphocytic esophagitis is a rare inflammatory disease of the esophagus, first described in 2006. Since that time, interest in this disease entity has steadily increased, yet specific data on the etiology of the disease are still lacking. Lymphocytic esophagitis co-occurs with esophageal motility disorders, Crohn’s disease, hypersensitivity (allergy, asthma), the use of certain medications, or immune disorders. Risk factors include smoking and alcohol abuse. The disease is more prevalent in women, developing predominantly within the sixth decade of life. The most important symptom is dysphagia, with odynophagia, epigastric, and chest pain or heartburn being less common. No particular endoscopic presentation is pathognomonic for lymphocytic esophagitis, the findings not infrequently resembling those of eosinophilic esophagitis. Conclusions: There is great need for an international consensus defining strict histopathological criteria for the diagnosis of lymphocytic esophagitis as well as relevant diagnostic and therapeutic management. This review paper presents the current state of knowledge on lymphocytic esophagitis.

Conformational plasticity links structural instability of NAA10F128I and NAA10F128L mutants to their catalytic deregulation

The acetylation of proteins' N-terminal amino groups by the N-acetyltransferase complexes plays a crucial role in modulating the spatial stability and functional activities of diverse human proteins. Mutations disrupting the stability and function of NAA10 result in X-linked rare genetic disorders. In this study, we conducted a global analysis of the impact of fifteen disease-associated missense mutations in NAA10. The analyses revealed that mutations in specific residues, such as Y43, V107, V111, and F128, predictably disrupted interactions essential for NAA10 stability, while most mutations (except R79C, A111W, Q129P, and N178K) expectedly led to structural destabilization. Mutations in many conserved residues within short linear motifs and post-translational modification sites were predicted to affect NAA10 functionality and regulation. All mutations were classified as pathogenic, with F128I and F128L identified as the most destabilizing mutations. The findings show that the F128L and F128I mutations employ different mechanisms for the loss of catalytic activities of NAA10F128L and NAA10F128I due to their structural instability. These two mutations induce distinct folding energy states that differentially modulate the structures of different regions of NAA10F128L and NAA10F128I. Specifically, the predicted instability caused by the F128I mutation results in decreased flexibility within the substrate-binding region, impairing the substrate peptide binding ability of NAA10F128I. Conversely, F128L is predicted to reduce the flexibility of the region containing the acetyl-CoA binding residues in NAA10F128L. Our study provides insights into the mechanism of catalytic inactivation of mutants of NAA10, particularly elucidating the mechanistic features of the structural and functional pathogenicity of the F128L and F128I mutations.

Precision medicine and Friedreich ataxia: promoting equity, beneficence, and informed consent for novel gene therapies

Friedreich Ataxia (FA) is an incurable neurodegenerative disease with systemic consequences affecting vital organs including those of the central and peripheral nervous systems. This article will use FA as an example to explore some of the practical and ethical issues emerging in precision medicine for rare diseases. It will first describe the existing management strategies available for FA patients, before considering the potential impact of gene therapy trials on the prevention and treatment of disease symptoms. Finally, ethical considerations will be discussed, including equity of access and managing resource allocation dilemmas; balancing benefits, burdens and harms; and gaining informed consent for novel treatments.

Variation Exists in Service Delivery: Similarities and Differences in the Provision of a Whole Genome Sequencing Service for Paediatric Rare Disease Patients in the English National Health Service.

The English National Health Service (NHS) is the first to offer whole genome sequencing (WGS) as part of standard care. As a high-income country with a universal healthcare system, England contributes a valuable perspective to global developments in WGS. We used an implementation science approach with mixed methods to characterise delivery of WGS for paediatric rare diseases. Observations and field notes of consent appointments in clinical genetics and mainstream settings and follow-up qualitative semi-structured interviews with the clinical team. Process maps were developed for each department to identify similarities and variations between sites, and thematic analysis of interview data to understand barriers and facilitators. Data collection occurred in 12 departments (7 genetic, 3 neurology, 1 cardiology and 1 general paediatric) across 7 NHS Trusts. 26 observations of 21 healthcare professionals were conducted, alongside 19 follow-up interviews. Two master maps were developed - one for clinical genetics and one for the mainstream. We identified 11 steps involved in delivering WGS, including 9 variations and 9 similarities. We identified most variation in the processes related to the 'who', 'when', 'how' and 'where' as these were aspects that could be adapted to fit into the specific set-up of the department. Barriers included reluctance to uptake in the mainstream and difficulties tracking samples. Recommendations include developing SOPs and hiring healthcare professionals responsible for facilitating consent alongside administrative aspects. These would reduce the burden on clinical geneticists and improve turnaround times as well as contribute to streamlining and standardisation of the service.

A descriptive analysis of 21 patients with pulmonary amyloidosis: An observational study.

Pulmonary amyloidosis is an extremely rare disease, often detected incidentally because of its asymptomatic nature and potential to result in fatal outcomes. In this study, we aimed to present the clinical and radiological features of patients diagnosed with pulmonary amyloidosis by biopsy. This descriptive study included 21 patients with pathologically diagnosed pulmonary amyloidosis. Pulmonary amyloidosis was classified as diffuse alveolar-septal amyloidosis (DASA), cystic amyloidosis (CPA), tracheobronchial amyloidosis (TBA), nodular amyloidosis (NPA), and extraparenchymal pulmonary amyloidosis (pleural and mediastinal lymph node). Clinical, bronchoscopic, and radiological specific characteristics were presented in detail to be used for differential diagnosis. The median age of the patients was 63 (40-83) years, and 14 (66.7%) were male. Twenty patients (95.2%) presented with at least 1 comorbidity. All patients diagnosed with tracheobronchial amyloidosis were symptomatic at presentation, whereas those diagnosed with NPA/extraparenchymal amyloidosis were often asymptomatic. The patients included 1 case of DASA, 1 case of CPA, 10 cases of NPA, 6 cases of TBA, and 3 cases of extraparenchymal amyloidosis involving the mediastinal lymph node and pleura. Sixteen patients (76.2%) were classified as localized amyloidosis, while 5 patients (23.8%) were classified as systemic amyloidosis following the diagnosis of multiple myeloma, monoclonal gammopathy of undetermined significance, systemic lupus erythematosus, Sjogren's syndrome, and B-cell lymphoma. Bronchoscopic biopsies were sufficient for diagnosis, and notably, even transbronchial needle aspiration could be a useful diagnostic method. During the follow-up, we observed that the disease remained stable without progression. However, it is important to note that patients with concurrent malignancies experience fatal outcomes. In conclusion, it is crucial to distinguish pulmonary amyloidosis from other pulmonary diseases such as malignancies, infectious diseases, and interstitial lung diseases, which may have similar clinical and radiological findings. Bronchoscopic diagnostic methods are usually sufficient for the diagnosis. Although patients with pulmonary involvement mostly remain stable during long-term follow-up without progression, it is important to consider the risk of malignancy.

MRNA therapy effective treatment of rare hereditary diseases

mRNA therapy, or mRNA-based drugs that have emerged thanks to vaccines against SARS-CoV-2, have successfully passed preclinical tests and are currently at various stages of clinical trials in the treatment of many diseases, including rare metabolic disorders. In the case of rare genetic metabolic diseases, the concept of mRNA therapy can be considered as an alternative to protein replacement therapy, where exogenous mRNA leads to the production of a fully active protein instead of a non-functional one, and also delivers it to the desired cellular compartment, such as mitochondria or the cell membrane. Preclinical studies on animal models of some rare genetic diseases have fully confrmed the validity of this concept. In this mini-review, we examine and discuss the mentioned preclinical studies on efficacy and safety in several animal models. For all the diseases considered, mRNA therapy restored functional protein to therapeutically significant levels in target organs, led to stable and reproducible results after each dose of mRNA, and was well tolerated, as confirmed by functional liver tests evaluated in animal models, including non-human primates. These data convincingly confirm the potential of clinical development of mRNA therapy for the treatment of various rare metabolic disorders.

Case report: Acute macular neuroretinopathy post-COVID-19 infection.

Acute macular neuroretinopathy (AMN) is a rare disease that causes transient or permanent visual disturbance. The exact etiology remains unknown, but vascular compromise of the deep retinal capillary plexus was postulated as the main mechanism. Retinal vascular event post-coronavirus disease 2019 (COVID-19) infection is recently highlighted during the pandemic, which includes AMN. To report a case of AMN post-COVID-19 infection. A 24-year-old Indian woman presented with acute-onset painless bilateral central scotoma for a day. The symptom was preceded by a history of COVID-19 infection 3 weeks prior. Ocular examination revealed a near-normal visual acuity for both eyes. Fundus examination showed bilateral dull foveal reflex with mild scattered cotton wool spot and vascular tortuosity. Optical coherence tomography macula revealed a distinct short hyperreflective band involving the outer plexiform and outer nuclear layers nasal to the fovea. The Bjerrum perimetry test revealed central scotoma temporal to the fixation. Optical coherence tomography lesions and scotomas are identical and congruous in both eyes. Serial fundus photographs are captured showing the evolving changes of near-normal macula to pigmented wedge-shaped petaloid lesions around the fovea. The patient was diagnosed as bilateral AMN and treated with oral prednisolone. On subsequent follow-up, the central scotoma improved. This case illustrates a clear temporal and possible causal relationship of COVID-19 infection with AMN. Further studies and data are required to justify its association, but the rising cases of AMN shall be anticipated as COVID-19 infections have become endemic worldwide.