Anaesthesia and orphan disease: Hutchinson-Gilford progeria syndrome, a case report and summary of previous cases.

Eur J Anaesthesiol. 2016 11;33(11):869-872

Authors: Vreeswijk SJ, Claahsen HL, Borstlap WA, Hendriks MP

PMID: 27749465 [PubMed - indexed for MEDLINE]

Anaesthesia and orphan disease: sedation with ketofol in two patients with Joubert syndrome.

Eur J Anaesthesiol. 2016 11;33(11):868-869

Authors: Atalay YO, Soylu AI, Tekcan D

PMID: 27326823 [PubMed - indexed for MEDLINE]

Cysticercosis of the tongue.

J Nepal Health Res Counc. 2014 May-Aug;12(27):147-9

Authors: Sharma BP, Gaunt F, Sigdel B

Abstract
Cysticercosis is a condition in which a human being acts as the intermediate host of Taenia solium, a pork tape worm. The oral mucosa is an uncommonly involved site. A rurally living 35 year old vegetarian female presented with a swelling over the right side of her tongue of seven months duration. Histopathology of excisional biopsy revealed it to be cysticercosis. Diagnosis of cysticercosis was clinically unsuspected. The patient was referred to the general medical clinic for further treatment.

PMID: 25575011 [PubMed - indexed for MEDLINE]

Pyridostigmine bromide versus fludrocortisone in the treatment of orthostatic hypotension in Parkinson's disease - reply.

Eur J Neurol. 2018 Feb;25(2):e27-e28

Authors: Schreglmann SR, Büchele F, Kägi G, Baumann CR, study authors

PMID: 29356263 [PubMed - in process]

An overview of the impact of rare disease characteristics on research methodology.

Orphanet J Rare Dis. 2018 Jan 19;13(1):14

Authors: Whicher D, Philbin S, Aronson N

Abstract
BACKGROUND: About 30 million individuals in the United States are living with a rare disease, which by definition have a prevalence of 200,000 or fewer cases in the United States ([National Organization for Rare Disorders], [About NORD], [2016]). Disease heterogeneity and geographic dispersion add to the difficulty of completing robust studies in small populations. Improving the ability to conduct research on rare diseases would have a significant impact on population health. The purpose of this paper is to raise awareness of methodological approaches that can address the challenges to conducting robust research on rare diseases.
APPROACH: We conducted a landscape review of available methodological and analytic approaches to address the challenges of rare disease research. Our objectives were to: 1. identify algorithms for matching study design to rare disease attributes and the methodological approaches applicable to these algorithms; 2. draw inferences on how research communities and infrastructure can contribute to the efficiency of research on rare diseases; and 3. to describe methodological approaches in the rare disease portfolio of the Patient-Centered Outcomes Research Institute (PCORI), a funder promoting both rare disease research and research infrastructure.
RESULTS: We identified three algorithms for matching study design to rare disease or intervention characteristics (Gagne, et.al, BMJ 349:g6802, 2014); (Gupta, et.al, J Clin Epidemiol 64:1085-1094, 2011); (Cornu, et. al, Orphet J Rare Dis 8:48,2012) and summarized the applicable methodological and analytic approaches. From this literature we were also able to draw inferences on how an effective research infrastructure can set an agenda, prioritize studies, accelerate accrual, catalyze patient engagement and terminate poorly performing studies. Of the 24 rare disease projects in the PCORI portfolio, 11 are randomized controlled trials (RCTs) using standard designs. Thirteen are observational studies using case-control, prospective cohort, or natural history designs. PCORI has supported the development of 9 Patient-Powered Research Networks (PPRNs) focused on rare diseases.
CONCLUSION: Matching research design to attributes of rare diseases and interventions can facilitate the completion of RCTs that are adequately powered. An effective research infrastructure can improve efficiency and avoid waste in rare disease research. Our review of the PCORI research portfolio demonstrates that it is feasible to conduct RCTs in rare disease. However, most of these studies are using standard RCT designs. This suggests that use of a broader array of methodological approaches to RCTs --such as adaptive trials, cross-over trials, and early escape designs can improve the productivity of robust research in rare diseases.

PMID: 29351763 [PubMed - in process]

7 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 2018/01/20

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.

Accelerating Scientific Advancement for Pediatric Rare Lung Disease Research. Report from a National Institutes of Health-NHLBI Workshop, September 3 and 4, 2015.

Ann Am Thorac Soc. 2016 Dec;13(12):385-393

Authors: Young LR, Trapnell BC, Mandl KD, Swarr DT, Wambach JA, Blaisdell CJ

Abstract
Pediatric rare lung disease (PRLD) is a term that refers to a heterogeneous group of rare disorders in children. In recent years, this field has experienced significant progress marked by scientific discoveries, multicenter and interdisciplinary collaborations, and efforts of patient advocates. Although genetic mechanisms underlie many PRLDs, pathogenesis remains uncertain for many of these disorders. Furthermore, epidemiology and natural history are insufficiently defined, and therapies are limited. To develop strategies to accelerate scientific advancement for PRLD research, the NHLBI of the National Institutes of Health convened a strategic planning workshop on September 3 and 4, 2015. The workshop brought together a group of scientific experts, intramural and extramural investigators, and advocacy groups with the following objectives: (1) to discuss the current state of PRLD research; (2) to identify scientific gaps and barriers to increasing research and improving outcomes for PRLDs; (3) to identify technologies, tools, and reagents that could be leveraged to accelerate advancement of research in this field; and (4) to develop priorities for research aimed at improving patient outcomes and quality of life. This report summarizes the workshop discussion and provides specific recommendations to guide future research in PRLD.

PMID: 27925785 [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 2018/01/18

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.

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 2018/01/18

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.

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 2018/01/17

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.

Cover Image, Volume 176A, Number 2, February 2018.

Am J Med Genet A. 2018 Feb;176(2):i

Authors: Chen MH, Choudhury S, Hirata M, Khalsa S, Chang B, Walsh CA

Abstract
The cover image, by Ming Hui Chen et al., is based on the Original Article Thoracic Aortic Aneurysm in Patients with Loss of Function Filamin A Mutations: Clinical Characterization, Genetics, and Recommendations, DOI: 10.1002/ajmg.a.38580.

PMID: 29334595 [PubMed - in process]

Thoracic aortic aneurysm in patients with loss of function Filamin A mutations: Clinical characterization, genetics, and recommendations.

Am J Med Genet A. 2018 Feb;176(2):337-350

Authors: Chen MH, Choudhury S, Hirata M, Khalsa S, Chang B, Walsh CA

Abstract
The frequency and gender distribution of thoracic aortic aneurysm as a cardiovascular manifestation of loss-of-function (LOF) X-linked FilaminA (FLNA) mutations are not known. Furthermore, there is very limited cardiovascular morbidity or mortality data in children and adults. We analyzed cardiac data on the largest series of 114 patients with LOF FLNA mutations, both children and adults, with periventricular nodular heterotopia (PVNH), including 48 study patients and 66 literature patients, median age of 22.0 years (88 F, 26 M, range: 0-71 years), with 75 FLNA mutations observed in 80 families. Most (64.9%) subjects had a cardiac anomaly or vascular abnormality (80.8% of males and 60.2% of females). Thoracic aortic aneurysms or dilatation (TAA) were found in 18.4% (n = 21), and were associated with other structural cardiac malformations in 57.1% of patients, most commonly patent ductus arteriosus (PDA) and valvular abnormalities. TAA most frequently involved the aortic root and ascending aorta, and sinus of Valsalva aneurysms were present in one third of TAA patients. Six TAA patients (28.5%) required surgery (median age 37 yrs, range 13-41 yrs). TAA with its associated complications was also the only recorded cause of premature, non-accidental mortality in adults (2 M, 2 F). Two adult patients (1 F, 1 M, median 38.5 yrs), died of spontaneous aortic rupture at aortic dimensions smaller than current recommendations for surgery for other aortopathies. Data from this largest series of LOF FLNA mutation patients underscore the importance of serial follow-up to identify and manage these potentially devastating cardiovascular complications.

PMID: 29334594 [PubMed - in process]

Finding patients using similarity measures in a rare diseases-oriented clinical data warehouse: Dr. Warehouse and the needle in the needle stack.

J Biomed Inform. 2017 Sep;73:51-61

Authors: Garcelon N, Neuraz A, Benoit V, Salomon R, Kracker S, Suarez F, Bahi-Buisson N, Hadj-Rabia S, Fischer A, Munnich A, Burgun A

Abstract
OBJECTIVE: In the context of rare diseases, it may be helpful to detect patients with similar medical histories, diagnoses and outcomes from a large number of cases with automated methods. To reduce the time to find new cases, we developed a method to find similar patients given an index case leveraging data from the electronic health records.
MATERIALS AND METHODS: We used the clinical data warehouse of a children academic hospital in Paris, France (Necker-Enfants Malades), containing about 400,000 patients. Our model was based on a vector space model (VSM) to compute the similarity distance between an index patient and all the patients of the data warehouse. The dimensions of the VSM were built upon Unified Medical Language System concepts extracted from clinical narratives stored in the clinical data warehouse. The VSM was enhanced using three parameters: a pertinence score (TF-IDF of the concepts), the polarity of the concept (negated/not negated) and the minimum number of concepts in common. We evaluated this model by displaying the most similar patients for five different rare diseases: Lowe Syndrome (LOWE), Dystrophic Epidermolysis Bullosa (DEB), Activated PI3K delta Syndrome (APDS), Rett Syndrome (RETT) and Dowling Meara (EBS-DM), from the clinical data warehouse representing 18, 103, 21, 84 and 7 patients respectively.
RESULTS: The percentages of index patients returning at least one true positive similar patient in the Top30 similar patients were 94% for LOWE, 97% for DEB, 86% for APDS, 71% for EBS-DM and 99% for RETT. The mean number of patients with the exact same genetic diseases among the 30 returned patients was 51%.
CONCLUSION: This tool offers new perspectives in a translational context to identify patients for genetic research. Moreover, when new molecular bases are discovered, our strategy will help to identify additional eligible patients for genetic screening.

PMID: 28754522 [PubMed - indexed for MEDLINE]

The TGF-β System As a Potential Pathogenic Player in Disease Modulation of Amyotrophic Lateral Sclerosis.

Front Neurol. 2017;8:669

Authors: Peters S, Zitzelsperger E, Kuespert S, Iberl S, Heydn R, Johannesen S, Petri S, Aigner L, Thal DR, Hermann A, Weishaupt JH, Bruun TH, Bogdahn U

Abstract
Amyotrophic lateral sclerosis (ALS) represents a fatal orphan disease with high unmet medical need, and a life time risk of approx. 1/400 persons per population. Based on increasing knowledge on pathophysiology including genetic and molecular changes, epigenetics, and immune dysfunction, inflammatory as well as fibrotic processes may contribute to the heterogeneity and dynamics of ALS. Animal and human studies indicate dysregulations of the TGF-β system as a common feature of neurodegenerative disorders in general and ALS in particular. The TGF-β system is involved in different essential developmental and physiological processes and regulates immunity and fibrosis, both affecting neurogenesis and neurodegeneration. Therefore, it has emerged as a potential therapeutic target for ALS: a persistent altered TGF-β system might promote disease progression by inducing an imbalance of neurogenesis and neurodegeneration. The current study assessed the activation state of the TGF-β system within the periphery/in life disease stage (serum samples) and a late stage of disease (central nervous system tissue samples), and a potential influence upon neuronal stem cell (NSC) activity, immune activation, and fibrosis. An upregulated TGF-β system was suggested with significantly increased TGF-β1 protein serum levels, enhanced TGF-β2 mRNA and protein levels, and a strong trend toward an increased TGF-β1 protein expression within the spinal cord (SC). Stem cell activity appeared diminished, reflected by reduced mRNA expression of NSC markers Musashi-1 and Nestin within SC-paralleled by enhanced protein contents of Musashi-1. Doublecortin mRNA and protein expression was reduced, suggesting an arrested neurogenesis at late stage ALS. Chemokine/cytokine analyses suggest a shift from a neuroprotective toward a more neurotoxic immune response: anti-inflammatory chemokines/cytokines were unchanged or reduced, expression of proinflammatory chemokines/cytokines were enhanced in ALS sera and SC postmortem tissue. Finally, we observed upregulated mRNA and protein expression for fibronectin in motor cortex of ALS patients which might suggest increased fibrotic changes. These data suggest that there is an upregulated TGF-β system in specific tissues in ALS that might lead to a "neurotoxic" immune response, promoting disease progression and neurodegeneration. The TGF-β system therefore may represent a promising target in treatment of ALS patients.

PMID: 29326641 [PubMed]

Dysfunctional sarcomere contractility contributes to muscle weakness in ACTA1-related nemaline myopathy (NEM3).

Ann Neurol. 2018 Jan 12;:

Authors: Joureau B, de Winter JM, Conijn S, Bogaards SJP, Kovacevic I, Kalganov A, Persson M, Lindqvist J, Stienen GJM, Irving TC, Ma W, Yuen M, Clarke NF, Rassier DE, Malfatti E, Romero NB, Beggs AH, Ottenheijm CAC

Abstract
OBJECTIVE: Nemaline myopathy (NM) is one of the most common congenital non-dystrophic myopathies and is characterized by muscle weakness, often from birth. Mutations in ACTA1 are a frequent cause of NM (i.e. NEM3). ACTA1 encodes alpha-actin 1, the main constituent of the sarcomeric thin filament. The mechanisms by which mutations in ACTA1 contribute to muscle weakness in NEM3 are incompletely understood. We hypothesized that sarcomeric dysfunction contributes to muscle weakness in NEM3 patients.
METHODS: To test this hypothesis, we performed contractility measurements in individual muscle fibers and myofibrils obtained from muscle biopsies of fourteen NEM3 patients with different ACTA1 mutations. To identify the structural basis for impaired contractility, low angle x-ray diffraction and stimulated emission-depletion microscopy were applied.
RESULTS: Our findings reveal that muscle fibers of NEM3 patients display a reduced maximal force generating capacity, which is caused by dysfunctional sarcomere contractility in the majority of patients, as revealed by contractility measurements in myofibrils. Low angle x-ray diffraction and stimulated emission-depletion microscopy indicate that dysfunctional sarcomere contractility in NEM3 patients involves a lower number of myosin heads binding to actin during muscle activation. This lower number is not the result of reduced thin filament length. Interestingly, the calcium sensitivity of force is unaffected in some patients, but decreased in others.
INTERPRETATION: Thus, dysfunctional sarcomere contractility is an important contributor to muscle weakness in the majority of NEM3 patients, information which is crucial for patient stratification in future clinical trials. This article is protected by copyright. All rights reserved.

PMID: 29328520 [PubMed - as supplied by publisher]

CAPD Catheter Exit-Site and Tunnel Infection with Fungal Etiology-Treatment and Catheter Reinsertion for an Extremely Rare Complication.

Perit Dial Int. 2017 Mar-Apr;37(2):237-239

Authors: Jhawar MS, Das J, George P, Luther A

Abstract
Fungal infection is an extremely rare etiology of exit-site and tunnel infection in patients on continuous ambulatory peritoneal dialysis (CAPD). There are few data available regarding its management-especially choice of antifungals, duration of therapy, and removal of catheter. There are no guidelines pertaining to reinsertion of the CAPD catheter following fungal exit-site and tunnel infection. This case report highlights Candida albicans as a rare cause of exit-site and tunnel infection of the CAPD catheter. The catheter was removed and the patient received appropriate antifungal therapy followed by reinsertion of the CAPD catheter and re-initiation on CAPD.

PMID: 28360371 [PubMed - indexed for MEDLINE]

Pharmacological Chaperoning: A Potential Treatment for PMM2-CDG.

Hum Mutat. 2017 Feb;38(2):160-168

Authors: Yuste-Checa P, Brasil S, Gámez A, Underhaug J, Desviat LR, Ugarte M, Pérez-Cerdá C, Martinez A, Pérez B

Abstract
The congenital disorder of glycosylation (CDG) due to phosphomannomutase 2 deficiency (PMM2-CDG), the most common N-glycosylation disorder, is a multisystem disease for which no effective treatment is available. The recent functional characterization of disease-causing mutations described in patients with PMM2-CDG led to the idea of a therapeutic strategy involving pharmacological chaperones (PC) to rescue PMM2 loss-of-function mutations. The present work describes the high-throughput screening, by differential scanning fluorimetry, of 10,000 low-molecular-weight compounds from a commercial library, to search for possible PCs for the enzyme PMM2. This exercise identified eight compounds that increased the thermal stability of PMM2. Of these, four compounds functioned as potential PCs that significantly increased the stability of several destabilizing and oligomerization mutants and also increased PMM activity in a disease model of cells overexpressing PMM2 mutations. Structural analysis revealed one of these compounds to provide an excellent starting point for chemical optimization since it passed tests based on a number of pharmacochemical quality filters. The present results provide the first proof-of-concept of a possible treatment for PMM2-CDG and describe a promising chemical structure as a starting point for the development of new therapeutic agents for this severe orphan disease.

PMID: 27774737 [PubMed - indexed for MEDLINE]

[Analysis of Social Network Support for Rare-Disease Patients From a Social Capital Perspective].

Hu Li Za Zhi. 2017 Oct;64(5):18-23

Authors: Tsai TF

PMID: 28948587 [PubMed - indexed for MEDLINE]

[Introduction to Genetic/Rare Disease and the Application of Genetic Counseling].

Hu Li Za Zhi. 2017 Oct;64(5):11-17

Authors: Chu SY, Weng CY

Abstract
Genetic disease or hereditary disease is a group of disorders that is caused by mutations in an individual's genome. The mutated genome or gene may be transmitted through the germ line during reproduction, causing certain recurrence risk in offspring and other family members. The heritability of these disorders is thus an important issue to deal with clinically. In Taiwan, a rare disease is defined as a disease that is prevalent in fewer than 1 in 10,000 individuals. As up to 80% of rare disease cases in Taiwan are genetic disease disorders, genetic disease may not rare. The pathophysiology of genetic/ rare disease is very complicated. Individual disorders may have their own unique mechanisms (such as Fragile X syndrome), with most of these mechanisms still unclear or unknown. The symptoms and signs of genetic/rare disease thus present the greatest variabilities and cause difficulties in making diagnoses. Most related patients may present multiple congenital anomalies, metabolic disorders, growth and developmental delays, defects in cognition, neuromuscular abnormalities, and defects in vision, hearing or other organ functions. Symptomatic and supportive treatment still comprise a major component of treatment of genetic/rare disease (with the exception of special formulae for several inborn errors of metabolic disease and enzyme replacement therapy in some lysosomal storage disease). Poor self-care ability is common and the burden on caregivers is huge. Most rare disease patients are treated using a comprehensive rehabilitation program that begins during very early childhood, receive individual educational programs, and are continuously monitored with regard to their growth, developmental, and nutritional status. Inter-professional patient care, genetic counseling, and the creation of family support networks play an important role in family management. Public awareness and the creation of appropriate social systems and resources allocation are mandatory for proper care. The incidence of each genetic/rare disease is rare, but collectively they are important public health issue and a challenge to medical care.

PMID: 28948586 [PubMed - indexed for MEDLINE]

Workshop Proceedings: Streamlined Development of Safety Assessment Programs Supporting Orphan/Rare Diseases-Are We There Yet?

Int J Toxicol. 2016 Jul;35(4):393-409

Authors: Allamneni KP, Parker S, O'Neill CA, Wright TL, King S, Andrews L

Abstract
A workshop entitled "Streamlined Development of Safety Assessment Programs Supporting Orphan/Rare Diseases-Are We There Yet?" was held at the 36th Annual Meeting of the American College of Toxicology in Summerlin, Nevada. The workshop was sponsored by Shire and Ultragenyx and was designed to present the nonclinical considerations for the development of various products for rare diseases. A panel of experts from industry and government highlighted the nonclinical considerations in developing toxicology programs supporting rare disease therapeutics, challenges in preclinical safety assessment, reviewed the current guidance, and presented the progress that has been made to date. The main learning from the workshop was that nonclinical testing of therapeutics targeting rare disease warrants special considerations, and early collaboration between sponsors and health authorities may help optimize the scope and timing of the supportive studies. Specific examples for nonclinical development programs for enzyme replacement therapy (ERT) were presented. Although the symposium focused on ERTs, the concepts are broadly applicable.

PMID: 27272885 [PubMed - indexed for MEDLINE]