Khirurgiia (Mosk). 2023;(5):101-104. doi: 10.17116/hirurgia2023051101.

ABSTRACT

We report a patient with combination of esophageal atresia, proximal tracheoesophageal fistula and meconium peritonitis. These two rare disorders have different etiology, pathogenetic mechanisms and require different diagnostic manipulations and surgical treatments. The authors discuss the features of diagnosis and surgical treatment of this disease.

PMID:37186657 | DOI:10.17116/hirurgia2023051101

Ann Ig. 2023 Jul-Aug;35(4):379-402. doi: 10.7416/ai.2023.2555. Epub 2023 Feb 3.

ABSTRACT

INTRODUCTION: Communication has a crucial role in public health, because it becomes an essential component of prevention; it is also a proactive tool in health promotion. From a planning perspective, it is appropriate to use communication means that can help the bidirectional communication process, such as face-to-face communication and telephone communication.

MATERIALS AND METHODS: In relation to this, the Italian National Institute of Health has developed the "Modello Operativo Comunicativo-Relazionale" (the "Communicative-Relational Operating Model"). It is based on the fundamental skills of the counselling, this gives a protocol to the health professionals that is replicable and organized and it allows health professionals to carry out a telephone communication that is efficient with the user through technical-scientific and communication-relational skills. The goal is to answer in a customized way to the various users' health needs. The Operating Model was created by experts of the National AIDS and Sexually Transmitted Infections Helpline of the Operational Unit of Psycho-Socio-Behavioural Research, Communication, Training, of the Infectious Diseases Department. Later, the Operating Model was proposed to the experts of the Helplines in the National Centre on Addictions and Doping and the National Helpline of the National Centre for Rare Diseases in the National Institute of Health that integrated this method into their telephone approach.

RESULTS: The Operating Model illustrated above was applied to several helplines of the National Institute of Health as an example of correct scientific information, updated and customized on sexual transmitted infections, addictions and rare diseases.

CONCLUSIONS: This article aims to illustrate the Operating Model, the theoretical prerequisites that subtend it and its possible application in the different public health structures that use the telephone for a profes-sional relationship with their users.

PMID:37184351 | DOI:10.7416/ai.2023.2555

Hepatology. 2023 May 16. doi: 10.1097/HEP.0000000000000458. Online ahead of print.

ABSTRACT

Acute liver failure (ALF) describes a clinical syndrome of rapid hepatocyte injury leading to liver failure manifested by coagulopathy and encephalopathy in the absence of pre-existing cirrhosis. The hallmark diagnostic features are a prolonged prothrombin time (i.e., an international normalized ratio of prothrombin time (INR) of ≥ 1.5) and any degree of mental status alteration (hepatic encephalopathy, HE). As a rare, orphan disease, it seemed an obvious target for a multi-center network. The Acute Liver Failure Study Group (ALFSG) began in 1997 to more thoroughly study and understand the causes, natural history, and management of ALF. Over the course of 22 years, 3,364 adult patients were enrolled in the study registry (2,614 ALF and 857 acute liver injury-INR 2.0 but no encephalopathy--ALI) and more than 150,000 bio-samples collected, including serum, plasma, urine, DNA, and liver tissue. Within the Registry study sites, four prospective substudies were conducted and published, two interventional (N-acetylcysteine (NAC) and ornithine phenylacetate (OPA)), one prognostic (13C-methacetin breath test (MBT)), and one mechanistic (rotational thromboelastometry (ROTEM)). To review ALFSG's accomplishments and consider next steps, a two-day in-person conference was held at UT Southwestern Medical Center, Dallas, Texas, entitled "Acute Liver Failure: Science and Practice," in May 2022. To summarize the important findings in the field, this review highlights the current state of understanding of ALF and, more importantly, asks what further studies are needed to improve our understanding of the pathogenesis, natural history, and management of this unique and dramatic condition.

PMID:37183883 | DOI:10.1097/HEP.0000000000000458

Expert Opin Drug Discov. 2023 May 15:1-13. doi: 10.1080/17460441.2023.2211802. Online ahead of print.

ABSTRACT

INTRODUCTION: Zebrafish larvae are one of the few vertebrates amenable to large-scale drug discovery screens. Larval swimming behavior is often used as an outcome variable and many fields of study have developed assays for evaluating swimming performance. An unintended consequence of this wide interest is that details related to assay methodology and interpretation become scattered across the literature. The aim of this review is to consolidate this information, particularly as it relates to high-throughput approaches.

AREAS COVERED: The authors describe larval swimming behaviors as this forms the basis for understanding their experimentally evoked swimming or spontaneous activity. Next, they detail how swimming activity can serve as an outcome variable, particularly in the multi-well formats used in large-scale screening studies. They also highlight biological and technical factors that can impact the sensitivity and variability of these measurements.

EXPERT OPINION: Careful attention to animal husbandry, experimental design, data acquisition, and interpretation of results can improve screen outcomes by maximizing swimming activity while minimizing intra- and inter-larval variability. The development of more sensitive, quantitative methods of assessing swimming performance that can be incorporated into high-throughput workflows will be important in order to take full advantage of the zebrafish model.

PMID:37183669 | DOI:10.1080/17460441.2023.2211802

Am J Med Genet A. 2023 May 14. doi: 10.1002/ajmg.a.63226. Online ahead of print.

ABSTRACT

Jansen-de Vries syndrome (JdVS) is a neurodevelopmental condition attributed to pathogenic variants in Exons 5 and 6 of PPM1D. As the full phenotypic spectrum and natural history remain to be defined, we describe a large cohort of children and adults with JdVS. This is a retrospective cohort study of 37 individuals from 34 families with disease-causing variants in PPM1D leading to JdVS. Clinical data were provided by treating physicians and/or families. Of the 37 individuals, 27 were male and 10 female, with median age 8.75 years (range 8 months to 62 years). Four families document autosomal dominant transmission, and 32/34 probands were diagnosed via exome sequencing. The facial gestalt, including a broad forehead and broad mouth with a thin and tented upper lip, was most recognizable between 18 and 48 months of age. Common manifestations included global developmental delay (35/36, 97%), hypotonia (25/34, 74%), short stature (14/33, 42%), constipation (22/31, 71%), and cyclic vomiting (6/35, 17%). Distinctive personality traits include a hypersocial affect (21/31, 68%) and moderate-to-severe anxiety (18/28, 64%). In conclusion, JdVS is a clinically recognizable neurodevelopmental syndrome with a characteristic personality and distinctive facial features. The association of pathogenic variants in PPM1D with cyclic vomiting bears not only medical attention but also further pathogenic and mechanistic evaluation.

PMID:37183572 | DOI:10.1002/ajmg.a.63226

Ther Adv Rare Dis. 2020 Oct 22;1:2633004020959349. doi: 10.1177/2633004020959349. eCollection 2020 Jan-Dec.

ABSTRACT

Paroxysmal nocturnal haemoglobinuria (PNH) is an ultra-orphan disease, which until 15 years ago had limited treatment options. Eculizumab, a monoclonal antibody that inhibits C5 in the terminal complement cascade, has revolutionised treatment for this disease, near normalising life expectancy and improving quality of life for patients. The treatment landscape of PNH is now evolving, with ravulizumab a second longer acting intravenous C5 inhibitor now licenced by the FDA and EMA. With different therapeutic targets in the complement cascade and difference modalities of treatment, including subcutaneous, oral and intravenous therapies being developed, increasing independence for patients and reducing healthcare requirements. This review discusses the current and future therapies for PNH.

LAY SUMMARY: Review of current and future treatments for patients with Paroxysmal Nocturnal Haemoglobinuria What is Paroxysmal Nocturnal Haemoglobinuria? Paroxysmal nocturnal haemoglobinuria (PNH) is a very rare disease. It arises from PNH stem cells in the bone marrow. In a normal bone marrow these are inactive; however, if there has been a problem in the bone marrow, the PNH stem cells can expand and make PNH red blood cells, white blood cells and platelets. The problem with these cells is that they lack the cell surface markers that usually protect them. Red blood cells are broken down in the circulation rather than the spleen, which gives rise to PNH symptoms such as abdominal pain, difficulty swallowing, erectile dysfunction and red or black urine (known as haemoglobinuria). The white blood cells and platelets are 'stickier' increasing the risk of blood clots. Previously life expectancy was reduced as there were limited treatment options available. What was the aim of this review? To provide an overview of current and future treatment options for PNH Which treatments are available? • Eculizumab is an treatment given through a vein (intravenous) every week for 5 weeks then every 2 weeks after this, and has been available for 13 years, improving life expectancy to near normal.• Ravulizumab is a newer intravenous treatment similar to eculizumab but is given every 8 weeks instead of every 2 weeks. In clinical studies it was comparable with eculizumab.• Future Treatments - There is new research looking at different methods of treatment delivery, including injections under the skin (subcutaneous) that patients can give themselves, treatments taken by mouth (oral) or a combination of an intravenous and oral treatment for those patients who are not optimally controlled on eculizumab or ravulizumab. What does this mean? PNH is now treatable. For years, the only drug available was eculizumab, but now different targets and drug trials are available. Ravulizumab is currently the only second licenced product available, in USA and Europe, there are other medications active in clinical trials. Why is this important? The benefit for patients, from treatment every 2 weeks to every 8 weeks is likely to be improved further with the development of these new treatments, providing patients with improved disease control and independence.As we move into an era of more patient-friendly treatment options, the PNH community both physicians and patients look forward to new developments as discussed in this article.

PMID:37180495 | PMC:PMC10032435 | DOI:10.1177/2633004020959349

Int J Mol Sci. 2023 Apr 26;24(9):7880. doi: 10.3390/ijms24097880.

ABSTRACT

Drug-Induced Enterocolitis Syndrome (DIES) is a drug-induced hypersensitivity reaction non-IgE mediated involving the gastrointestinal system that occurs 2 to 4 h after drug administration. Antibiotics, specifically amoxicillin or amoxicillin/clavulanate, represent the most frequent drugs involved. Symptoms include nausea, vomiting, abdominal pain, diarrhea, pallor, lethargy, and dehydration, which can be severe and result in hypovolemic shock. The main laboratory finding is neutrophilic leukocytosis. To the best of our knowledge, 12 cases of DIES (9 children-onset and 3 adult-onset cases) were described in the literature. DIES is a rare clinically well-described allergic disease; however, the pathogenetic mechanism is still unclear. It requires to be recognized early and correctly treated by physicians.

PMID:37175584 | PMC:PMC10178722 | DOI:10.3390/ijms24097880

Cancers (Basel). 2023 Apr 28;15(9):2527. doi: 10.3390/cancers15092527.

ABSTRACT

T-prolymphocytic leukemia (T-PLL) is a rare and mature T-cell malignancy with characteristic chemotherapy-refractory behavior and a poor prognosis. Molecular concepts of disease development have been restricted to protein-coding genes. Recent global microRNA (miR) expression profiles revealed miR-141-3p and miR-200c-3p (miR-141/200c) as two of the highest differentially expressed miRs in T-PLL cells versus healthy donor-derived T cells. Furthermore, miR-141/200c expression separates T-PLL cases into two subgroups with high and low expression, respectively. Evaluating the potential pro-oncogenic function of miR-141/200c deregulation, we discovered accelerated proliferation and reduced stress-induced cell death induction upon stable miR-141/200c overexpression in mature T-cell leukemia/lymphoma lines. We further characterized a miR-141/200c-specific transcriptome involving the altered expression of genes associated with enhanced cell cycle transition, impaired DNA damage responses, and augmented survival signaling pathways. Among those genes, we identified STAT4 as a potential miR-141/200c target. Low STAT4 expression (in the absence of miR-141/200c upregulation) was associated with an immature phenotype of primary T-PLL cells as well as with a shortened overall survival of T-PLL patients. Overall, we demonstrate an aberrant miR-141/200c-STAT4 axis, showing for the first time the potential pathogenetic implications of a miR cluster, as well as of STAT4, in the leukemogenesis of this orphan disease.

PMID:37173993 | DOI:10.3390/cancers15092527

Ugeskr Laeger. 2023 May 1;185(18):V01230060.

ABSTRACT

Cholesterol pericarditis is an extremely rare type of pericarditis characterized by a continuous pericardial effusion containing high amounts of cholesterol crystals. This case report of a 51-year-old male with syncopal episodes and a massive, cholesterol-rich pericardial effusion highlights the interdisciplinary approach and rationale in treating this rare condition of largely unknown pathogenesis.

PMID:37170745

Orphanet J Rare Dis. 2023 May 11;18(1):114. doi: 10.1186/s13023-023-02713-6.

ABSTRACT

BACKGROUND: Rare disease is a general term for a disease that affects a small number of people but recognized as a global public health priority. Governments worldwide are paying more and more attention to the academical research and drug investment of rare diseases. The conduct of rare disease clinical trials is still difficult, despite the promotion of government policies and the awakening of social consciousness. In this article, we outlined the characteristics and obstacles of clinical trials of rare diseases in China and expected to provide reference for subsequent clinical trials in this field.

RESULTS: In recent years, China has made some progress in clinical trials of rare diseases in the past 10 years. There were 481 clinical trials on rare diseases in total, covering more than 10 rare diseases with high incidence. Clinical trial applications on rare diseases for a total of 481 were submitted and with an average annual growth rate of 28.2% from 2013 to 2022. The number of clinical trial application for rare diseases in 2016 dramatically increased by 80% compared to 2015 due to the policy document issued by China for clinical research in rare diseases in 2015. Besides, about 70% of applications registering for clinical trials could recruit subjects as expected. Despite this, the number of clinical trials of rare diseases in China was less compared with the United States, Europe and Japan, and the types of infant drugs were limited to biological products and chemical drugs lacking other new treatments.

CONCLUSIONS: Efforts have been made in recent years to develop clinical research on rare diseases in China. The number of clinical trials for rare diseases in China was growing steadily every year, which was inseparable from the support of the country, society and rare disease patients. Still, there was a large gap between China and other developed countries in this field and this merit further investigation.

PMID:37170366 | PMC:PMC10173236 | DOI:10.1186/s13023-023-02713-6

An Sist Sanit Navar. 2023 Apr 29;46(1):e1038. doi: 10.23938/ASSN.1038.

NO ABSTRACT

PMID:37166237 | DOI:10.23938/ASSN.1038

Nephrol Ther. 2023 May 11;19(3):1-14. doi: 10.1684/ndt.2023.10. Online ahead of print.

ABSTRACT

Hyperoxaluria is defined by an increase of urinary oxalate, leading to kidney stones, nephrocalcinosis and/or chronic kidney disease. There are different diseases related to hyperoxaluria: (1) kidney stones, 50% of them being explained by intermittent hyperoxaluria, secondary to dietary mistakes such as low hydration, excess of oxalate consumption and/or low calcium consumption; (2) primary hyperoxaluria, a genetic orphan disease inducing a massive production of oxalate by the liver, leading to increased plasma oxalate increase and saturation, and further systemic oxalosis with oxalate deposition, nephrocalcinosis and ultimately kidney failure, the management of this disease being currently dramatically modified by the onset of new therapeutic tools such as RNA interference; and (3) enteric hyperoxaluria, resulting from increased intestinal oxalate absorption because of intestinal malabsorption (short bowel syndrome, bariatric surgery, exocrine pancreatic insufficiency, etc.). Diagnosis and therapeutic management of these diseases require a full understanding of oxalate physiology that we detail in this review.

PMID:37166780 | DOI:10.1684/ndt.2023.10

Tuberc Respir Dis (Seoul). 2023 May 10. doi: 10.4046/trd.2023.0010. Online ahead of print.

ABSTRACT

Bronchiectasis is characterized by irreversibly damaged and dilated bronchi, which causes significant symptoms, poor quality of life, increased economic burden and mortality rates. Despite increasing prevalence and clinical significance of bronchiectasis, bronchiectasis was previously regarded as an orphan disease, and ideal treatment of this disease have been poorly understood. European Respiratory Society and British Thoracic Society have recently published guidelines to assist physicians in the clinical field. Guidelines and reports suggest comprehensive management including both non-pharmacological and pharmacological treatments. Physiotherapy and pulmonary rehabilitation are one of the most important non-pharmacologic therapies in bronchiectasis patients; long-term inhaled antibiotics and macrolide therapy have gained significant evidences in reducing exacerbation risk in frequent exacerbators. In this review, we summarized recent update on bronchiectasis treatment to prevent exacerbation and management of clinical deteriorations.

PMID:37165624 | DOI:10.4046/trd.2023.0010

Sci Adv. 2023 May 10;9(19):eadi1215. doi: 10.1126/sciadv.adi1215. Epub 2023 May 10.

ABSTRACT

Novel drug targets are identified in lymphangioleiomyomatosis (LAM), a rare disease in women. These targets focus on uterine transcription factors necessary for LAM cell survival.

PMID:37163598 | DOI:10.1126/sciadv.adi1215

Orphanet J Rare Dis. 2023 May 9;18(1):109. doi: 10.1186/s13023-023-02650-4.

ABSTRACT

BACKGROUND: Many patients with rare diseases are still lacking a timely diagnosis and approved therapies for their condition despite the tremendous efforts of the research community, biopharmaceutical, medical device industries, and patient support groups. The development of clinical research networks for rare diseases offers a tremendous opportunity for patients and multi-disciplinary teams to collaborate, share expertise, gain better understanding on specific rare diseases, and accelerate clinical research and innovation. Clinical Research Networks have been developed at a national or continental level, but global collaborative efforts to connect them are still lacking. The International Rare Diseases Research Consortium set a Task Force on Clinical Research Networks for Rare Diseases with the objective to analyse the structure and attributes of these networks and to identify the barriers and needs preventing their international collaboration. The Task Force created a survey and sent it to pre-identified clinical research networks located worldwide.

RESULTS: A total of 34 responses were received. The survey analysis demonstrated that clinical research networks are diverse in their membership composition and emphasize community partnerships including patient groups, health care providers and researchers. The sustainability of the networks is mostly supported by public funding. Activities and research carried out at the networks span the research continuum from basic to clinical to translational research studies. Key elements and infrastructures conducive to collaboration are well adopted by the networks, but barriers to international interoperability are clearly identified. These hurdles can be grouped into five categories: funding limitation; lack of harmonization in regulatory and contracting process; need for common tools and data standards; need for a governance framework and coordination structures; and lack of awareness and robust interactions between networks.

CONCLUSIONS: Through this analysis, the Task Force identified key elements that should support both developing and established clinical research networks for rare diseases in implementing the appropriate structures to achieve international interoperability worldwide. A global roadmap of actions and a specific research agenda, as suggested by this group, provides a platform to identify common goals between these networks.

PMID:37161573 | DOI:10.1186/s13023-023-02650-4

BMJ. 2023 May 9;381:e073242. doi: 10.1136/bmj-2022-073242.

ABSTRACT

OBJECTIVE: To analyze the US Food and Drug Administration (FDA) approval, trials, unmet needs, benefit, and pricing of ultra-rare (<6600 affected US citizens), rare (6600-200 000 citizens), and common (>200 000 citizens) orphan cancer drug indications and non-orphan cancer drug indications.

DESIGN: Cross sectional analysis.

SETTING: Data from Drugs@FDA, FDA labels, Global Burden of Disease study, and Medicare and Medicaid.

POPULATION: 170 FDA approved drugs across 455 cancer indications between 2000 and 2022.

MAIN OUTCOME MEASURES: Comparison of non-orphan and ultra-rare, rare, and common orphan indications regarding regulatory approval, trials, epidemiology, and price. Hazard ratios for overall survival and progression-free survival were meta-analyzed.

RESULTS: 161 non-orphan and 294 orphan cancer drug indications were identified, of which 25 were approved for ultra-rare diseases, 205 for rare diseases, and 64 for common diseases. Drugs for ultra-rare orphan indications were more frequently first in class (76% v 48% v 38% v 42%; P<0.001), monotherapies (88% v 69% v 72% v 55%; P=0.001), for hematologic cancers (76% v 66% v 0% v 0%; P<0.001), and supported by smaller trials (median 85 v 199 v 286 v 521 patients; P<0.001), of single arm (84% v 44% v 28% v 21%; P<0.001) phase 1/2 design (88% v 45% v 45% v 27%; P<0.001) compared with rare and common orphan indications and non-orphan indications. Drugs for common orphan indications were more often biomarker directed (69% v 26% v 12%; P<0.001), first line (77% v 39% v 20%; P<0.001), small molecules (80% v 62% v 48%; P<0.001) benefiting from quicker time to first FDA approval (median 5.7 v 7.1 v 8.9 years; P=0.02) than those for rare and ultra-rare orphan indications. Drugs for ultra-rare, rare, and common orphan indications offered a significantly greater progression-free survival benefit (hazard ratio 0.53 v 0.51 v 0.49 v 0.64; P<0.001), but not overall survival benefit (0.50 v 0.73 v 0.71 v 0.74; P=0.06), than non-orphans. In single arm trials, tumor response rates were greater for drugs for ultra-rare orphan indications than for rare or common orphan indications and non-orphan indications (objective response rate 57% v 48% v 55% v 33%; P<0.001). Disease incidence/prevalence, five year survival, and the number of available treatments were lower, whereas disability adjusted life years per patient were higher, for ultra-rare orphan indications compared with rare or common indications and non-orphan indications. For 147 on-patent drugs with available data in 2023, monthly prices were higher for ultra-rare orphan indications than for rare or common orphan indications and non-orphan indications ($70 128 (£55 971; €63 370) v $33 313 v $16 484 v $14 508; P<0.001). For 48 on-patent drugs with available longitudinal data from 2005 to 2023, prices increased by 94% for drugs for orphan indications and 50% for drugs for non-orphan indications on average.

CONCLUSIONS: The Orphan Drug Act of 1983 incentivizes development of drugs not only for rare diseases but also for ultra-rare diseases and subsets of common diseases. These orphan indications fill significant unmet needs, yet their approval is based on small, non-robust trials that could overestimate efficacy outcomes. A distinct ultra-orphan designation with greater financial incentives could encourage and expedite drug development for ultra-rare diseases.

PMID:37160306 | DOI:10.1136/bmj-2022-073242

BMJ. 2023 May 9;381:e072796. doi: 10.1136/bmj-2022-072796.

NO ABSTRACT

PMID:37160303 | DOI:10.1136/bmj-2022-072796

Pneumologie. 2023 May;77(5):303-307. doi: 10.1055/a-2028-6032. Epub 2023 May 9.

ABSTRACT

Case discussion of a 40-year-old male patient with a history of recurrent pneumothoraces due to Birt-Hogg-Dubé syndrome. In addition to conservative treatment of a pneumothorax on the left side, a subtotal parietal pleurectomy on the right side was performed after recurrence of a pneumothorax 6 years later. CT of the thorax showed high-grade structural remodelling of the lung parenchyma with cystic lung lesions on both sides with a diameter of up to 7.5 cm. After exclusion of alpha-1 antitrypsin deficiency, underlying immunological disease, unremarkable family and occupational history, Birt-Hogg-Dubé syndrome was suspected based on the morphological distribution pattern of the cystic lung lesions. Genetic examination helped detect a heterozygous pathogenic variant in the FLCN gene, namely c.1294_1298del;p.(Ser432Argfs*22). Birt-Hogg-Dubé syndrome is a rare genetic disorder clinically characterized by pulmonary cysts, fibrofolliculomas of the skin and occurrence of clustered renal tumors. In particular, the increased risk of renal malignancies and the risk of spontaneous pneumothoraces underlines the importance of early diagnosis and screening of affected patients and their families.

PMID:37160111 | DOI:10.1055/a-2028-6032

JAMA Netw Open. 2023 May 1;6(5):e2312231. doi: 10.1001/jamanetworkopen.2023.12231.

ABSTRACT

IMPORTANCE: Newborn genome sequencing (NBSeq) can detect infants at risk for treatable disorders currently undetected by conventional newborn screening. Despite broad stakeholder support for NBSeq, the perspectives of rare disease experts regarding which diseases should be screened have not been ascertained.

OBJECTIVE: To query rare disease experts about their perspectives on NBSeq and which gene-disease pairs they consider appropriate to evaluate in apparently healthy newborns.

DESIGN, SETTING, AND PARTICIPANTS: This survey study, designed between November 2, 2021, and February 11, 2022, assessed experts' perspectives on 6 statements related to NBSeq. Experts were also asked to indicate whether they would recommend including each of 649 gene-disease pairs associated with potentially treatable conditions in NBSeq. The survey was administered between February 11 and September 23, 2022, to 386 experts, including all 144 directors of accredited medical and laboratory genetics training programs in the US.

EXPOSURES: Expert perspectives on newborn screening using genome sequencing.

MAIN OUTCOMES AND MEASURES: The proportion of experts indicating agreement or disagreement with each survey statement and those who selected inclusion of each gene-disease pair were tabulated. Exploratory analyses of responses by gender and age were conducted using t and χ2 tests.

RESULTS: Of 386 experts invited, 238 (61.7%) responded (mean [SD] age, 52.6 [12.8] years [range 27-93 years]; 126 [52.9%] women and 112 [47.1%] men). Among the experts who responded, 161 (87.9%) agreed that NBSeq for monogenic treatable disorders should be made available to all newborns; 107 (58.5%) agreed that NBSeq should include genes associated with treatable disorders, even if those conditions were low penetrance; 68 (37.2%) agreed that actionable adult-onset conditions should be sequenced in newborns to facilitate cascade testing in parents, and 51 (27.9%) agreed that NBSeq should include screening for conditions with no established therapies or management guidelines. The following 25 genes were recommended by 85% or more of the experts: OTC, G6PC, SLC37A4, CYP11B1, ARSB, F8, F9, SLC2A1, CYP17A1, RB1, IDS, GUSB, DMD, GLUD1, CYP11A1, GALNS, CPS1, PLPBP, ALDH7A1, SLC26A3, SLC25A15, SMPD1, GATM, SLC7A7, and NAGS. Including these, 42 gene-disease pairs were endorsed by at least 80% of experts, and 432 genes were endorsed by at least 50% of experts.

CONCLUSIONS AND RELEVANCE: In this survey study, rare disease experts broadly supported NBSeq for treatable conditions and demonstrated substantial concordance regarding the inclusion of a specific subset of genes in NBSeq.

PMID:37155167 | PMC:PMC10167563 | DOI:10.1001/jamanetworkopen.2023.12231

Front Neurol. 2023 Apr 21;14:1108222. doi: 10.3389/fneur.2023.1108222. eCollection 2023.

ABSTRACT

OBJECTIVE: We retrospectively screened 350,116 electronic health records (EHRs) to identify suspected patients for Pompe disease. Using these suspected patients, we then describe their phenotypical characteristics and estimate the prevalence in the respective population covered by the EHRs.

METHODS: We applied Symptoma's Artificial Intelligence-based approach for identifying rare disease patients to retrospective anonymized EHRs provided by the "University Hospital Salzburg" clinic group. Within 1 month, the AI screened 350,116 EHRs reaching back 15 years from five hospitals, and 104 patients were flagged as probable for Pompe disease. Flagged patients were manually reviewed and assessed by generalist and specialist physicians for their likelihood for Pompe disease, from which the performance of the algorithms was evaluated.

RESULTS: Of the 104 patients flagged by the algorithms, generalist physicians found five "diagnosed," 10 "suspected," and seven patients with "reduced suspicion." After feedback from Pompe disease specialist physicians, 19 patients remained clinically plausible for Pompe disease, resulting in a specificity of 18.27% for the AI. Estimating from the remaining plausible patients, the prevalence of Pompe disease for the greater Salzburg region [incl. Bavaria (Germany), Styria (Austria), and Upper Austria (Austria)] was one in every 18,427 people. Phenotypes for patient cohorts with an approximated onset of symptoms above or below 1 year of age were established, which correspond to infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD), respectively.

CONCLUSION: Our study shows the feasibility of Symptoma's AI-based approach for identifying rare disease patients using retrospective EHRs. Via the algorithm's screening of an entire EHR population, a physician had only to manually review 5.47 patients on average to find one suspected candidate. This efficiency is crucial as Pompe disease, while rare, is a progressively debilitating but treatable neuromuscular disease. As such, we demonstrated both the efficiency of the approach and the potential of a scalable solution to the systematic identification of rare disease patients. Thus, similar implementation of this methodology should be encouraged to improve care for all rare disease patients.

PMID:37153672 | PMC:PMC10160659 | DOI:10.3389/fneur.2023.1108222