Front Immunol. 2022 May 30;13:854414. doi: 10.3389/fimmu.2022.854414. eCollection 2022.

ABSTRACT

Premature infants are known to have immature immune systems compared to term infants; however, the impacts of ex utero immune development are not well characterized. Our previous retrospective clinical review showed prolonged T cell lymphopenia in a subset of extremely premature infants, suggesting that they may have lasting abnormalities in their T cell compartments. We used T cell receptor (TCR) repertoire sequencing to analyze the composition of the T cell compartment in premature and term infants in our NICU. We collected twenty-eight samples from individual subjects and analyzed the number of clonotypes, repertoire diversity, CDR3 length, and V gene usage between groups based on gestational age at birth and postmenstrual age at the time of sample collection. Further, we examined the TCR repertoire in infants with severe bronchopulmonary dysplasia (BPD) and those with abnormal T cell receptor excision circle (TREC) assays. Former extremely premature infants who were corrected to term postmenstrual age had TCR repertoire diversity that was more similar to term born infants than extremely premature infants, supporting normal maturation of the repertoire. Infants with severe BPD did not appear to have increased abnormalities in repertoire diversity. Decreased TCR repertoire diversity was associated with repeatedly abnormal TREC screening, although the diversity was within the normal range for subjects without low TRECs. This study suggests that extremely premature infants demonstrate normal maturation of the T cell repertoire ex utero. Further work is needed to better characterize postnatal T cell development and function in this population.

PMID:35707545 | PMC:PMC9189380 | DOI:10.3389/fimmu.2022.854414

Arch Bronconeumol. 2021 Sep;57(9):590. doi: 10.1016/j.arbr.2020.01.019.

NO ABSTRACT

PMID:35698938 | DOI:10.1016/j.arbr.2020.01.019

J Nucl Med Technol. 2022 Jun 14:jnmt.122.263813. doi: 10.2967/jnmt.122.263813. Online ahead of print.

ABSTRACT

The 2018 FDA approval of 177Lu-DOTATATE for the treatment of somatostatin receptor-positive (SSTR) neuroendocrine tumors (NETs) represents a paradigm shifting approach to cancer treatments around the globe. Gastroenteropancreatic (GEP) NETs overexpress the somatostatin subtype receptor 2, which is now exploited for receptor-based imaging and therapy, thus generating significant progress in the diagnosis and treatment of this orphan disease. The recent FDA approval of receptor-based PET radiopharmaceuticals and a new peptide receptor radiopharmaceutical therapy (PRRT), 177Lu-DOTATATE, has dramatically impacted NET patient management. The focus of this paper is to review clinical considerations associated with implementing a 177Lu-DOTATATE program. We review receptor-based NET radiopharmaceuticals, 177Lu-DOTATATE patient selection criteria, administration methods, clinical, regulatory, and radiation safety considerations, technical factors, tissue dosimetry, and reimbursement guidelines.

PMID:35701215 | DOI:10.2967/jnmt.122.263813

Stem Cell Res. 2022 Jun 8;63:102833. doi: 10.1016/j.scr.2022.102833. Online ahead of print.

ABSTRACT

Vici syndrome is a rare, congenital disorder that affects multiple systems and is caused by mutations in the EPG5 gene that encodes for ectopic P-granules autophagy protein 5 (EPG5). The induced pluripotent stem cell (iPSC) line described here was generated from a dermal fibroblast cell line from an 8-year-old male donor with a homozygous recessive c.1007A>G (p.Q336R) mutation in the EPG5 gene. This iPSC model of Vici syndrome provides a unique and valuable resource for investigators to study the pathology of EPG5 mutations and the aetiology of the disease as well as develop therapeutic treatments for those with Vici syndrome.

PMID:35700637 | DOI:10.1016/j.scr.2022.102833

Orphanet J Rare Dis. 2022 Jun 13;17(1):218. doi: 10.1186/s13023-022-02390-x.

ABSTRACT

BACKGROUND: Since 2014, the Canadian Agency for Drugs and Technologies in Health (CADTH), which performs health technology assessments for all federal, provincial and territorial government drug programs (except Quebec's) and the pan-Canadian Pharmaceutical Alliance (pCPA), which conducts price negotiations with manufacturers for all government drug programs, have been aligning their processes.

OBJECTIVE: To examine trends in CADTH recommendations for non-oncology drugs for rare disorders (DRDs) released between 2014 and 2021, results of pCPA negotiations for the same drugs, and listings in government drug plans to assess who benefits from the alignment.

RESULTS: Recommendations were positive in 87% of the reviews, although all included clinical criteria for use and/or economic conditions. Almost 90% of the DRDs with a positive recommendation had a successful price negotiation and 71% of those with a negative recommendation had no negotiation. Although no recommendation published before mid-2016 had a specified price reduction, almost 95% of those issued afterwards included the price reduction required to achieve a specific low cost-effectiveness threshold. The median time between the DRDs receiving marketing approval and a completed price negotiation was 663 days. Negotiations for DRDs completed after 2017 generally had fewer listings in government drug plans, but there was no distinct trend. The drug's price likely played a role in listing decisions. When DRDs were listed, drug plans had access criteria consistent with CADTH's or stronger for all the DRDs.

CONCLUSIONS: The governments who own, fund and manage CADTH and the pCPA benefit from their alignment. The alignment is less beneficial for patients waiting for access to the DRDs. The time taken by CADTH and pCPA actions and individual government drug plans to make listing decisions delays access. CADTH's clinical criteria have become more extensive and are applied rigorously by drug plans which restricts patient access to DRDs. Canadians with rare disorders urgently need their governments to implement a long-overdue, comprehensive rare disease strategy to ensure DRDs are reviewed and reimbursed quickly and equitably to provide adequate health care to all who need them.

PMID:35698235 | DOI:10.1186/s13023-022-02390-x

Orphanet J Rare Dis. 2022 Jun 13;17(1):222. doi: 10.1186/s13023-022-02373-y.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) has a vast and heterogeneous mutational spectrum in Europe. This variability has also been described in Spain, and there are numerous studies linking CFTR variants with the symptoms of the disease. Most of the studies analysed determinate clinical manifestations or specific sequence variants in patients from clinical units. Others used registry data without addressing the genotype-phenotype relationship. Therefore, the objective of this study is to describe the genetic and clinical characteristics of people with CF and to analyse the relationship between both using data from the rare disease registry of a region in southeastern Spain.

METHODS: A cross-sectional study was carried out in people with a confirmed diagnosis of CF registered in the Rare Diseases Information System (SIER) of the Region of Murcia (Spain). The patients were classified into two genotypes according to the functional consequence that the genetic variants had on the CFTR protein.

RESULTS: There were 192 people diagnosed with CF reported in the Region of Murcia as of 31 December 2018. Seventy-six genotypes and 49 different variants were described, with c.1521_1523delCTT (p. Phe508del) being the most common in 58.3% of the CF patients and 37.0% of the alleles. In addition, 67% of the patients were classified as a high-risk genotype, which was associated with a lower percentage of FEV1 (OR: 5.3; 95% CI: 1.2, 24.4), an increased risk of colonization by Pseudomonas aeruginosa (OR: 7.5; 95% CI: 1.7, 33.0) and the presence of pancreatic insufficiency (OR: 28.1; 95% CI: 9.3, 84.4) compared to those with a low-risk genotype.

CONCLUSIONS: This is the first study in Spain that describes the mutational spectrum and its association with clinical manifestations in patients with CF using data from a rare disease registry. The results obtained allow planning for the health resources needed by people with this disease, thus contributing to the development of personalized medicine that helps to optimize health care in CF patients.

PMID:35698092 | DOI:10.1186/s13023-022-02373-y

J Coll Physicians Surg Pak. 2022 Jun;32(6):817-819. doi: 10.29271/jcpsp.2022.06.817.

ABSTRACT

Berardinelli-Seip Congenital Lipodystrophy (BSCL), also known as congenital generalised lipodystrophy, is a genetic disorder where there is an absolute deficiency of adipose tissue. It affects the development of adipocytes and ultimately leads to an inability to store fat in adipocytes. It is extremely rare. Most of the cases reported are from Africa and North America. Only a handful of cases have been reported in the world. The aim of this case report is to highlight the significance of this rare metabolic disorder, which should be considered whilst managing young patients with severe insulin resistance. We present a case of a young Asian child with an increasing need for insulin for his diabetes. He was previously managed on the lines of type 1 diabetes mellitus and his insulin requirements kept on increasing. Diagnosis on the basis of genetic studies was not possible due to the non-availability of the test in Pakistan. BSCL is an infrequent condition leading to several cardiometabolic complications. Timely diagnosis can lead to better management and prevention of complications. Keywords: Insulin resistance, Lipodystrophy, Acanthosis nigricans, Hypertriglyceridemia, Genetic disease.

PMID:35686420 | DOI:10.29271/jcpsp.2022.06.817

Int J Environ Res Public Health. 2022 May 26;19(11):6456. doi: 10.3390/ijerph19116456.

ABSTRACT

Many people living with rare disease (RD) report a difficult diagnostic process from the symptom onset until they obtain the definitive diagnosis. The aim of this study was thus to ascertain the diagnostic process in RDs, and explore the determinants related with having to wait for more than one year in this process (defined as "diagnostic delay"). We conducted a case-control study, using a purpose-designed form from the Spanish Rare Diseases Patient Registry for data-collection purposes. A descriptive analysis was performed and multivariate backward logistic regression models fitted. Based on data on 1216 patients living with RDs, we identified a series of determinants associated with experiencing diagnostic delay. These included: having to travel to see a specialist other than that usually consulted in the patient's home province (OR 2.1; 95%CI 1.6-2.9); visiting more than 10 specialists (OR 2.6; 95%CI 1.7-4.0); being diagnosed in a region other than that of the patient's residence at the date of symptom onset (OR 2.3; 95%CI 1.5-3.6); suffering from a RD of the nervous system (OR 1.4; 95%CI 1.0-1.8). In terms of time taken to see a specialist, waiting more than 6 months to be referred from the first medical visit was the period of time which most contributed to diagnostic delay (PAR 30.2%). In conclusion, this is the first paper to use a collaborative study based on a nationwide registry to address the diagnostic process of patients living with RDs. While the evidence shows that the diagnostic process experienced by these persons is complex, more studies are needed to determine the implications that this has for their lives and those of their families at a social, educational, occupational, psychological, and financial level.

PMID:35682039 | PMC:PMC9180264 | DOI:10.3390/ijerph19116456

Nat Commun. 2022 Jun 10;13(1):3243. doi: 10.1038/s41467-022-30968-3.

ABSTRACT

Cerebral organoids can be used to gain insights into cell type specific processes perturbed by genetic variants associated with neuropsychiatric disorders. However, robust and scalable phenotyping of organoids remains challenging. Here, we perform RNA sequencing on 71 samples comprising 1,420 cerebral organoids from 25 donors, and describe a framework (Orgo-Seq) to integrate bulk RNA and single-cell RNA sequence data. We apply Orgo-Seq to 16p11.2 deletions and 15q11-13 duplications, two loci associated with autism spectrum disorder, to identify immature neurons and intermediate progenitor cells as critical cell types for 16p11.2 deletions. We further applied Orgo-Seq to identify cell type-specific driver genes. Our work presents a quantitative phenotyping framework to integrate multi-transcriptomic datasets for the identification of cell types and cell type-specific co-expressed driver genes associated with neuropsychiatric disorders.

PMID:35688811 | DOI:10.1038/s41467-022-30968-3

Clin Transl Med. 2022 Jun;12(6):e922. doi: 10.1002/ctm2.922.

NO ABSTRACT

PMID:35678127 | DOI:10.1002/ctm2.922

Adv Ther. 2022 Jul;39(7):3361-3377. doi: 10.1007/s12325-022-02186-2. Epub 2022 Jun 8.

ABSTRACT

INTRODUCTION: Determining the epidemiology of disease is critical for multiple reasons, including to perform risk assessment, compare disease rates in varying populations, support diagnostic decisions, evaluate health care needs and disease burden, and determine the economic benefit of treatment. However, establishing epidemiological measures for rare diseases can be difficult owing to small patient populations, variable diagnostic techniques, and potential disease and diagnostic heterogeneity. To determine the epidemiology of rare diseases, investigators often develop estimation models to account for missing or unobtainable data, and to ensure that their findings are representative of their desired patient population.

METHODS: A modeling methodology to estimate the prevalence of rare diseases in one such population-patients with long-chain fatty acid oxidation disorders (LC-FAOD)-as an illustrative example of its applicability.

RESULTS: The proposed model begins with reliable source data from newborn screening reports and applies to them key modifiers. These modifiers include changes in population growth over time and variable standardization rates of LC-FAOD screening that lead to (1) a confirmed diagnosis and (2) improvements in standards of care and survival estimates relative to the general population. The model also makes necessary assumptions to allow the broad applicability of the estimation of LC-FAOD prevalence, including rates of diagnosed versus undiagnosed patients in the USA over time.

CONCLUSIONS: Although each rare disease is unique, the approach described here and demonstrated in the estimation of LC-FAOD prevalence provides the necessary tools to calculate key epidemiological estimates useful in performing risk assessment analyses; comparing disease rates between different subgroups of people; supporting diagnostic decisions; planning health care needs; comparing disease burden, including cost; and determining the economic benefit of treatment.

PMID:35674971 | PMC:PMC9239941 | DOI:10.1007/s12325-022-02186-2

Radiologia (Engl Ed). 2022 May-Jun;64(3):274-276. doi: 10.1016/j.rxeng.2021.04.002.

NO ABSTRACT

PMID:35676060 | DOI:10.1016/j.rxeng.2021.04.002

Stud Health Technol Inform. 2022 Jun 6;290:56-60. doi: 10.3233/SHTI220031.

ABSTRACT

Primary Immunodeficiencies (PIDs) are associated with more than 400 rare monogenic diseases affecting various biological functions (e.g., development, regulation of the immune response) with a heterogeneous clinical expression (from no symptom to severe manifestations). To better understand PIDs, the ATRACTion project aims to perform a multi-omics analysis of PIDs cases versus a control group patients, including single-cell transcriptomics, epigenetics, proteomics, metabolomics, metagenomics and lipidomics. In this study, our goal is to develop a common data model integrating clinical and omics data, which can be used to obtain standardized information necessary for characterization of PIDs patients and for further systematic analysis. For that purpose, we extend the OMOP Common Data Model (CDM) and propose a multi-omics ATRACTion OMOP-CDM to integrate multi-omics data. This model, available for the community, is customizable for other types of rare diseases (https://framagit.org/imagine-plateforme-bdd/pub-rhu4-atraction).

PMID:35672970 | DOI:10.3233/SHTI220031

Curr Opin Anaesthesiol. 2022 Jun 1;35(3):419-424. doi: 10.1097/ACO.0000000000001136.

ABSTRACT

PURPOSE OF REVIEW: Despite a very low individual prevalence, rare or orphan diseases are estimated to collectively affect as much as 6-8% of the general population. These diseases provide a challenge to anesthetic delivery because of the lack of evidence to guide optimal management.

RECENT FINDINGS: The expansion of information technology has made facts about individual orphan diseases easier to find. Several reputable websites, hosted variously by anesthetic societies, rare disease organizations, and government agencies, provide information about rare diseases and anesthetic management.

SUMMARY: Improved access to resources of knowledge may allow for more informed anesthetic management of orphan diseases. The combination of a thorough review of existing knowledge about individual diseases and a structured anesthetic assessment may assist in the delivery of well tolerated anesthetic care of rare conditions.

PMID:35671032 | DOI:10.1097/ACO.0000000000001136

Dermatol Online J. 2022 Mar 15;28(2). doi: 10.5070/D328257400.

ABSTRACT

Acroangiodermatitis (AAD)[KL1] is a rare vasoproliferative disorder often involving the extremities that has been classified into two variants. Mali-type AAD is more common and associated with chronic venous stasis. Stewart-Bluefarb syndrome[KL2], the other variant, is associated with underlying arteriovenous abnormalities. Mali-type AAD is a relatively benign diagnosis but it may mimic more harmful etiologies such as Kaposi sarcoma both clinically and histologically. A 67-year-old woman with a history of varicose veins, deep vein thrombosis, stroke, and obesity presented to our outpatient clinic with verrucous red-brown papules and plaques on her right lower extremity worsening for three years. Biopsy was consistent with a diagnosis of Mali-type AAD. Providers should be aware of AAD and its variants to accurately differentiate it from more harmful entities.

PMID:35670687 | DOI:10.5070/D328257400

Ital J Pediatr. 2022 Jun 3;48(1):82. doi: 10.1186/s13052-022-01274-x.

ABSTRACT

BACKGROUND: Ophthalmoplegic migraine, renamed "Recurrent Painful Ophthalmoplegic Neuropathy" (RPON) in 2013 by the International Headache Society is a rare neurologic disorder characterized by recurrent attacks of ophthalmoplegia associated to ipsilateral headache. The etiology is still unknown. Typical magnetic resonance imaging findings show a focal nerve thickening and contrast enhancement. In the majority of cases, there is a full recovery within days or weeks. There is no evidence supporting a specific treatment. The review defines the characteristics of the recurrent painful ophthalmoplegic neuropathy in patients within 2 years of age underlying the importance of the role of magnetic resonance imaging even in presence of the first attack. Thus, an emblematic case report is presented.

CASE PRESENTATION: The authors present a case of third cranial nerve paresis in a 17-month-old male child, presenting a neuroradiological pattern highly suggestive of schwannoma, aneurism or recurrent painful ophthalmoplegic neuropathy. Thus, a review of the literature with the pediatric casuistry of recurrent painful ophthalmoplegic neuropathy occurred within 2 years of age focusing on diagnostic considerations is presented. The authors highlight the importance to consider recurrent painful ophthalmoplegic neuropathy in presence of magnetic resonance imaging findings and clinical symptoms referable to aneurysm or schwannoma. Thus, the review defines the characteristics and the neuroradiological findings at the first RPON attack occurred under 2 years of age.

CONCLUSION: Although two attacks are necessary, the review strongly suggests to consider recurrent painful ophthalmoplegic neuropathy even at the first attack, in presence of described characteristics and the aforementioned magnetic resonance imaging findings.

PMID:35659705 | PMC:PMC9164546 | DOI:10.1186/s13052-022-01274-x

Sci Rep. 2022 Jun 4;12(1):9325. doi: 10.1038/s41598-022-13364-1.

ABSTRACT

CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental condition characterized primarily by seizures and impairment of cognitive and motor skills. Additional phenotypes include microcephaly, dysmorphic facial features, and scoliosis. Mutations in cyclin-dependent kinase-like 5 (CDKL5) gene, encoding a kinase essential for normal brain development and function, are responsible for CDD. Zebrafish is an accepted biomedical model for the study of several genetic diseases and has many advantages over other models. Therefore, this work aimed to characterize the phenotypic, behavioral, and molecular consequences of the Cdkl5 protein disruption in a cdkl5 mutant zebrafish line (sa21938). cdkl5sa21938 mutants displayed a reduced head size, suggesting microcephaly, a feature frequently observed in CDD individuals. Double staining revealed shorter craniofacial cartilage structures and decrease bone mineralization in cdkl5 homozygous zebrafish indicating an abnormal craniofacial cartilage development and impaired skeletal development. Motor behavior analysis showed that cdkl5sa21938 embryos had less frequency of double coiling suggesting impaired glutamatergic neurotransmission. Locomotor behavior analysis revealed that homozygous embryos swim shorter distances, indicative of impaired motor activity which is one of the main traits of CCD. Although no apparent spontaneous seizures were observed in these models, upon treatment with pentylenetetrazole, seizure behavior and an increase in the distance travelled were observed. Quantitative PCR showed that neuronal markers, including glutamatergic genes were dysregulated in cdkl5sa21938 mutant embryos. In conclusion, homozygous cdkl5sa21938 zebrafish mimic several characteristics of CDD, thus validating them as a suitable animal model to better understand the physiopathology of this disorder.

PMID:35665761 | DOI:10.1038/s41598-022-13364-1

J Am Heart Assoc. 2022 Jun 6:e024931. doi: 10.1161/JAHA.121.024931. Online ahead of print.

ABSTRACT

Background Idiopathic recurrent pericarditis (IRP) is an orphan disease that carries significant morbidity, partly driven by corticosteroid dependence. Innate immune modulators, colchicine and anti-interleukin-1 agents, pioneered in monogenic autoinflammatory diseases, have demonstrated remarkable efficacy in trials, suggesting that autoinflammation may contribute to IRP. This study characterizes the phenotype of patients with IRP and monogenic autoinflammatory diseases, and establishes whether autoinflammatory disease genes are associated with IRP. Methods and Results We retrospectively analyzed the medical records of patients with IRP (n=136) and monogenic autoinflammatory diseases (n=1910) attending a national center (London, UK) between 2000 and 2021. We examined 4 genes (MEFV, MVK, NLRP3, TNFRSF1A) by next-generation sequencing in 128 patients with IRP and compared the frequency of rare deleterious variants to controls obtained from the Genome Aggregation Database. In this cohort of patients with IRP, corticosteroid dependence was common (39/136, 28.7%) and was associated with chronic pain (adjusted odds ratio 2.8 [95% CI, 1.3-6.5], P=0.012). IRP frequently manifested with systemic inflammation (raised C-reactive protein [121/136, 89.0%] and extrapericardial effusions [68/136, 50.0%]). Pericarditis was observed in all examined monogenic autoinflammatory diseases (0.4%-3.7% of cases). Rare deleterious MEFV variants were more frequent in IRP than in ancestry-matched controls (allele frequency 9/200 versus 2932/129 200, P=0.040). Conclusions Pericarditis is a feature of interleukin-1 driven monogenic autoinflammatory diseases and IRP is associated with variants in MEFV, a gene involved in interleukin-1β processing. We also found that corticosteroid dependence in IRP is associated with chronic noninflammatory pain. Together these data implicate autoinflammation in IRP and support reducing reliance on corticosteroids in its management.

PMID:35658515 | DOI:10.1161/JAHA.121.024931

Front Immunol. 2022 May 17;13:899073. doi: 10.3389/fimmu.2022.899073. eCollection 2022.

ABSTRACT

Castleman disease (CD) is a rare lymphoproliferative disorder. The mechanistic target of rapamycin (mTOR) pathway is a key regulator of various cellular functions, which may be related with the potential mechanisms of CD occurrence. We retrospectively collected the clinical information of 60 CD patients diagnosed in the First Affiliated Hospital of Zhengzhou University. And FFPE biopsy specimens were collected from 31 patients (12 unicentric CD patients and 19 multicentric CD patients) to detect the mTOR pathway protein expression. We are the first to demonstrate that thrombocytopenia and hypoalbuminemia are independent poor prognostic factors for CD. Moreover, mTOR activation was higher in CD compared to reactive lymphoid hyperplasia (used as a control group). This study offers some elucidation for the management and treatment of CD patients.

PMID:35655778 | PMC:PMC9152317 | DOI:10.3389/fimmu.2022.899073

PLoS Genet. 2022 Jun 2;18(6):e1010228. doi: 10.1371/journal.pgen.1010228. eCollection 2022 Jun.

ABSTRACT

NGLY1 deficiency, a rare disease with no effective treatment, is caused by autosomal recessive, loss-of-function mutations in the N-glycanase 1 (NGLY1) gene and is characterized by global developmental delay, hypotonia, alacrima, and seizures. We used a Drosophila model of NGLY1 deficiency to conduct an in vivo, unbiased, small molecule, repurposing screen of FDA-approved drugs to identify therapeutic compounds. Seventeen molecules partially rescued lethality in a patient-specific NGLY1 deficiency model, including multiple serotonin and dopamine modulators. Exclusive dNGLY1 expression in serotonin and dopamine neurons, in an otherwise dNGLY1 deficient fly, was sufficient to partially rescue lethality. Further, genetic modifier and transcriptomic data supports the importance of serotonin signaling in NGLY1 deficiency. Connectivity Map analysis identified glycogen synthase kinase 3 (GSK3) inhibition as a potential therapeutic mechanism for NGLY1 deficiency, which we experimentally validated with TWS119, lithium, and GSK3 knockdown. Strikingly, GSK3 inhibitors and a serotonin modulator rescued size defects in dNGLY1 deficient larvae upon proteasome inhibition, suggesting that these compounds act through NRF1, a transcription factor that is regulated by NGLY1 and regulates proteasome expression. This study reveals the importance of the serotonin pathway in NGLY1 deficiency, and serotonin modulators or GSK3 inhibitors may be effective therapeutics for this rare disease.

PMID:35653343 | PMC:PMC9162339 | DOI:10.1371/journal.pgen.1010228