Mol Ther Methods Clin Dev. 2021 Oct 28;23:644-658. doi: 10.1016/j.omtm.2021.10.007. eCollection 2021 Dec 10.

ABSTRACT

AAV-mediated gene therapy holds promise for the treatment of lysosomal storage diseases (LSDs), some of which are already in clinical trials. Yet, ultra-rare subtypes of LSDs, such as some glycoproteinoses, have lagged. Here, we report on a long-term safety and efficacy preclinical study conducted in the murine model of galactosialidosis, a glycoproteinosis caused by a deficiency of protective protein/cathepsin A (PPCA). One-month-old Ctsa -/- mice were injected intravenously with a high dose of a self-complementary AAV2/8 vector expressing human CTSA in the liver. Treated mice, examined up to 12 months post injection, appeared grossly indistinguishable from their wild-type littermates. Sustained expression of scAAV2/8-CTSA in the liver resulted in the release of the therapeutic precursor protein in circulation and its widespread uptake by cells in visceral organs and the brain. Increased cathepsin A activity resolved lysosomal vacuolation throughout the affected organs and sialyl-oligosacchariduria. No signs of hyperplasia or inflammation were detected in the liver up to a year of age. Clinical chemistry panels, blood cell counts, and T cell immune responses were normal in all treated animals. These results warrant a close consideration of this gene therapy approach for the treatment of galactosialidosis, an orphan disease with no cure in sight.

PMID:34901309 | PMC:PMC8640647 | DOI:10.1016/j.omtm.2021.10.007

Annu Int Conf IEEE Eng Med Biol Soc. 2021 Nov;2021:2294-2298. doi: 10.1109/EMBC46164.2021.9630043.

ABSTRACT

The identification of rare diseases from clinical notes with Natural Language Processing (NLP) is challenging due to the few cases available for machine learning and the need of data annotation from clinical experts. We propose a method using ontologies and weak supervision. The approach includes two steps: (i) Text-to-UMLS, linking text mentions to concepts in Unified Medical Language System (UMLS), with a named entity linking tool (e.g. SemEHR) and weak supervision based on customised rules and Bidirectional Encoder Representations from Transformers (BERT) based contextual representations, and (ii) UMLS-to-ORDO, matching UMLS concepts to rare diseases in Orphanet Rare Disease Ontology (ORDO). Using MIMIC-III US intensive care discharge summaries as a case study, we show that the Text-to-UMLS process can be greatly improved with weak supervision, without any annotated data from domain experts. Our analysis shows that the overall pipeline processing discharge summaries can surface rare disease cases, which are mostly uncaptured in manual ICD codes of the hospital admissions.

PMID:34891745 | DOI:10.1109/EMBC46164.2021.9630043

Medicine (Baltimore). 2021 Dec 10;100(49):e28208. doi: 10.1097/MD.0000000000028208.

ABSTRACT

RATIONALE: Necrotizing sarcoid granulomatosis (NSG) has recently been termed "sarcoidosis with NSG pattern" for the disease entity representing nodular sarcoidosis with granulomatous pulmonary angiitis. It is characterized by sarcoid-like granulomas, vasculitis, and a variable degree of necrosis. Its rarity and nonspecific clinical symptoms can easily lead to misdiagnosis or delayed diagnosis.

PATIENT CONCERNS: We report a 67-year-old female with a biopsy-confirmed sarcoidosis with NSG pattern mimicking pulmonary malignancy on initial chest computed tomography scan.

DIAGNOSES: Sarcoidosis with NSG pattern.

INTERVENTIONS: The patient underwent video-assisted thoracoscopic surgery with a lung biopsy. No further treatment was performed after the lung biopsy.

OUTCOMES: Follow-up imaging studies revealed spontaneous regression of the disease after 2 months.

LESSONS: Awareness of this rare benign disease entity and overlapping radiologic manifestations with pulmonary malignancy or other granulomatous diseases can be helpful for making a precise diagnosis with a better differential diagnosis.

PMID:34889304 | PMC:PMC8663815 | DOI:10.1097/MD.0000000000028208

Int J Mol Sci. 2021 Nov 27;22(23):12829. doi: 10.3390/ijms222312829.

ABSTRACT

Diagnosis and cure for rare diseases represent a great challenge for the scientific community who often comes up against the complexity and heterogeneity of clinical picture associated to a high cost and time-consuming drug development processes. Here we show a drug repurposing strategy applied to nephropathic cystinosis, a rare inherited disorder belonging to the lysosomal storage diseases. This approach consists in combining mechanism-based and cell-based screenings, coupled with an affordable computational analysis, which could result very useful to predict therapeutic responses at both molecular and system levels. Then, we identified potential drugs and metabolic pathways relevant for the pathophysiology of nephropathic cystinosis by comparing gene-expression signature of drugs that share common mechanisms of action or that involve similar pathways with the disease gene-expression signature achieved with RNA-seq.

PMID:34884638 | PMC:PMC8657658 | DOI:10.3390/ijms222312829

Int J Environ Res Public Health. 2021 Nov 25;18(23):12395. doi: 10.3390/ijerph182312395.

ABSTRACT

Rare diseases (RDs), with distinctive and complex features, pose a serious public health concern and represent a considerable challenge for the Slovenian healthcare system. One of the potential approaches to tackling this problem and treating patients with RDs in a quality and effective manner is to form an RD ecosystem. This represents a functional environment that integrates all stakeholders, procedures, and relationships required for the coordinated and effective treatment of patients. This paper explores the current situation in the field of RDs, especially in light of the proposed ecosystemic arrangement, and provides an outline for the design of an RD ecosystem in Slovenia. The research applies a case-study design, where focus groups are used to collect evidence from the field, assess the state of affairs, and generate ideas. Structured focus group discussions were conducted with preeminent experts affiliated with the leading institutions in the field of RDs in Slovenia. Analyses and interpretations of the obtained data were carried out by means of conventional content analysis. Setting up an RD ecosystem in Slovenia would lead to significant benefits for patients, as it could promote the coordination of healthcare treatment and facilitate extensive monitoring of the treatment parameters and outcomes. A well-organized RD ecosystem could garner considerable systemic benefits for evidence-informed policymaking, a better utilization of resources, and technological innovation. Delivering quality healthcare in this complex field is largely reliant on the effective integration and collaboration of all entities within the RD ecosystem, the alignment of related systemic factors, and the direction of healthcare services to support the needs and well-being of patients with RDs.

PMID:34886121 | PMC:PMC8656847 | DOI:10.3390/ijerph182312395

Turk Kardiyol Dern Ars. 2021 Dec;49(8):685-687. doi: 10.5543/tkda.2021.21054.

ABSTRACT

Congenital absence of the pericardium (CAP) is a rare cardiac malformation and can be defined as the partial or total absence of the fibroelastic sac that surrounds the heart and great vessels. As the patients are often asymptomatic or have nonspecific symptoms, the diagnosis of this rare congenital anomaly is difficult. Therefore, it is usually diagnosed incidentally during imaging, intraoperatively, or during postmortem examinations. In this regard, it is important to keep specific images in mind during the examination and to suspect CAP to make an accurate diagnosis. In this report, we present a case of a 42-year-old male who presented with a complaint of atypical chest pain and was diagnosed with CAP using multimodality imaging.

PMID:34881708 | DOI:10.5543/tkda.2021.21054

Probl Sotsialnoi Gig Zdravookhranenniiai Istor Med. 2021 Nov;29(6):1490-1497. doi: 10.32687/0869-866X-2021-29-6-1490-1497.

ABSTRACT

The medication support of patients with rare (orphan) diseases is an actual issue, since it requires significant financial costs due to high price of medications. The accessibility of these medications to such patients should be regulated by state incentives for development of orphan medications with following taking out to the market, by procedure of composing list of medications for treatment of orphan diseases and determination of financial support sources. The article considers aspects of regulation of issues related to orphan diseases and orphan medications in the Russian Federation and Europe. On the basis of regulated list of orphan diseases in Russia, the results of comparative analysis of list of orphan medications in Russia and list published at website of the European Union are presented. On the basis of data obtained, it was established that many medications for treatment of rare diseases registered in Europe are not available in Russia. Also, many orphan drugs in Europe do not have this status in Russia. At the same time, there are no state incentives for development of orphan medications in the Russian Federation, and there are only some benefits in registration procedure of such drugs. The analysis demonstrated availability of development and taking out to the Russian pharmaceutical market large list of orphan drugs from the European listing for National corresponding manufacturers.

PMID:34882322 | DOI:10.32687/0869-866X-2021-29-6-1490-1497

Med Sci (Paris). 2021 Nov;37 Hors série n° 1:56-59. doi: 10.1051/medsci/2021198. Epub 2021 Dec 8.

NO ABSTRACT

PMID:34878401 | DOI:10.1051/medsci/2021198

Ital J Pediatr. 2021 Dec 7;47(1):232. doi: 10.1186/s13052-021-01184-4.

ABSTRACT

In this article, we describe the advances in the field of pediatrics that have been published in the Italian Journal of Pediatrics in 2020. We report progresses in understanding allergy, autoinflammatory disorders, critical care, endocrinology, genetics, infectious diseases, microbiota, neonatology, neurology, nutrition, orthopedics, respiratory tract illnesses, rheumatology in childhood.

PMID:34876198 | PMC:PMC8650733 | DOI:10.1186/s13052-021-01184-4

BMJ Case Rep. 2021 Dec 7;14(12):e244240. doi: 10.1136/bcr-2021-244240.

ABSTRACT

Alkaptonuria (AKU) is a rare autosomal recessive disorder with a global incidence of 1 in 250 000 to 1 million people worldwide. It results from a deficiency of the enzyme homogentisic acid (HGA) oxidase which when absent, leads to an accumulation of HGA. Without this enzymatic degradation, HGA deposits in connective tissues resulting in pigmentation (ochronosis), plaque formation and accelerated cartilage destruction. With this, many patients who suffer from AKU develop ochronotic arthropathies, tendon ruptures, fractures, and chronic joint pain. Similarly, patients can develop cardiac valvular dysfunction and interstitial renal disease. Our two cases highlight the array of pathologies seen in AKU and, in light of newly published research, give us a platform from which we can discuss the developments in management of this rare disease.

PMID:34876442 | DOI:10.1136/bcr-2021-244240

JAMA Dermatol. 2021 Dec 8. doi: 10.1001/jamadermatol.2021.4635. Online ahead of print.

ABSTRACT

IMPORTANCE: Palmoplantar pustulosis (PPP) is a is a chronic, orphan disease with limited epidemiological data.

OBJECTIVE: To describe the clinical characteristics, treatments, longitudinal disease course, and health care utilization in adults with PPP across the US.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective, longitudinal case series from 20 academic dermatology practices in the US included a consecutive sample of 197 adults who met the European Rare and Severe Psoriasis Expert Network consensus definition for PPP between January 1, 2007, and December 31, 2018. Data analysis was performed June 2020 to December 2020.

MAIN OUTCOMES AND MEASURES: The primary outcome was to describe the patient characteristics, associated medical comorbidities, treatment patterns, complications, and PPP-specific health care utilization.

RESULTS: Of 197 patients, 145 (73.6%) were female, and the mean (SD) age at presentation was 53.0 (12.6) years, with a mean (SD) follow-up time of 22.1 (28.0) months. On initial presentation, 95 (48.2%) patients reported skin pain, and 39 (19.8%) reported difficulty using hands and/or feet. Seventy patients (35.5%) were treated with systemic treatments, and use of more than 20 different systemic therapies was reported. In patients with at least 6 months of follow-up (n = 128), a median (IQR) of 3.7 (4-10) dermatology visits per year were reported; 24 (18.8%) patients had 5 or more visits during the study period.

CONCLUSIONS AND RELEVANCE: In this case series, PPP was associated with persistent symptoms, continued health care utilization, and a lack of consensus regarding effective treatments, emphasizing the unmet medical need in this population. Additional research is necessary to understand treatment response in these patients.

PMID:34878495 | DOI:10.1001/jamadermatol.2021.4635

JAMA Dermatol. 2021 Dec 8. doi: 10.1001/jamadermatol.2021.4640. Online ahead of print.

ABSTRACT

IMPORTANCE: Generalized pustular psoriasis (GPP) is a chronic, orphan disease with limited epidemiological data.

OBJECTIVE: To describe the clinical characteristics, treatments, longitudinal disease course, and disease-specific health care utilization among patients with GPP across the United States.

DESIGN, SETTING, AND PARTICIPANTS: A retrospective longitudinal case series involving 95 adults who met the European Rare and Severe Psoriasis Expert Network consensus definition for GPP and were treated at 20 US academic dermatology practices between January 1, 2007, and December 31, 2018.

MAIN OUTCOMES AND MEASURES: The primary outcome is to describe the patient characteristics, associated medical comorbidities, treatment patterns complications, and GPP-specific health care utilization.

RESULTS: Sixty-seven of 95 patients (70.5%) were women (mean age, 50.3 years [SD, 16.1 years]). In the initial encounter, 35 patients (36.8%) were hospitalized and 64 (67.4%) were treated with systemic therapies. In total, more than 20 different systemic therapies were tried. During the follow-up period, 19 patients (35.8%) reported hospitalizations at a median rate of 0.5 hospitalizations per year (IQR, 0.4-1.6). Women had a decreased risk of an emergency department or hospital encounter (odds ratio, 0.19; 95% CI, 0.04-0.83).

CONCLUSIONS AND RELEVANCE: Generalized pustular psoriasis is a rare, chronic disease without standard treatment and is associated with continued health care utilization over time.

PMID:34878491 | DOI:10.1001/jamadermatol.2021.4640

Allergy Asthma Proc. 2021 Nov 1;42(6):537-542. doi: 10.2500/aap.2021.42.210067.

ABSTRACT

Background: Alpha-1-antitrypsin deficiency (AATD) is an orphan disease that mainly affecting the liver and the lung. This creates difficulties to ensure that comprehensive care is administered to both organ systems. Past assessments of care delivered to patients with AATD demonstrated that improvements are needed. For that reason, we reassessed a population of patients with AATD in a large health care system to see if past findings affected present care. Methods: We performed electronic health record (EHR) reviews on all patients with documented AATD and confirmed the diagnosis by evidence of genotyping. We then selected the patients with the ZZ genotype to review comprehensive care. We further compared the findings in patients treated by different specialists (allergy immunology, gastroenterology, and pulmonary). The data were captured and assessed by using a secure web application for building and managing online surveys and data bases. REDCap. Results: We found a total of 329 patients with diagnostic codes for AATD, of these, 203 patients had a confirmed abnormal genotype. Confirmed genotypes were MZ (n = 69), ZZ (n = 48), MS (n = 22), SZ (n = 22). Further focus was applied to the care of the ZZ population secondary to a predisposition to potential severe lung and liver disease. The findings suggest that care can be improved no matter which specialist cares for the patient. Conclusion: Our study demonstrated that all three subspecialty groups had room for improvement in providing care to patients with AATD. Our study further demonstrated the need for recurrent quality-assurance programs that may be aided by care suggestions built into the EHR.

PMID:34871162 | DOI:10.2500/aap.2021.42.210067

Clin Hemorheol Microcirc. 2021 Dec 2. doi: 10.3233/CH-211253. Online ahead of print.

ABSTRACT

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an inherited orphan disease, in which the absence of capillary beds between arterioles and venules lead to arteriovenous shunts. Epistaxis is the core symptom. Several case reports have described the nonselective beta-adrenergic receptor antagonist timolol as a successful treatment method of nosebleeds due in HHT patients.

OBJECTIVE: TIM-HHT is a single-site, prospective, randomized, placebo-controlled, double-blind, cross-over study to investigate whether the efficacy of standard laser treatment of epistaxis in HHT patients can be increased by the additional use of timolol nasal spray (1 mg/d).

METHODS: Twenty patients will be randomly allocated to one of two treatment sequences. Primary outcome is the severity of epistaxis determined by the Epistaxis Severity Score (ESS). Secondary outcomes are subjective satisfaction, quality of life, as well as the hemoglobin, ferritin, and transferrin levels of the participating patients. Safety outcome is assessed by means of pulse, blood pressure, and adverse events.

CONCLUSION: TIM-HHT will evaluate the efficacy and safety of timolol as an additional treatment of epistaxis in HHT patients in a three-month trial period. Benzalkonium chloride is used as a placebo, which has no documented positive effect on the nasal mucosa and hence on epistaxis in HHT patients (in contrast to saline).

TRIAL REGISTRATION: German Clinical Trials Register (DRKS), DRKS00020994. Registered on 10 March 2020.

PMID:34864649 | DOI:10.3233/CH-211253

Eur J Endocrinol. 2021 Dec 1:EJE-21-1044.R1. doi: 10.1530/EJE-21-1044. Online ahead of print.

ABSTRACT

This European expert consensus statement provides recommendations for the diagnosis and management of primary hyperparathyroidism (PHPT), chronic hypoparathyroidism in adults (HypoPT), and parathyroid disorders in relation to pregnancy and lactation. Specified areas of interest and unmet needs identified by experts at the second ESE Educational Program of Parathyroid Disorders (PARAT) in 2019, were discussed during two virtual workshops in 2021, and subsequently developed by working groups with interest in the specified areas. PHPT is a common endocrine disease. However, its differential diagnosing to familial hypocalciuric hypercalcemia (FHH), the definition and clinical course of normocalcemic PHPT, and the optimal management of its recurrence after surgery represent areas of uncertainty requiring clarifications. HypoPT is an orphan disease characterized by low calcium concentrations due to insufficient PTH secretion, most often secondary to neck surgery. Prevention and prediction of surgical injury to the parathyroid glands are essential to limit the disease-related burden. Long-term treatment modalities including the place for PTH replacement therapy and the optimal biochemical monitoring and imaging surveillance for complications to treatment in chronic HypoPT, need to be refined. The physiological changes in calcium metabolism occurring during pregnancy and lactation modify the clinical presentation and management of parathyroid disorders in these periods of life. Modern interdisciplinary approaches to PHPT and HypoPT in pregnant and lactating women and their newborns children are proposed. The recommendations on clinical management presented here will serve as background for further educational material aimed for a broader clinical audience, and were developed with focus on endocrinologists in training.

PMID:34863037 | DOI:10.1530/EJE-21-1044

Ned Tijdschr Geneeskd. 2021 Oct 28;165:D5444.

ABSTRACT

BACKGROUND: Leber hereditary optic neuropathy (LHON) is an orphan disease which leads to painless subacute loss of central vision in both eyes. It develops mainly in young adults and is more common in males. It most often leads to lifelong blindness. Idebenone has shown to have a favourable effect in promoting vision recovery in LHON-patients with recent visual impairement.

CASE DESCRIPTION: Two male LHON patients, aged 27 and 54 years of age were misdiagnosed during one year with optic neuritis and conversion disorder. The delay caused unnecessary emotional suffering and took away the opportunity of idebenone treatment. This can be prevented by greater awareness of disease characteristcs and OCT-scanning.

CONCLUSION: Therapy for LHON requires a timely diagnosis.

PMID:34854587

Cien Saude Colet. 2021 Nov;26(11):5547-5560. doi: 10.1590/1413-812320212611.26722020. Epub 2020 Jul 29.

ABSTRACT

This study aims to describe the profile for the requested incorporation of rare disease drugs submitted to CONITEC and its recommendations, comparing the incorporation criteria employed by other HTA agencies globally. To this end, requests for the treatment of rare diseases submitted to CONITEC from July 2012 to June 2019 and its recommendations to the Brazilian Unified Health System (SUS) were included in this study. Subsequently, we compared the criteria used by CONITEC and other HTA agencies to incorporate these drugs. Sixty medicine incorporation requests to treat thirty rare diseases were submitted to CONITEC. Pharmaceutical companies made the most requests (66%). Budget impact analyses were presented in 85% of the requests and HT economic analyses in 68%. A total of 52% of the requests were incorporated into the SUS. CONITEC's justifications for the non-incorporation were the lack of quality clinical evidence, non-cost-effective technologies, and modest clinical benefits that do not justify the high prices. International HTA agencies (CAN, UK, FR, AUS) use different criteria for rare diseases assessments. The data indicate that most of the evaluated drugs were incorporated into the SUS, and adopting different criteria to assess the incorporation of rare diseases medicines will possibly strengthen decision-making.

PMID:34852089 | DOI:10.1590/1413-812320212611.26722020

Cien Saude Colet. 2021 Nov;26(11):5533-5546. doi: 10.1590/1413-812320212611.34542020. Epub 2021 Mar 2.

ABSTRACT

As a scientific and technological practice, the evaluation of health technologies (HTA) is, at the same time, a challenge to determine the value of the technologies to be incorporated. This study aimed to explore and compare the results and technical elements of the evaluations issued for rare diseases between the English (NICE) and the Brazilian agency (CONITEC). The first part of the study involved the systematic search for evaluations from 2013 to 2019. In the second stage, the reports were analyzed based on: (i) descriptive narrative review; and (ii) calculation of the absolute and relative frequency according to each domain and component (element) applied in the European HTA network model. Twenty-four medicines were distinctly assessed during the study period. Through 126 questions (elements) distributed among nine domains, the analysis revealed that 67 (53.2%) and 44 (35.0%) were described in the reports, 42 (33.3%) and 59 (47.0 %) were only considered partially, and 17 (13.5%) and 23 (18.0%) were not considered in the NICE and CONITEC reports, respectively. We identified a relatively low agreement between the Brazilian agency with the English agency in the reports issued for rare diseases. It remains to be seen whether the agencies are able to capture the various values ​​of these medicines, as well as manage uncertainties in the evaluations.

PMID:34852088 | DOI:10.1590/1413-812320212611.34542020

Cien Saude Colet. 2021 Nov;26(11):5441-5452. doi: 10.1590/1413-812320212611.15642021. Epub 2021 Aug 18.

ABSTRACT

This study analyzed the import applications for unavailable vital medicines (MVND) submitted to INVIMA and the records of MVND reimbursement requests submitted to the ADRES in the 2016-2017 period. Approximately 76% of the 2,321 MVND import applications were authorized. Eighty-eight applicants, 73 therapeutic subgroups, 195 active ingredients, and 368 diagnoses were identified. Most of the patients registered in the import applications (66%) are linked to the contributory regime, to a lesser extent to the subsidized regime and the Special or exceptional regimes. The total value of the reimbursement requests related to MVND granted by lawsuits, was USD 8,577,583, equivalent to 38,483 UPCs. The results showed that the implementation of Decree N° 481/2004 has ensured access to medicines for rare diseases. However, it is not alien to the structural inequality of access to health services and medicines of the Colombian Health System, which impacts public health and the allocated budget, either because of the high cost of importing MVND or because of the lack of MVND regulation within the national market.

PMID:34852081 | DOI:10.1590/1413-812320212611.15642021

J Clin Invest. 2021 Nov 30:e150789. doi: 10.1172/JCI150789. Online ahead of print.

ABSTRACT

Functional gastrointestinal disorders (FGIDs) have prominent sex differences in incidence, symptoms, and treatment response that are not well understood. Androgens are steroid hormones present at much higher levels in males than females and could be involved in these differences. In adults with irritable bowel syndrome (IBS), a FGID that affects 5-10% of the population worldwide, we found that free testosterone levels were lower than those in healthy controls and inversely correlated with symptom severity. To determine how this diminished androgen signaling could contribute to bowel dysfunction, we depleted gonadal androgens in adult mice and found that this caused a profound deficit in gastrointestinal transit. Restoring a single androgen hormone was sufficient to rescue this deficit, suggesting that circulating androgens are essential for normal bowel motility in vivo. To determine the site of action, we probed androgen receptor expression in the intestine and discovered, unexpectedly, that a large subset of enteric neurons became androgen-responsive upon puberty. Androgen signaling to these neurons was required for normal colonic motility in adult mice. Taken together, these observations establish a role for gonadal androgens in the neural regulation of bowel function and link altered androgen levels with a common digestive disorder.

PMID:34847080 | DOI:10.1172/JCI150789