iScience. 2022 Jan 10:103760. doi: 10.1016/j.isci.2022.103760. Online ahead of print.

ABSTRACT

Impressive global efforts have identified both rare and common gene variants associated with severe COVID-19 using sequencing technologies. However, these studies lack the sensitivity to accurately detect several classes of variants, especially large structural variants (SVs), which account for a substantial proportion of genetic diversity including clinically relevant variation. We performed optical genome mapping on 52 severely-ill COVID-19 patients to identify rare/unique SVs as decisive predisposition factors associated with COVID-19. We identified 7 SVs involving genes implicated in two key host-viral interaction pathways: innate immunity and inflammatory response, and viral replication and spread in 9 patients, of which SVs in STK26 and DPP4 genes are the most intriguing candidates. This study is the first to systematically assess the potential role of SVs in the pathogenesis of COVID-19 severity and highlights the need to evaluate SVs along with sequencing variants to comprehensively associate genomic information with inter-individual variability in COVID-19 phenotypes.

PMID:35036860 | PMC:PMC8744399 | DOI:10.1016/j.isci.2022.103760

Blood Adv. 2022 Jan 14:bloodadvances.2021005948. doi: 10.1182/bloodadvances.2021005948. Online ahead of print.

ABSTRACT

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell lymphoproliferative malignancy, caused by human T-cell leukemia virus type 1 (HTLV-1). ATL is an orphan disease with no curative drug treatment regimens, urgently needing new combination therapy. HTLV-1-infected cells rely on viral proteins, Tax and HBZ (HTLV-1-b-ZIP factor), to activate the transcription of various host genes that are critical for promoting leukemic transformation. Inhibition of bromodomain and extra-terminal motif (BET) protein was previously shown to collapse the transcriptional network directed by BATF3 super-enhancer and thereby induced ATL cell apoptosis. In the current work, by using xenograft, ex vivo, and in vitro models, we demonstrated that I-BET762 (BETi) synergized with copanlisib (PI3Ki) and bardoxolone methyl (NF-κBi) to dramatically decrease the growth of ATL cells. Mechanistically, the triple combination exhibited synergistic activity by down-regulating the expression of c-MYC while up-regulating the level of the glucocorticoid-induced leucine zipper (GILZ). The triple combination also enhanced apoptosis induction by elevating the expression of active caspase-3 and cleaved PARP. Importantly, the triple combination prolonged the survival of ATL-bearing xenograft mice and inhibited the proliferation of ATL cells from PBMCs of both acute and smoldering/chronic ATL patients. Therefore, our data provide the rationale for a clinical trial exploring the multi-agent combination of BET, PI3K/AKT, and NF-κB inhibitors for ATL patients, and expands the potential treatments for this recalcitrant malignancy.

PMID:35030628 | DOI:10.1182/bloodadvances.2021005948

Rom J Morphol Embryol. 2021 Apr-Jun;62(2):621-624. doi: 10.47162/RJME.62.2.32.

ABSTRACT

Eosinophilic sialodochitis (ES) is a rare clinical entity which presents as recurrent major salivary gland swelling and the presence of eosinophil-rich mucus plugs or histopathological evidence of eosinophilic infiltration around the larger salivary gland ducts. We present a case of ES not related with underwent a left submaxillectomy because recurrent episodes of submandibular gland swelling associated for the last three years. The laboratory workup demonstrated eosinophils slightly elevated and high levels of immunoglobulin E (IgE) in peripheral blood. Pathology slides confirmed the final diagnosis of ES, showing a dense periductal eosinophil-rich inflammatory infiltrate and periductal fibrosis. Although the entity is well described in the literature, diagnosis is often difficult due to its clinical presentation being similar to other conditions. Lesions that should be taken into consideration in differential diagnosis are mentioned. This will be the first ES case report in Eastern European literature.

PMID:35024754 | DOI:10.47162/RJME.62.2.32

Einstein (Sao Paulo). 2022 Jan 5;19:eAI6683. doi: 10.31744/einstein_journal/2021AI6683. eCollection 2022.

NO ABSTRACT

PMID:35019035 | PMC:PMC8687649 | DOI:10.31744/einstein_journal/2021AI6683

Orphanet J Rare Dis. 2022 Jan 10;17(1):14. doi: 10.1186/s13023-021-02169-6.

ABSTRACT

BACKGROUND: Experienced fatigue is an under-recognized and under-researched feature in persons with many different rare diseases. A better overview of the characteristics of existing research on experienced fatigue in children and adults with rare diseases is needed. The purpose of this review was to map and describe characteristics of existing research on experienced fatigue in a selection of rare diseases in rare developmental defects or anomalies during embryogenesis and rare genetic diseases. Furthermore, to identify research gaps and point to research agendas.

METHODS: We applied a scoping review methodology, and performed a systematic search in March 2020 in bibliographic databases. References were sorted and evaluated for inclusion using EndNote and Rayyan. Data were extracted on the main research questions concerning characteristics of research on experienced fatigue (definition and focus on fatigue, study populations, research questions investigated and methods used).

RESULTS: This review included 215 articles on ten different rare developmental defects/anomalies during embryogenesis and 35 rare genetic diseases. Of the 215 articles, 82 had investigation of experienced fatigue as primary aim or outcome. Included were 9 secondary research articles (reviews) and 206 primary research articles. A minority of articles included children. There were large differences in the number of studies in different diseases. Only 29 of 215 articles gave a description of how they defined the concept of experienced fatigue. The most common research-question reported on was prevalence and/ -or associations to fatigue. The least common was diagnostics (development or validation of fatigue assessment methods for a specific patient group). A large variety of methods were used to investigate experienced fatigue, impeding comparisons both within and across diagnoses.

CONCLUSION: This scoping review on the characteristics of fatigue research in rare diseases found a large variety of research on experienced fatigue. However, the minority of studies had investigation of experienced fatigue as a primary aim. There was large variation in how experienced fatigue was defined and also in how it was measured, both within and across diagnoses. More research on experienced fatigue is needed, both in children and adults with rare diseases. This review offers a basis for further research.

PMID:35012596 | PMC:PMC8751355 | DOI:10.1186/s13023-021-02169-6

Semin Neurol. 2022 Jan 11. doi: 10.1055/s-0041-1741495. Online ahead of print.

ABSTRACT

Internet-connected devices, including personal computers, smartphones, smartwatches, and voice assistants, have evolved into powerful multisensor technologies that billions of people interact with daily to connect with friends and colleagues, access and share information, purchase goods, play games, and navigate their environment. Digital phenotyping taps into the data streams captured by these devices to characterize and understand health and disease. The purpose of this article is to summarize opportunities for digital phenotyping in neurology, review studies using everyday technologies to obtain motor and cognitive information, and provide a perspective on how neurologists can embrace and accelerate progress in this emerging field.

PMID:35016250 | DOI:10.1055/s-0041-1741495

Rev Esp Salud Publica. 2022 Jan 10;96:e202201001.

ABSTRACT

BACKGROUND: The aims of the International Consortium for Rare Diseases Research (IRDiRC) include that the diagnosis of a known rare disease (RD) must be made within a year. The objective of this systematic review was to identify the scientific evidence about the time to diagnosis in patients affected by RDs and also to know if there is a diagnostic delay (more than one year) according to the objective set by the IRDiRC.

METHODS: A systematic review was carried out according to PRISMA criteria in the PubMed, Scopus and Web of Science (WoS) databases. The quality of the articles was assessed using the STROBE statement.

RESULTS: 17 articles were included. They were devoted to specific RDs, most of them metabolic diseases, neurological and disorders that affect immunity. The study designs were mainly cross-sectional, and two retrospective cohorts were also included. Most articles showed that it takes more than a year to get a diagnosis for these RDs.

CONCLUSIONS: Scientific literature quantifying the time to diagnosis is still scarce and no study addresses RDs as a whole. In most cases, it takes more than one year to obtain a diagnosis of a RD, so there is an obvious delay according to the objective set by the IRDiRC. Therefore, new advances in the RD field are necessary to reduce the time from the onset of symptoms to the accurate diagnosis.

PMID:35001905

Curr Probl Cardiol. 2022 Jan 7:101110. doi: 10.1016/j.cpcardiol.2022.101110. Online ahead of print.

ABSTRACT

The coexistence of MDS and pulmonary hypertension (PH) is not a common finding and often goes unnoticed because symptoms such as dyspnea can be confused with the underlying pathology. The annual incidence of idiopathic pulmonary arterial hypertension (PAH) is only around 0.2 cases per 100,000 inhabitants, while MDS is 1 to 8 cases per 100,000 inhabitants. This review summarizes the clinical manifestations, functional respiratory tests, hemodynamic parameters using right heart catheterization, and imaging findings using echocardiography and tomography of pulmonary hypertension in myelodysplastic syndrome. We centered our discussion on the diagnosis of these patients within the hematologic disorders, especially in patients with the detriment of the functional class, as we were not used to looking for this diagnosis as a first choice. Several specialties dealing with patients with hematologic disorders (internists, hematologists, family physicians, geriatrics, oncologists) will find helpful the contents of this review.

PMID:35007638 | DOI:10.1016/j.cpcardiol.2022.101110

An Pediatr (Engl Ed). 2022 Jan;96(1):8-16. doi: 10.1016/j.anpede.2020.09.014. Epub 2022 Jan 3.

ABSTRACT

INTRODUCTION: Inborn errors of metabolism are a highly heterogeneous group of orphan diseases. Diet therapy and enzyme and coenzyme replacement are the most frequently used treatment. There are few patients and published studies about inborn errors of metabolism. The main objective of this study was to describe the effectiveness of orphan drugs in inborn errors of metabolism in paediatric patients.

MATERIAL AND METHODS: Retrospective descriptive study of 24 months on patients diagnosed with inborn errors of metabolism during childhood and who attended the pharmacy clinic or Day-Care Unit of a 630-bed general hospital.

RESULTS: The study included 15 patients with a median age of 17.8 years and were treated with nine different drugs: sapropterin, sodium phenylbutyrate, miglustat, velaglucerase, sebelipase, idursulfase, 5-hydroxytryptophan, succinate, and riboflavin. Seven different inborn errors of metabolism were observed: phenylketonuria, defects of the urea cycle, Gaucher, Nieman-Pick, Hunter's disease, along with acid lipase deficiency, and mitochondrial diseases. Orphan drugs used for the treatment of inborn errors of metabolism accounted for 1.3% of hospital drug costs. Some orphan drugs achieved asymptomatic patients, but others just produced a modest symptomatic improvement. Most patients showed good tolerance to the treatment.

CONCLUSIONS: Orphan drugs used in inborn errors of metabolism had an easy to manage toxicity profile, with many disparities in effectiveness. These drugs have a high economic impact. The cost-effectiveness ratio for orphan drugs is a controversial issue due to their high cost and the inconclusive clinical evidence.

PMID:34992005 | DOI:10.1016/j.anpede.2020.09.014

J Mark Access Health Policy. 2021 Dec 29;10(1):2022353. doi: 10.1080/20016689.2021.2022353. eCollection 2022.

NO ABSTRACT

PMID:34992762 | PMC:PMC8725676 | DOI:10.1080/20016689.2021.2022353

Acta Neurol Taiwan. 2022 Jan 25;31(1):15-23.

ABSTRACT

OBJECTIVE: Neurofibromatosis is one of the most common dominantly inherited genetic disorders. This study aimed to study the demographic and clinical profile of neurofibromatosis patients.

METHODS: This study is cross-sectional conducted in 2020 on the population of patients with neurofibromatosis. Patients who are members of the Neurofibromatosis Association answered the online demographic and clinical information questionnaire.

RESULTS: 446 patients with neurofibromatosis participated in this study with a mean age of 33.39 plus or minus 12.87 years. 297 patients (66.6%) were women and 378 (84.8%) patients had type 1 neurofibromatosis. The disease visibility was reported to be moderate in 254 patients (54.9%) and the severity of the disease was mild in 238 (53.4%) patients. The type of neurofibromatosis was not significantly related to gender, age groups, parental education, and ethnicity. The relationship between severity and age (p is equal to less than 0.001) and gender (p is equal to 0.042) was significant and the relationship between visibility and age (p is equal to less than 0.001) was significant but despite the fact that the disease was more visible in men than women, it was not significantly related to gender.

CONCLUSIONS: The study results showed that the most common complication in the study population was Cafe au lait spot. In addition, visibility and severity of the disease were mild and moderate, respectively. Keyword: Neurofibromatosis, Demographic information, Clinical Information.

PMID:34988950

Graefes Arch Clin Exp Ophthalmol. 2022 Jan 6. doi: 10.1007/s00417-021-05535-z. Online ahead of print.

ABSTRACT

BACKGROUND: Neurotrophic keratopathy (NK) is an orphan disease, with an estimated prevalence of 1-5/10,000. No data regarding the incidence exists. The primary aim was to evaluate incidence and prevalence of NK at a tertiary referral center in Germany, and the secondary aim was to analyze demographic parameters, etiology, and clinical features and therapeutic outcomes.

METHODS AND MATERIAL: All patients treated for NK with serum eye drops (SED), amnionic membrane transplantation (AMT), or penetrating keratoplasty (PK) in 2013-2017 were identified. Age, sex, etiology of NK, visual acuity, disease stage, treatment, and visual acuity were analyzed. Incidence and prevalence of NK in our hospital and the overall population of the city were calculated.

RESULTS: In 63 eyes of 60 patients (56.7% male; 68 ± 16 years), the most common underlying diseases were herpetic infections (23.8%), neurological causes (19%), and diabetes mellitus (14.3%). The annual incidence of NK in our tertiary referral center ranges between 5/10,000 and 3/10,000, the prevalence between 9/10,00 and 22/10,000. In all patients treated with corneal ulcers, the prevalence was up to 27% (2706/10,000). The incidence in the overall population is estimated at 0.1-0.3/10,000, the prevalence at 0.2-0.5/10,000 to 0.5/10,000.

CONCLUSION: Based on our assessment, the prevalence of NK in the overall population is lower than estimated before. However, in patients with corneal ulcers, the percentage of NK is comparably high. The disease may still be underdiagnosed due to the variety of underlying disorders and unknown comorbidities. Thus, in cases of therapy-refractive superficial keratopathy or ulcerations, NK should be considered more frequently.

PMID:34989864 | DOI:10.1007/s00417-021-05535-z

Am J Gastroenterol. 2022 Jan 1;117(1):195-196. doi: 10.14309/ajg.0000000000001510.

NO ABSTRACT

PMID:34983891 | DOI:10.14309/ajg.0000000000001510

Praxis (Bern 1994). 2022 Jan;110(1):38-43. doi: 10.1024/1661-8157/a003772.

ABSTRACT

Chronic Fatigue: When to Suspect an Inherited Metabolic Disease? Abstract. Chronic fatigue is a non-specific symptom, frequent in outpatient adults' consultations. Persistent physical fatigue of unknown etiology should prompt the search for rare diseases including inherited metabolic disorder (IMD) after elimination of common causes. The main characteristic of chronic fatigue in IMD is its dynamic nature, worsened by circumstances leading to an increased metabolism such as physical exertion, cold, fasting or infection. IMD leading to chronic fatigue are metabolic myopathies, in particular glycogen storage disease affecting muscle, fatty acid oxidation disorders and mitochondrial diseases. The diagnosis is confirmed by specific biochemical and/or molecular analyzes with multidisciplinary management.

PMID:34983209 | DOI:10.1024/1661-8157/a003772

Praxis (Bern 1994). 2022 Jan;110(1):1-6. doi: 10.1024/1661-8157/a003773.

ABSTRACT

Chronic Fatigue: When to Suspect an Inherited Metabolic Disease? Abstract. Chronic fatigue is a non-specific symptom, frequent in outpatient adults' consultations. Persistent physical fatigue of unknown etiology should prompt the search for rare diseases including inherited metabolic disorder (IMD) after elimination of common causes. The main characteristic of chronic fatigue in IMD is its dynamic nature, worsened by circumstances leading to an increased metabolism such as physical exertion, cold, fasting or infection. IMD leading to chronic fatigue are metabolic myopathies, in particular glycogen storage disease affecting muscle, fatty acid oxidation disorders and mitochondrial diseases. The diagnosis is confirmed by specific biochemical and/or molecular analyzes with multidisciplinary management.

PMID:34983208 | DOI:10.1024/1661-8157/a003773

Croat Med J. 2021 Dec 31;62(6):553-560.

ABSTRACT

AIM: To assess the European Union's (EU) impact on the Croatian health policy, and identify which mechanisms and processes were used to shape a particular health policy on the EU and national levels. The study focused on the rare diseases policy to obtain a better insight into the process of policy shaping, starting at the EU level and moving down to the Croatian national level.

METHODS: We conducted actor analysis, policy networks, and semi-structured qualitative interviews with key policy actors at the EU and domestic level. The analysis of actors included actor mapping, the analysis of their relationships, and of their interdependence. Policy networks involved identifying key actors and analyzing them separately to create both policy networks to explain their hierarchy and relationships. Semi-structured interviews included ten key experts at the EU and national health policy levels.

RESULTS: The implementation of the EU health policy is complex. Hard and soft law were complementary in the way they affected the translation of EU rare diseases policy into Croatian law. Strong and interconnected EU and domestic actors were significant in this process, which resulted in the creation of Croatia's rare diseases policy.

CONCLUSION: Given that the rare diseases policy area is a developing policy area, this study contributes to a better understanding of the implementation of the EU health policy, clarifying a mechanism that can enable national governments to adopt specific health policies.

PMID:34981687

Yale J Biol Med. 2021 Dec 29;94(4):693-702. eCollection 2021 Dec.

ABSTRACT

Rare diseases affect an estimated 6-10% of the Australian population, a prevalence similar to that seen in other regions worldwide. These multi-system conditions are often severely debilitating and affect multiple domains of a person's life. A salient necessity for effective care provision thus, is holistic care, achieved by appropriate and continual multi-disciplinary and cross-sectoral collaboration. Synonymous with this priority for collaborative care, is the need for increased partnerships between the health and education sectors. This partnership has the potential to benefit people with rare disease of all educational ages, but in particular, school-aged children and young adults. More than 70% of rare diseases affect children, and this population often experiences difficulties with overall well-being and functioning, including impaired school performance and confounding mental and social comorbidities. Ensuring adequate schooling needs and experiences along with provision of adequate medical care, is crucial in ensuring overall well-being for this population. For this, effective partnerships between the health and education sectors are paramount. This article highlights fundamental elements of health and education priorities, ingrained in current strategic documents, to build a policy foundation that informs and supports increased inter-sectoral partnerships between health and education services. Shared priorities identified in both sectors' guidelines, co-developed with those with lived experience of rare diseases, build a strong policy base for future advocative initiatives to mold better integration between the sectors, a partnership which is vital to improving the overall quality of life, experiences and journeys of people living with rare disease.

PMID:34970108 | PMC:PMC8686785

Yale J Biol Med. 2021 Dec 29;94(4):687-692. eCollection 2021 Dec.

ABSTRACT

There is great value in understanding the patient perspective in rare disease diagnosis and research, and in partnering actively with patients and their families throughout the process. Meaningful and respectful interaction between patients and researchers leads to learning on both sides, and ultimately, to better research outcomes. Researchers can help patients understand how research is conducted and what the latest advances and perceived gaps in research are, and patients, who have direct experience living with their health conditions, can impart to researchers what is most important to them. We describe our engagement with patients in the Undiagnosed Diseases Network (UDN) program, as well as the lessons we have learned to date. In the UDN, patients have been instrumental in bringing meaning to the work of clinicians and researchers, building patient communities, making the network aware of unmet patient needs, advocating for additional research funding, and disseminating UDN research findings. Although patient engagement in the UDN has already had a significant positive impact on our work, we continue to strive to involve patients earlier in the process, in the research design itself, and in addressing power dynamics that may arise between clinicians, researchers, and patients.

PMID:34970107 | PMC:PMC8686769

Can J Gastroenterol Hepatol. 2021 Dec 21;2021:1959832. doi: 10.1155/2021/1959832. eCollection 2021.

ABSTRACT

IgG4-related sclerosing cholangitis, a biliary manifestation of an IgG4-related disease, belongs to the spectrum of sclerosing cholangiopathies which result in biliary stenosis. It presents with signs of cholestasis and during differential diagnosis it should be distinguished from cholangiocarcinoma or from other forms of sclerosing cholangitis (primary and secondary sclerosing cholangitis). Despite increasing information and recently established diagnostic criteria, IgG4-related sclerosing cholangitis remains underdiagnosed in routine clinical practice. The diagnosis is based on a combination of the clinical picture, laboratory parameters, histological findings, and a cholangiogram. Increased serum IgG4 levels are nonspecific but are indeed a part of the diagnostic criteria proposed by the Japan Biliary Association and the HISORt criteria for IgG4-SC. High serum IgG4 retains clinical utility depending on the magnitude of elevation. Approximately 90% of patients have concomitant autoimmune pancreatitis, while 10% present with isolated biliary involvement only. About 26% of patients have other organ involvement, such as IgG4-related dacryoadenitis/sialadenitis, IgG4-related retroperitoneal fibrosis, or IgG4-related renal lesions. A full-blown histological finding characterized by IgG4-enriched lymphoplasmacytic infiltrates, obliterative phlebitis, and storiform fibrosis is difficult to capture in practice because of its subepithelial localization. However, the histological yield is increased by immunohistochemistry, with evidence of IgG4-positive plasma cells. Based on a cholangiogram, IgG-4 related sclerosing cholangitis is classified into four subtypes according to the localization of stenoses. The first-line treatment is corticosteroids. The aim of the initial treatment is to induce clinical and laboratory remission and cholangiogram normalization. Even though 30% of patients have a recurrent course, in the literature data, there is no consensus on chronic immunosuppressive maintenance therapy. The disease has a good prognosis when diagnosed early.

PMID:34970512 | PMC:PMC8714375 | DOI:10.1155/2021/1959832

Pan Afr Med J. 2021 Nov 17;40:164. doi: 10.11604/pamj.2021.40.164.30316. eCollection 2021.

ABSTRACT

Sacrococcygeal chordoma is a rare disease. It has been described in less than 3% of cases. We here report the case of a female patient with locally advanced sacrococcygeal chordoma treated at the Oujda Regional Oncology Center in Morocco. The treatment was based on exclusive radiotherapy; surgical resection couldn't be performed. At 2-year follow-up the tumor is clinically and radiologically stable and general condition of the patient is good.

PMID:34970406 | PMC:PMC8683457 | DOI:10.11604/pamj.2021.40.164.30316