A father's fight to help his sons - and fix clinical trials.

Nature. 2019 01;565(7738):148-151

Authors: Adam D

Abstract

PMID: 30626961 [PubMed - indexed for MEDLINE]

A Rare Cause of Uveitis: Vemurafenib

Turk J Ophthalmol. 2018 12 27;48(6):323-325

Authors: Sızmaz S, Görkemli N, Esen E, Demircan N

Abstract
A 25-year-old female presented with a decrease of vision and redness in both eyes. She had a history of nodular melanoma in her right shoulder, which was excised surgically and she was under oral vemurafenib treatment. She was diagnosed with moderately severe bilateral panuveitis and hospitalized for systemic investigation and workup. The laboratory test results were unremarkable and systemic workup failed to reveal an etiology. The condition was considered vemurafenib-induced uveitis, as the drug is known to be associated with uveitis. After reevaluation with the oncology department, vemurafenib was stopped and topical and systemic corticosteroid therapy was started. The uveitis resolved and her vision returned to normal. No sign of recurrence was detected at 8-month follow-up.

PMID: 30605942 [PubMed - indexed for MEDLINE]

9 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 2019/06/18

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.

Safety and efficacy of deferiprone for pantothenate kinase-associated neurodegeneration: a randomised, double-blind, controlled trial and an open-label extension study.

Lancet Neurol. 2019 Jul;18(7):631-642

Authors: Klopstock T, Tricta F, Neumayr L, Karin I, Zorzi G, Fradette C, Kmieć T, Büchner B, Steele HE, Horvath R, Chinnery PF, Basu A, Küpper C, Neuhofer C, Kálmán B, Dušek P, Yapici Z, Wilson I, Zhao F, Zibordi F, Nardocci N, Aguilar C, Hayflick SJ, Spino M, Blamire AM, Hogarth P, Vichinsky E

Abstract
BACKGROUND: Pantothenate kinase-associated neurodegeneration (PKAN) is a rare genetic disorder characterised by progressive generalised dystonia and brain iron accumulation. We assessed whether the iron chelator deferiprone can reduce brain iron and slow disease progression.
METHODS: We did an 18-month, randomised, double-blind, placebo-controlled trial (TIRCON2012V1), followed by a pre-planned 18-month, open-label extension study, in patients with PKAN in four hospitals in Germany, Italy, England, and the USA. Patients aged 4 years or older with a genetically confirmed diagnosis of PKAN, a total score of at least 3 points on the Barry-Albright Dystonia (BAD) scale, and no evidence of iron deficiency, neutropenia, or abnormal hepatic or renal function, were randomly allocated (2:1) to receive an oral solution of either deferiprone (30 mg/kg per day divided into two equal doses) or placebo for 18 months. Randomisation was done with a centralised computer random number generator and with stratification based on age group at onset of symptoms. Patients were allocated to groups by a randomisation team not masked for study intervention that was independent of the study. Patients, caregivers, and investigators were masked to treatment allocation. Co-primary endpoints were the change from baseline to month 18 in the total score on the BAD scale (which measures severity of dystonia in eight body regions) and the score at month 18 on the Patient Global Impression of Improvement (PGI-I) scale, which is a patient-reported interpretation of symptom improvement. Efficacy analyses were done on all patients who received at least one dose of the study drug and who provided a baseline and at least one post-baseline efficacy assessment. Safety analyses were done for all patients who received at least one dose of the study drug. Patients who completed the randomised trial were eligible to enrol in a single-arm, open-label extension study of another 18 months, in which all participants received deferiprone with the same regimen as the main study. The trial was registered on ClinicalTrials.gov, number NCT01741532, and EudraCT, number 2012-000845-11.
FINDINGS: Following a screening of 100 prospective patients, 88 were randomly assigned to the deferiprone group (n=58) or placebo group (n=30) between Dec 13, 2012, and April 21, 2015. Of these, 76 patients completed the study (49 in the deferiprone group and 27 in the placebo group). After 18 months, the BAD score worsened by a mean of 2·48 points (SE 0·63) in patients in the deferiprone group versus 3·99 points (0·82) for patients in the control group (difference -1·51 points, 95% CI -3·19 to 0·16, p=0·076). No subjective change was detected as assessed by the PGI-I scale: mean scores at month 18 were 4·6 points (SE 0·3) for patients in the deferiprone group versus 4·7 points (0·4) for those in the placebo group (p=0·728). In the extension study, patients continuing deferiprone retained a similar rate of disease progression as assessed by the BAD scale (1·9 points [0·5] in the first 18 months vs 1·4 points [0·4] in the second 18 months, p=0·268), whereas progression in patients switching from placebo to deferiprone seemed to slow (4·4 points [1·1] vs 1·4 points [0·9], p=0·021). Patients did not detect a change in their condition after the additional 18 months of treatment as assessed by the PGI-I scale, with mean scores of 4·1 points [0·2] in the deferiprone-deferiprone group and of 4·7 points [0·3] in the placebo-deferiprone group. Deferiprone was well tolerated and adverse events were similar between the treatment groups, except for anaemia, which was seen in 12 (21%) of 58 patients in the deferiprone group, but was not seen in any patients in the placebo group. No patient discontinued therapy because of anaemia, and three discontinued because of moderate neutropenia. There was one death in each group of the extension study and both were secondary to aspiration. Neither of these events was considered related to deferiprone use.
INTERPRETATION: Deferiprone was well tolerated, achieved target engagement (lowering of iron in the basal ganglia), and seemed to somewhat slow disease progression at 18 months, although not significantly, as assessed by the BAD scale. These findings were corroborated by the results of an additional 18 months of treatment in the extension study. The subjective PGI-I scale was largely unchanged during both study periods, indicating that might not be an adequate tool for assessment of disease progression in patients with PKAN. Our trial provides the first indication of a decrease in disease progression in patients with neurodegeneration with brain iron accumulation. The extensive information collected and long follow-up of patients in the trial will improve the definition of appropriate endpoints, increase the understanding of the natural history, and thus help to shape the design of future trials in this ultra-orphan disease.
FUNDING: European Commission, US Food and Drug Administration, and ApoPharma Inc.

PMID: 31202468 [PubMed - in process]

Ocular albinism with bilateral ocular coloboma - A rare association.

Indian J Ophthalmol. 2019 Mar;67(3):397-398

Authors: Raval V, Rao S, Das T

Abstract

PMID: 30777963 [PubMed - indexed for MEDLINE]

[Rare diseases with epigenetic background].

Postepy Biochem. 2018 Dec 29;64(4):330-337

Authors: Leśniak W

Abstract
Rare diseases with epigenetic background arise due to dysregulation of factors/processes that control epigenetic modifications of chromatin and miRNA level. They are usually caused by point mutations or chromosomal aberrations, such as deletions, which occur de novo during early embryonic development. They represent a heterogeneous group of multisystem diseases that mostly affect the nervous system and account for intellectual disability, mild to severe, of affected people. Studies on animal models not only provide a better insight into the molecular mechanisms of the observed anomalies and allow us to causally link the initial alteration in the genome with disease symptoms, but also deliver invaluable data that facilitate the design of effective therapies. Patients suffering from these diseases should receive comprehensive medical care, undergo adequate behavioral and/or occupational therapies, and have access to advanced treatment methods. This work provides information on typical symptoms, molecular basis and the current state of knowledge about selected rare diseases with epigenetic background.

PMID: 30656918 [PubMed - indexed for MEDLINE]

25 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 2019/06/14

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.

MANAGEMENT OF ENDOCRINE DISEASE: Unmet therapeutic, educational and scientific needs in parathyroid disorders.

Eur J Endocrinol. 2019 Jun 01;:

Authors: Bollerslev J, Schalin-Jantti C, Rejnmark L, Siggelkow H, Morreau H, Thakker RV, Sitges-Serra A, Cetani F, Marcocci C

Abstract
PARAT, a new European Society of Endocrinology program, aims to identify unmet scientific and educational needs of parathyroid disorders, such as primary hyperparathyroidism (PHPT), including parathyroid cancer (PC), and hypoparathyroidism (HypoPT). The discussions and consensus statements from the first PARAT workshop (September 2018) are reviewed. PHPT has a high prevalence in Western communities, PHPT has a high prevalence in Western communities, yet evidence is sparse concerning the natural history and whether morbidity and long-term outcomes are related to hypercalcemia or plasma PTH concentrations, or both. Cardiovascular mortality and prevalence of low energy fractures are increased, whereas Quality of Life is decreased, although their reversibility by treatment of PHPT has not been convincingly demonstrated. PC is a rare cause of PHPT, with an increasing incidence, and international collaborative studies are required to advance knowledge of the genetic mechanisms, biomarkers for disease activity, and optimal treatments. For example, ~20% of PCs demonstrate high mutational burden, and identifying targetable DNA variations, gene amplifications and gene fusions may facilitate personalized care, such as different forms of immunotherapy or targeted therapy. HypoPT, a designated orphan disease, is associated with a high risk of symptoms and complications. Most cases are secondary to neck surgery. However, there is a need to better understand the relation between disease biomarkers and intellectual function, and to establish the role of PTH in target tissues, as these may facilitate the appropriate use of PTH substitution therapy. Management of parathyroid disorders is challenging, and PARAT has highlighted the need for international transdisciplinary scientific and educational studies in advancing in this field.

PMID: 31176307 [PubMed - as supplied by publisher]

The Importance of Collaboration in Advancing Understanding of Rare Disorders: US/EU Joint Initiative on Silver-Russell Syndrome.

Pediatr Endocrinol Rev. 2017 Nov;15(Suppl 1):98-101

Authors: Salem JB, Netchine I, Harbison MD

Abstract
Patient-support organizations can facilitate a significant change in the way rare disorders are approached. Besides connecting families with each other and directing patients to experienced medical specialists, these groups, by collaborating with government initiatives like COST, can effect the direction and funding of rare disease research. By concentrating the rare disease patient population and funneling them to specific centers of excellence, these organizations help build specialists' experience and their study populations. It requires a basic spirit of collaboration, driven parent leaders, a well-organized support platform, sources of funding, supportive clinical and research professionals and finally an effective method of collecting and disseminating information. Silver-Russell Syndrome is an excellent example of a rare disorder that has become better recognized, understood and treated because patient-support organizations, using the internet as a critical tool, have worked together with clinical care/research specialists and public funding agencies to build collaboration.

PMID: 29292872 [PubMed - indexed for MEDLINE]

10 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 2019/06/07

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.

11 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 2019/06/06

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.

Exonuclease requirements for mammalian ribosomal RNA biogenesis and surveillance.

Nat Struct Mol Biol. 2019 Jun 03;:

Authors: Pirouz M, Munafò M, Ebrahimi AG, Choe J, Gregory RI

Abstract
Ribosomal RNA (rRNA) biogenesis is a multistep process requiring several nuclear and cytoplasmic exonucleases. The exact processing steps for mammalian 5.8S rRNA remain obscure. Here, using loss-of-function approaches in mouse embryonic stem cells (mESCs) and deep sequencing of rRNA intermediates, we investigate the requirements of exonucleases known to be involved in 5.8S maturation at nucleotide resolution and explore the role of the Perlman syndrome-associated 3'-5' exonuclease Dis3l2 in rRNA processing. We uncover a novel cytoplasmic intermediate that we name '7SB' rRNA that is generated through sequential processing by distinct exosome complexes. 7SB rRNA can be oligoadenylated by an unknown enzyme and/or oligouridylated by TUT4/7 and subsequently processed by Dis3l2 and Eri1. Moreover, exosome depletion triggers Dis3l2-mediated decay (DMD) as a surveillance pathway for rRNAs. Our data identify previously unknown 5.8S rRNA processing steps and provide nucleotide-level insight into the exonuclease requirements for mammalian rRNA processing.

PMID: 31160785 [PubMed - as supplied by publisher]

[Review of small bowel disease (non-CD) -tumor, inflammation, and rare disease].

Nihon Shokakibyo Gakkai Zasshi. 2018;115(7):575-586

Authors: Hisamatsu T, Saito D, Hayashida M

PMID: 29998980 [PubMed - indexed for MEDLINE]

Assessment and Characterization of Hyaloid Vessels in Mice.

J Vis Exp. 2019 May 15;(147):

Authors: Wang Z, Liu CH, Huang S, Chen J

Abstract
In the eye, the embryonic hyaloid vessels nourish the developing lens and retina and regress when the retinal vessels develop. Persistent or failed regression of hyaloid vessels can be seen in diseases such as persistent hyperplastic primary vitreous (PHPV), leading to an obstructed light path and impaired visual function. Understanding the mechanisms underlying the hyaloid vessel regression may lead to new molecular insights into the vascular regression process and potential new ways to manage diseases with persistent hyaloid vessels. Here we describe the procedures for imaging hyaloid in live mice with optical coherence tomography (OCT) and fundus fluorescein angiography (FFA) and a detailed technical protocol of isolating and flat-mounting hyaloid ex vivo for quantitative analysis. Low-density lipoprotein receptor-related protein 5 (LRP5) knockout mice were used as an experimental model of persistent hyaloid vessels, to illustrate the techniques. Together, these techniques may facilitate a thorough assessment of hyaloid vessels as an experimental model of vascular regression and studies on the mechanism of persistent hyaloid vessels.

PMID: 31157789 [PubMed - in process]

Preventing gatekeeping delays in the diagnosis of rare diseases.

Br J Gen Pract. 2018 03;68(668):145-146

Authors: de Vries E, Fransen L, van den Aker M, Meijboom BR

PMID: 29472225 [PubMed - indexed for MEDLINE]

6 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 2019/06/03

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.

Transmesenteric hernia: a rare case of acute abdominal pain in children: a case report and review of the literature.

Acta Chir Belg. 2018 Dec;118(6):388-391

Authors: Willems E, Willaert B, Van Slycke S

Abstract
In this report, we discuss the case of an 11-year old girl presenting with acute abdominal pain caused by gangrene of a large part of the small bowel. During urgent surgical exploration, the cause of gangrene appeared to be herniation of the small bowel through a congenital defect in the mesentery with subsequent strangulation. A resection was performed leaving the patient with only 130 cm of small bowel remaining. Transmesenteric hernia is a rare type of internal herniation consisting of a small congenital defect in the small bowel mesentery through which the intestine can herniate and subsequently become strangulated. We present a case of transmesenteric hernia with disastrous effects and review the literature regarding this rare type of hernia.

PMID: 29115904 [PubMed - indexed for MEDLINE]

Hypovolemic shock caused by delayed-onset superior gluteal artery rupture, successfully treated with arteriographic embolization.

Acta Chir Belg. 2018 Dec;118(6):380-383

Authors: Kim Y, Lee W

Abstract
INTRODUCTION: Rupture of the superior gluteal artery (SGA) is usually associated with pelvic bone fractures and acetabular fractures secondary to blunt trauma. However, despite recent advances in technologies and tools, rupture of the SGA remains a challenging problem because it is difficult to manage and is frequently associated with significantly high mortality and morbidity.
PATIENTS AND METHODS: We present a case of an 82-year-old man, who presented to our emergency department after a cultivator turnover accident and who showed stable initial vital signs and manifested only as blunt buttock traumatic contusion without any pelvic bone or acetabular fracture, which resulted in delayed massive bleeding from the SGA on eight days after trauma.
RESULTS: A hypovolemic shock and abrupt 4.2 g/dl hemoglobin decrease caused by massive bleeding from delayed-onset SGA rupture, was successfully treated with urgent angiographic embolization.
CONCLUSIONS: A delayed SGA bleeding should be considered in late-onset shock associated with blunt buttock trauma. Furthermore, early detection and embolization not only prevent further complications, such as compartment syndrome and hypovolemic shock, but also eliminate the need for any surgical interventions.

PMID: 28978258 [PubMed - indexed for MEDLINE]

19 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 2019/05/30

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.

19 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 2019/05/30

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.