Probl Endokrinol (Mosk). 2020 Oct 24;66(5):70-78. doi: 10.14341/probl12654.

ABSTRACT

BACKGROUND: Children with congenital hyperinsulinism (CHI), a severe orphan disease, are still one of the most demanding patients in the endocrinology practice. The use of first- and second-line drugs is not always effective and has a number of restrictions. Lanreotide - long-acting somatostatin - represents an alternative insulinostatic therapy. The main advantage of lanreotide is stable concentration of the drug in the blood that enables minimizing the number of injections. However, the experience of using lanreotide in the treatment of CHI is limited to small groups of patients. There is also a problem of the absence of a standardized regimen in clinical practice; and the calculator for evaluating the initial effective drug dose is needed.AIM of the study is to evaluate the effectiveness and safety of lanreotide therapy in the treatment of CHI in children.

MATERIALS AND METHODS: An open single-center observational study was conducted on the basis of Endocrinology Research Centre. The study included diazoxide-unresponsive pediatric patients with CHI who were initially treated with octreotide in different modes: multiple daily subcutaneous injections or continuous subcutaneous infusion via pumps. The indicators of the effectiveness and safety of the lanreotide therapy were evaluated shortly after the first injection and lately on a regular visit after further injections.

RESULTS: The study group included 12 patients. Persistent euglycaemia was achieved in 67% of the subjects (8/12). Complete effectiveness of the therapy was observed in 8/12 patients (67%), partial - in 3/12 (25%), and lack of effectiveness - in 1/12 of the patient (8%). The age of the patients at the time of lanreotide administration was 6 months (5; 15). According to the study, the most effective dose of lanreotide is 3.5-5.5 mg/ kg/ month. There were no significant side effects observed.

CONCLUSIONS: The use of lanreotide in patients with diazoxide-resistant congenital hyperinsulinism was effective and safe in the vast majority of the patients. Moreover, we were able to calculate the effective dosage of lanreotide in CHI patients which fulfilled the clinical demand.

PMID:33369374 | DOI:10.14341/probl12654

The impact of COVID-19 on rare metabolic patients and healthcare providers: results from two MetabERN surveys.

Orphanet J Rare Dis. 2020 12 03;15(1):341

Authors: Lampe C, Dionisi-Vici C, Bellettato CM, Paneghetti L, van Lingen C, Bond S, Brown C, Finglas A, Francisco R, Sestini S, Heard JM, Scarpa M, MetabERN collaboration group

Abstract
The ongoing coronavirus disease 2019 (COVID-19) pandemic has caused disruption in all aspects of daily life, including the management and treatment of rare inherited metabolic disorders (IMDs). To perform a preliminary assessment of the incidence of COVID-19 in IMD patients and the impact of the coronavirus emergency on the rare metabolic community between March and April 2020, the European Reference Network for Hereditary Metabolic Diseases (MetabERN) has performed two surveys: one directed to patients' organizations (PO) and one directed to healthcare providers (HCPs). The COVID-19 incidence in the population of rare metabolic patients was lower than that of the general European population (72.9 × 100,000 vs. 117 × 100,000). However, patients experienced extensive disruption of care, with the majority of appointments and treatments cancelled, reduced, or postponed. Almost all HCPs (90%) were able to substitute face-to-face visits with telemedicine, about half of patients facing treatment changes switched from hospital to home therapy, and a quarter reported difficulties in getting their medicines. During the first weeks of emergency, when patients and families lacked relevant information, most HCPs contacted their patients to provide them with support and information. Since IMD patients require constant follow-up and treatment adjustments to control their disease and avoid degradation of their condition, the results of our surveys are relevant for national health systems in order to ensure appropriate care for IMD patients. They highlight strong links in an interconnected community of HCPs and PO, who are able to work quickly and effectively together to support and protect fragile persons during crisis. However, additional studies are needed to better appreciate the actual impact of COVID-19 on IMD patients' health and the mid- and long-term effects of the pandemic on their wellbeing.

PMID: 33272301 [PubMed - indexed for MEDLINE]

The Undiagnosed Diseases Network International: Five years and more!

Mol Genet Metab. 2020 04;129(4):243-254

Authors: Taruscio D, Baynam G, Cederroth H, Groft SC, Klee EW, Kosaki K, Lasko P, Melegh B, Riess O, Salvatore M, Gahl WA

Abstract
Undiagnosed rare diseases (URDs) account for a significant portion of the overall rare disease burden, depending upon the country. Hence, URDs represent an unmet medical need. A specific challenge posed by the ensemble of the URD patient cohort is the heterogeneity of its composition; the group, indeed, includes very rare, still unidentified conditions as well as clinical variants of recognized rare diseases. Exact disease recognition requires new approaches that cut across national and institutional boundaries, may need the implementation of methods new to diagnostics, and embrace clinical care and research. To address these issues, the Undiagnosed Diseases Network International (UDNI) was established in 2014, with the major aims of providing diagnoses to patients, implementing additional diagnostic tools, and fostering research on novel diseases, their mechanisms, and their pathways. The UDNI involves centres with internationally recognized expertise, and its scientific resources and know-how aim to fill the knowledge gaps that impede diagnosis, in particularly for ultra-rare diseases. Consequently, the UDNI fosters the translation of research into medical practice, aided by active patient involvement. The goals of the UDNI are to work collaboratively and at an international scale to: 1) provide diagnoses for individuals who have conditions that have eluded diagnosis by clinical experts; 2) gain insights into the etiology and pathogenesis of novel diseases; 3) contribute to standards of diagnosing unsolved patients; and 4) share the results of UDNI research in a timely manner and as broadly as possible.

PMID: 32033911 [PubMed - indexed for MEDLINE]

8 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2020/12/22

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Deprivation and prognosis in patients with pulmonary arterial hypertension: missing the effect of deprivation on a rare disease?

Eur Respir J. 2020 08;56(2):

Authors: Sofianopoulou E, Church C, Coghlan G, Howard L, Johnson M, Kiely DG, Lawrie A, Lordan J, Wilkins MR, Wort SJ, Morrell NW, Toshner MR

PMID: 32299862 [PubMed - indexed for MEDLINE]

The Path to and Impact of Disease Recognition with AI.

IEEE Pulse. 2020 Jan-Feb;11(1):13-16

Authors: Gurovich Y

Abstract
The Process of rare disease identification by clinical geneticists is closely associated with the ability to correlate the phenotype of a patient with the relevant genetic syndromes. In order to perform this correlation, the phenotype has to be described in a canonical form or language. One such language is the human phenotype ontology, which defines the human phenotypes in a hierarchical form and facilitates the association between specific phenotypes and diseases. With such a structure, clinicians are able to evaluate the specific phenotypic features during the clinical evaluation process and then correlate those phenotypes to relevant diseases.

PMID: 32175846 [PubMed - indexed for MEDLINE]

Inheritance of mitochondrial DNA in humans: implications for rare and common diseases.

J Intern Med. 2020 06;287(6):634-644

Authors: Wei W, Chinnery PF

Abstract
The first draft human mitochondrial DNA (mtDNA) sequence was published in 1981, paving the way for two decades of discovery linking mtDNA variation with human disease. Severe pathogenic mutations cause sporadic and inherited rare disorders that often involve the nervous system. However, some mutations cause mild organ-specific phenotypes that have a reduced clinical penetrance, and polymorphic variation of mtDNA is associated with an altered risk of developing several late-onset common human diseases including Parkinson's disease. mtDNA mutations also accumulate during human life and are enriched in affected organs in a number of age-related diseases. Thus, mtDNA contributes to a wide range of human pathologies. For many decades, it has generally been accepted that mtDNA is inherited exclusively down the maternal line in humans. Although recent evidence has challenged this dogma, whole-genome sequencing has identified nuclear-encoded mitochondrial sequences (NUMTs) that can give the false impression of paternally inherited mtDNA. This provides a more likely explanation for recent reports of 'bi-parental inheritance', where the paternal alleles are actually transmitted through the nuclear genome. The presence of both mutated and wild-type variant alleles within the same individual (heteroplasmy) and rapid shifts in allele frequency can lead to offspring with variable severity of disease. In addition, there is emerging evidence that selection can act for and against specific mtDNA variants within the developing germ line, and possibly within developing tissues. Thus, understanding how mtDNA is inherited has far-reaching implications across medicine. There is emerging evidence that this highly dynamic system is amenable to therapeutic manipulation, raising the possibility that we can harness new understanding to prevent and treat rare and common human diseases where mtDNA mutations play a key role.

PMID: 32187761 [PubMed - indexed for MEDLINE]

Comment on "Market Exclusivity for Drugs with Multiple Orphan Approvals (1983-2017) and Associated Budget Impact in the US".

Pharmacoeconomics. 2020 12;38(12):1373-1374

Authors: Manning R

PMID: 33164138 [PubMed - indexed for MEDLINE]

Reply to Comment on "Market Exclusivity for Drugs with Multiple Orphan Approvals (1983-2017) and Associated Budget Impact in the US".

Pharmacoeconomics. 2020 12;38(12):1375-1376

Authors: Padula WV, Parasrampuria S, Socal MP, Conti RM, Anderson GF

PMID: 33164137 [PubMed - indexed for MEDLINE]

Glanzmann's thrombasthenia: a rare bleeding disorder in a Nigerian girl.

Afr Health Sci. 2020 Jun;20(2):753-757

Authors: Ezenwosu OU, Chukwu BF, Uwaezuoke NA, Ezenwosu IL, Ikefuna AN, Emodi IJ

Abstract
Introduction: Glanzmann's Thrombasthenia (GT) is a rare autosomal recessive bleeding disorder due to defective platelet membrane glycoprotein GP IIb/IIIa (integrin αIIbβ3). The prevalence is estimated at 1:1,000,000 and it is commonly seen in areas where consanguinity is high.
Case Presentation: The authors report a 12 year old Nigerian girl of Igbo ethnic group, born of non-consanguineous parents, who presented with prolonged heavy menstrual bleeding which started at menarche 3 months earlier, weakness and dizziness. She had a past history of recurrent episodes of prolonged epistaxis, gastrointestinal bleeding and gum bleeding during early childhood. On examination, she was severely pale with a haemic murmur and vaginal bleeding. The initial diagnosis was menorrhagia secondary to bleeding diathesis possibly von Willebrand's Disease. She was on supportive treatment with fresh whole blood, fresh frozen plasma and platelets until diagnosis of GT was made in the USA. Currently, she is on 3 monthly intramuscular Depo-provera with remarkable improvement.
Conclusion: To the best of our knowledge, this is the first documented report of GT in our environment where consanguinity is rarely practised. Our health facilities require adequate diagnostic and treatment facilities for rare diseases like GT.

PMID: 33163040 [PubMed - indexed for MEDLINE]

[Use of targeting therapy in Erdheim-Chester disease: A case report with neurologic involvement].

Rev Med Interne. 2020 Jun;41(6):413-417

Authors: Berthe P, Rouzic N, Daelman L, Jacobzone C, Espitia A, Cohen-Aubart F, Haroche J, Émile JF, Lorleac'h A

Abstract
INTRODUCTION: Erdheim-Chester disease (ECD) is a rare multisystemic disease characterised by an infiltration of various organs by CD68+ CD1a- histiocytes. The clinical and radiological presentation is very variable.
CASE REPORT: We report the case of a 71-year-old woman with ECD which was revealed by neurological and cutaneous manifestations. The diagnosis was confirmed by skin biopsy and the BRAFV600E mutation was identified in skin tissue, leading to the use of combined therapy targeting the RAS-RAF-ERK-MEK pathway. This therapy allowed an improvement of cutaneous manifestations but neurological manifestations lead to death, underlying their notable severity.
CONCLUSION: Our case report shows the persistent diagnostic difficulty of the ECD and the particular gravity of neurologic involvement.

PMID: 32113636 [PubMed - indexed for MEDLINE]

Transplantation of a New Biological Product in Rare Diseases, Such as Epidermolysis Bullosa: Response and Clinical Outcome.

Transplant Proc. 2020 Sep;52(7):2239-2243

Authors: Pliszczyński J, Nita M, Kowalewski C, Woźniak K, Eljaszewicz A, Moniuszko M, Kamiński A, Śladowski D, Zimek Z, Majewski S, Kosieradzki M, Fiedor P

Abstract
BACKGROUND: Epidermolysis bullosa (EB) is a phenotypically diverse group of hereditary blistering disorders involving mutations in 20 different genes. Those debilitating disorders are currently incurable; however, there are a number of promising preclinical trials, where some treatments already approach the stage of early clinical trial. In this paper we introduce a novel surgical approach to the treatment of EB-induced ulcerations. The purpose of our study was to evaluate the safety and efficacy of a new biological dressing in the form of an allogenic human skin equivalent graft before using multipotent stem cells, classified as an advanced therapy medicinal product.
METHODS: Implanted human acellular dermal matrices were prepared from the superficial layers of donated human skin. Scaffold sterilization was conducted via irradiation with the use of a linear electron accelerator. Following water-knife debridement, wounds were surgically covered with accordingly prepared grafts and dressed in burn-injury fashion. Subsequently, the wounds were monitored for infection and viability.
RESULTS: Our data indicate that grafting as a potential new medicinal product was safe and effective in patients with rare diseases, such as EB, and may be used for stem cells to create new Advanced Therapy Medicinal Products. During a 200-day follow-up, we proved the safety of using human scaffolds (allogeneic graft) by observing no apparent infection or necrosis. Instead, we noted fewer required dressing changes, promoted wound healing, pain reduction, and an overall improvement in the quality of life in patients with EB.
CONCLUSION: The protocol for grafting allogenic acellular epidermal sheets is the most promising treatment for severely affected skin areas in EB patients to date.

PMID: 32334796 [PubMed - indexed for MEDLINE]

Translational genomics for rare cancers: Challenges and opportunity.

Semin Cancer Biol. 2020 04;61:iii-iv

Authors: Tan AC, Huang PH

PMID: 32092353 [PubMed - indexed for MEDLINE]

Thymoma and pure red cell aplasia with hypoplasia of megakaryocytopoiesis: A rare and life-treating condition.

Transfus Apher Sci. 2020 Apr;59(2):102656

Authors: Lo Iacono G, Gigli F, Gherzi L, Avenoso D, Fiori S, Sedda G, Tarella C, Spaggiari L

Abstract
Thymic tumors are rare diseases with an incidence of 0.15 cases per 100,000 person-years. They can be associated with a variety of other syndromes, such as Myasthenia Gravis or autoimmune disorders. Among them, pure red cell aplasia is a hemato-pathological condition characterized by anemia, reticulocytopenia and erythroid cell hypoplasia of bone marrow. Here, we reported a case of a 62-year-old female with a long history of neurologic symptoms due to Myasthenia Gravis. She was diagnosed with thymoma, with mediastinal mass and pleural thickening. After chemoradiotherapy treatment, she was surgically resected successfully, but she developed anemia and severe thrombocytopenia, worsening in respiratory failure requiring intubation. A bone marrow biopsy was performed resulting in a red-cell aplasia with marked hypoplasia of megakaryocytopoiesis compatible with pure red cell aplasia with acquired thrombocytopenia. Considering that there are no standard treatments, clinical condition improvement was achieved only after some lines of medical treatment. Our data, together with the few already published, help to raise the attention towards acquired cytopenias and the need to optimize the treatment for a potentially life-threatening condition.

PMID: 31606335 [PubMed - indexed for MEDLINE]

Statistical genomics in rare cancer.

Semin Cancer Biol. 2020 04;61:1-10

Authors: Abbas-Aghababazadeh F, Mo Q, Fridley BL

Abstract
Rare cancers make of more than 20% of cancer cases. Due to the rare nature, less research has been conducted on rare cancers resulting in worse outcomes for patients with rare cancers compared to common cancers. The ability to study rare cancers is impaired by the ability to collect a large enough set of patients to complete an adequately powered genomic study. In this manuscript we outline analytical approaches and public genomic datasets that have been used in genomic studies of rare cancers. These statistical analysis approaches and study designs include: gene set / pathway analyses, pedigree and consortium studies, meta-analysis or horizontal integration, and integration of multiple types of genomic information or vertical integration. We also discuss some of the publicly available resources that can be leveraged in rare cancer genomic studies.

PMID: 31437624 [PubMed - indexed for MEDLINE]

26 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2020/12/15

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

26 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2020/12/15

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

The polymicrogyria-associated GPR56 promoter preferentially drives gene expression in developing GABAergic neurons in common marmosets.

Sci Rep. 2020 Dec 09;10(1):21516

Authors: Murayama AY, Kuwako KI, Okahara J, Bae BI, Okuno M, Mashiko H, Shimogori T, Walsh CA, Sasaki E, Okano H

Abstract
GPR56, a member of the adhesion G protein-coupled receptor family, is abundantly expressed in cells of the developing cerebral cortex, including neural progenitor cells and developing neurons. The human GPR56 gene has multiple presumptive promoters that drive the expression of the GPR56 protein in distinct patterns. Similar to coding mutations of the human GPR56 gene that may cause GPR56 dysfunction, a 15-bp homozygous deletion in the cis-regulatory element upstream of the noncoding exon 1 of GPR56 (e1m) leads to the cerebral cortex malformation and epilepsy. To clarify the expression profile of the e1m promoter-driven GPR56 in primate brain, we generated a transgenic marmoset line in which EGFP is expressed under the control of the human minimal e1m promoter. In contrast to the endogenous GPR56 protein, which is highly enriched in the ventricular zone of the cerebral cortex, EGFP is mostly expressed in developing neurons in the transgenic fetal brain. Furthermore, EGFP is predominantly expressed in GABAergic neurons, whereas the total GPR56 protein is evenly expressed in both GABAergic and glutamatergic neurons, suggesting the GABAergic neuron-preferential activity of the minimal e1m promoter. These results indicate a possible pathogenic role for GABAergic neuron in the cerebral cortex of patients with GPR56 mutations.

PMID: 33299078 [PubMed - in process]

FDA oversight of NSIGHT genomic research: the need for an integrated systems approach to regulation.

NPJ Genom Med. 2019 Dec 10;4(1):32

Authors: Milko LV, Chen F, Chan K, Brower AM, Agrawal PB, Beggs AH, Berg JS, Brenner SE, Holm IA, Koenig BA, Parad RB, Powell CM, Kingsmore SF

Abstract
The National Institutes of Health (NIH) funded the Newborn Sequencing In Genomic medicine and public HealTh (NSIGHT) Consortium to investigate the implications, challenges, and opportunities associated with the possible use of genomic sequence information in the newborn period. Following announcement of the NSIGHT awardees in 2013, the Food and Drug Administration (FDA) contacted investigators and requested that pre-submissions to investigational device exemptions (IDE) be submitted for the use of genomic sequencing under Title 21 of the Code of Federal Regulations (21 CFR) part 812. IDE regulation permits clinical investigation of medical devices that have not been approved by the FDA. To our knowledge, this marked the first time the FDA determined that NIH-funded clinical genomic research projects are subject to IDE regulation. Here, we review the history of and rationale behind FDA oversight of clinical research and the NSIGHT Consortium's experiences in navigating the IDE process. Overall, NSIGHT investigators found that FDA's application of existing IDE regulations and medical device definitions aligned imprecisely with the aims of publicly funded exploratory clinical research protocols. IDE risk assessments by the FDA were similar to, but distinct from, protocol risk assessments conducted by local Institutional Review Boards (IRBs), and had the potential to reflect novel oversight of emerging genomic technologies. However, the pre-IDE and IDE process delayed the start of NSIGHT research studies by an average of 10 months, and significantly limited the scope of investigation in two of the four NIH approved projects. Based on the experience of the NSIGHT Consortium, we conclude that policies and practices governing the development and use of novel genomic technologies in clinical research urgently need clarification in order to mitigate potentially conflicting or redundant oversight by IRBs, NIH, FDA, and state authorities.

PMID: 33293547 [PubMed]

A Novel Variant in the TBC1D24 Lipid-Binding Pocket Causes Autosomal Dominant Hearing Loss: Evidence for a Genotype-Phenotype Correlation.

Front Cell Neurosci. 2020;14:585669

Authors: Parzefall T, Frohne A, Koenighofer M, Neesen J, Laccone F, Eckl-Dorna J, Waters JJ, Schreiner M, Amr SS, Ashton E, Schoefer C, Gstœttner W, Frei K, Lucas T

Abstract
Background: Hereditary hearing loss is a disorder with high genetic and allelic heterogeneity. Diagnostic screening of candidate genes commonly yields novel variants of unknown clinical significance. TBC1D24 is a pleiotropic gene associated with recessive DOORS syndrome, epileptic encephalopathy, myoclonic epilepsy, and both recessive and dominant hearing impairment. Genotype-phenotype correlations have not been established to date but could facilitate diagnostic variant assessment and elucidation of pathomechanisms. Methods and Results: Whole-exome and gene panel screening identified a novel (c.919A>C; p.Asn307His) causative variant in TBC1D24 in two unrelated Caucasian families with Autosomal dominant (AD) nonsyndromic late-onset hearing loss. Protein modeling on the Drosophila TBC1D24 ortholog Skywalker crystal structure showed close interhelix proximity (6.8Å) between the highly conserved residue p.Asn307 in α18 and the position of the single known pathogenic dominant variation (p.Ser178Leu) in α11 that causes a form of deafness with similar clinical characteristics. Conclusion: Genetic variants affecting two polar hydrophilic residues in neighboring helices of TBC1D24 cause AD nonsyndromic late-onset hearing loss. The spatial proximity of the affected residues suggests the first genotype-phenotype association in TBC1D24-related disorders. Three conserved residues in α18 contribute to the formation of a functionally relevant cationic phosphoinositide binding pocket that regulates synaptic vesicle trafficking which may be involved in the molecular mechanism of disease.

PMID: 33281559 [PubMed]