Common symptoms for a rare disease in a girl with sarcoidosis: a case report.

Ital J Pediatr. 2018 Jun 28;44(1):74

Authors: Giovannini M, Luzzati M, Ferrara G, Buccoliero AM, Simonini G, de Martino M, Cimaz R, Giani T

Abstract
BACKGROUND: Sarcoidosis in pediatric age is uncommon and challenging diagnosis, because manifestations can be significantly variable and non-specific since it is a multisystem disease, and virtually any organ system may be involved.
CASE PRESENTATION: In this report, we describe the case of a 12-year-old girl presenting with fatigue and weight loss, with a painless hepato-splenomegaly without additional clinical signs on physical examination. In our patient, once we had ruled out infections, malignancies and granulomatous diseases of childhood, we made diagnosis of sarcoidosis, finding suggestive histological features in two different tissues (liver and lymph nodes) with lung involvement.
CONCLUSIONS: Our case points out that pediatricians should consider sarcoidosis in the differential diagnosis in case of systemic symptoms, even in absence of other specific clinical clues, because they represent the most common clinical manifestations on presentation in children, in order to refer promptly the young patient to specialist evaluation.

PMID: 29954416 [PubMed - indexed for MEDLINE]

A rare case of bilateral ocular neuromyotonia.

Can J Ophthalmol. 2018 02;53(1):e4-e6

Authors: Ali ZC, Usmani HA, Ansons A

PMID: 29426461 [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 2019/01/08

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 2019/01/05

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 2019/01/05

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.

14 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 2019/01/04

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.

14 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 2019/01/04

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.

16 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 2019/01/03

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.

Approaches to sample size calculation for clinical trials in rare diseases.

Pharm Stat. 2018 05;17(3):214-230

Authors: Miller F, Zohar S, Stallard N, Madan J, Posch M, Hee SW, Pearce M, Vågerö M, Day S

Abstract
We discuss 3 alternative approaches to sample size calculation: traditional sample size calculation based on power to show a statistically significant effect, sample size calculation based on assurance, and sample size based on a decision-theoretic approach. These approaches are compared head-to-head for clinical trial situations in rare diseases. Specifically, we consider 3 case studies of rare diseases (Lyell disease, adult-onset Still disease, and cystic fibrosis) with the aim to plan the sample size for an upcoming clinical trial. We outline in detail the reasonable choice of parameters for these approaches for each of the 3 case studies and calculate sample sizes. We stress that the influence of the input parameters needs to be investigated in all approaches and recommend investigating different sample size approaches before deciding finally on the trial size. Highly influencing for the sample size are choice of treatment effect parameter in all approaches and the parameter for the additional cost of the new treatment in the decision-theoretic approach. These should therefore be discussed extensively.

PMID: 29322632 [PubMed - indexed for MEDLINE]

Large mesenteric lymphangioma in an adult patient: an unusual presentation of a rare disease.

BMJ Case Rep. 2018 Oct 07;2018:

Authors: Wall KC, Schmitz R, Carney JM, Blazer Iii DG

Abstract
Lymphangiomas are most commonly described as a small painless mass in the neck or a vesicular rash in an infant patient. Ninety per cent of cases are diagnosed before the age of 2. Treatment usually involves surgical resection. Intra-abdominal lymphangiomas and mesenteric lymphangiomas, as described in our case report, represent a rare pathology. The exact prevalence of this condition is unclear but it has been suggested in the literature that there have been as few as 820 cases since the 16th century. The clinical presentation is usually subacute and diagnosis made incidentally during a workup of chronic gastrointestinal symptoms. Acute abdominal symptoms, as in our case presentation, are unusual but may be explained by the mass effect of a large intra-abdominal lesion. Cross-sectional imaging is key in preoperative workup and operative planning. Complete surgical resection is recommended and curative in the majority of cases with a low risk of local recurrence.

PMID: 30297495 [PubMed - indexed for MEDLINE]

The 100 000 Genomes Project: bringing whole genome sequencing to the NHS.

BMJ. 2018 04 24;361:k1687

Authors: Turnbull C, Scott RH, Thomas E, Jones L, Murugaesu N, Pretty FB, Halai D, Baple E, Craig C, Hamblin A, Henderson S, Patch C, O'Neill A, Devereau, Smith K, Martin AR, Sosinsky A, McDonagh EM, Sultana R, Mueller M, Smedley D, Toms A, Dinh L, Fowler T, Bale M, Hubbard T, Rendon A, Hill S, Caulfield MJ, 100 000 Genomes Project

PMID: 29691228 [PubMed - indexed for MEDLINE]

Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease.

N Engl J Med. 2018 11 29;379(22):2131-2139

Authors: Splinter K, Adams DR, Bacino CA, Bellen HJ, Bernstein JA, Cheatle-Jarvela AM, Eng CM, Esteves C, Gahl WA, Hamid R, Jacob HJ, Kikani B, Koeller DM, Kohane IS, Lee BH, Loscalzo J, Luo X, McCray AT, Metz TO, Mulvihill JJ, Nelson SF, Palmer CGS, Phillips JA, Pick L, Postlethwait JH, Reuter C, Shashi V, Sweetser DA, Tifft CJ, Walley NM, Wangler MF, Westerfield M, Wheeler MT, Wise AL, Worthey EA, Yamamoto S, Ashley EA, Undiagnosed Diseases Network

Abstract
BACKGROUND: Many patients remain without a diagnosis despite extensive medical evaluation. The Undiagnosed Diseases Network (UDN) was established to apply a multidisciplinary model in the evaluation of the most challenging cases and to identify the biologic characteristics of newly discovered diseases. The UDN, which is funded by the National Institutes of Health, was formed in 2014 as a network of seven clinical sites, two sequencing cores, and a coordinating center. Later, a central biorepository, a metabolomics core, and a model organisms screening center were added.
METHODS: We evaluated patients who were referred to the UDN over a period of 20 months. The patients were required to have an undiagnosed condition despite thorough evaluation by a health care provider. We determined the rate of diagnosis among patients who subsequently had a complete evaluation, and we observed the effect of diagnosis on medical care.
RESULTS: A total of 1519 patients (53% female) were referred to the UDN, of whom 601 (40%) were accepted for evaluation. Of the accepted patients, 192 (32%) had previously undergone exome sequencing. Symptoms were neurologic in 40% of the applicants, musculoskeletal in 10%, immunologic in 7%, gastrointestinal in 7%, and rheumatologic in 6%. Of the 382 patients who had a complete evaluation, 132 received a diagnosis, yielding a rate of diagnosis of 35%. A total of 15 diagnoses (11%) were made by clinical review alone, and 98 (74%) were made by exome or genome sequencing. Of the diagnoses, 21% led to recommendations regarding changes in therapy, 37% led to changes in diagnostic testing, and 36% led to variant-specific genetic counseling. We defined 31 new syndromes.
CONCLUSIONS: The UDN established a diagnosis in 132 of the 382 patients who had a complete evaluation, yielding a rate of diagnosis of 35%. (Funded by the National Institutes of Health Common Fund.).

PMID: 30304647 [PubMed - indexed for MEDLINE]

Patient re-contact after revision of genomic test results: points to consider-a statement of the American College of Medical Genetics and Genomics (ACMG).

Genet Med. 2018 Dec 22;:

Authors: David KL, Best RG, Brenman LM, Bush L, Deignan JL, Flannery D, Hoffman JD, Holm I, Miller DT, O'Leary J, Pyeritz RE, ACMG Social Ethical Legal Issues Committee

Abstract

PMID: 30578420 [PubMed - as supplied by publisher]

Achieving orphan designation for placental insufficiency: annual incidence estimations in Europe.

BJOG. 2018 Dec 21;:

Authors: Spencer R, Rossi C, Lees M, Peebles D, Brocklehurst P, Martin J, Hansson SR, Hecher K, Marsal K, Figueras F, Gratacos E, David AL, EVERREST Consortium

Abstract
OBJECTIVE: To determine whether a novel therapy for placental insufficiency could achieve orphan drug status by estimating the annual incidence of placental insufficiency, defined as an estimated fetal weight below the 10th centile in the presence of abnormal umbilical artery Doppler velocimetry, per 10,000 European Union (EU) population as part of an application for European Medicines Agency (EMA) orphan designation.
DESIGN: Incidence estimation based on literature review and published national and EU statistics.
SETTING AND POPULATION: European Union.
METHODS: Data were drawn from published literature, including national and international guidelines, international consensus statements, cohort studies and randomised controlled trials, and published national and EU statistics, including birth rates and stillbirth rates. Rare disease databases were also searched.
RESULTS: The proportion of affected pregnancies was estimated as 3.17% (95% CI 2.93% to 3.43%), using a weighted average of the results from two cohort studies. Using birth rates from 2012 and adjusting for a pregnancy loss rate of 1/100 gave an estimated annual incidence of 3.33 per 10,000 EU population (95% CI 3.07 to 3.60 per 10,000 EU population). This fell below the EMA threshold of 5 per 10,000 EU population.
CONCLUSIONS: Maternal vascular endothelial growth factor gene therapy for placental insufficiency was granted EMA orphan status in 2015 after we demonstrated that it is a rare, life-threatening or chronically debilitating and currently untreatable disease. Developers of other potential obstetric therapies should consider applying for orphan designation, which provides financial and regulatory benefits. This article is protected by copyright. All rights reserved.

PMID: 30576053 [PubMed - as supplied by publisher]

Mitochondrial dysfunction is a key determinant of the rare disease lymphangioleiomyomatosis and provides a novel therapeutic target.

Oncogene. 2018 Dec 20;:

Authors: Abdelwahab EMM, Pal S, Kvell K, Sarosi V, Bai P, Rue R, Krymskaya V, McPhail D, Porter A, Pongracz JE

Abstract
Lymphangioleiomyomatosis (LAM) is a rare and progressive systemic disease affecting mainly young women of childbearing age. A deterioration in lung function is driven by neoplastic growth of atypical smooth muscle-like LAM cells in the pulmonary interstitial space that leads to cystic lung destruction and spontaneous pneumothoraces. Therapeutic options for preventing disease progression are limited and often end with lung transplantation temporarily delaying an inevitable decline. To identify new therapeutic strategies for this crippling orphan disease, we have performed array based and metabolic molecular analysis on patient-derived cell lines. Our results point to the conclusion that mitochondrial biogenesis and mitochondrial dysfunction in LAM cells provide a novel target for treatment.

PMID: 30573768 [PubMed - as supplied by publisher]

Effect of Mexiletine on Muscle Stiffness in Patients With Nondystrophic Myotonia Evaluated Using Aggregated N-of-1 Trials.

JAMA. 2018 12 11;320(22):2344-2353

Authors: Stunnenberg BC, Raaphorst J, Groenewoud HM, Statland JM, Griggs RC, Woertman W, Stegeman DF, Timmermans J, Trivedi J, Matthews E, Saris CGJ, Schouwenberg BJ, Drost G, van Engelen BGM, van der Wilt GJ

Abstract
Importance: In rare diseases it is difficult to achieve high-quality evidence of treatment efficacy because of small cohorts and clinical heterogeneity. With emerging treatments for rare diseases, innovative trial designs are needed.
Objective: To investigate the effectiveness of mexiletine in nondystrophic myotonia using an aggregated N-of-1 trials design and compare results between this innovative design and a previously conducted RCT.
Design, Setting, and Participants: A series of aggregated, double-blind, randomized, placebo-controlled N-of-1-trials, performed in a single academic referral center. Thirty Dutch adult patients with genetically confirmed nondystrophic myotonia (38 patients screened) were enrolled between February 2014 and June 2015. Follow-up was completed in September 2016.
Interventions: Mexiletine (600 mg daily) vs placebo during multiple treatment periods of 4 weeks.
Main Outcomes and Measures: Reduction in daily-reported muscle stiffness on a scale of 1 to 9, with higher scores indicating more impairment. A Bayesian hierarchical model aggregated individual N-of-1 trial data to determine the posterior probability of reaching a clinically meaningful effect of a greater than 0.75-point difference.
Results: Among 30 enrolled patients (mean age, 43.4 [SD, 15.24] years; 22% men; 19 CLCN1 and 11 SCN4A genotype), 27 completed the study and 3 dropped out (1 because of a serious adverse event). In 24 of the 27 completers, a clinically meaningful treatment effect was found. In the Bayesian hierarchical model, mexiletine resulted in a 100% posterior probability of reaching a clinically meaningful reduction in self-reported muscle stiffness for the nondystrophic myotonia group overall and the CLCN1 genotype subgroup and 93% posterior probability for the SCN4A genotype subgroup. In the total nondystrophic myotonia group, the median muscle stiffness score was 6.08 (interquartile range, 4.71-6.80) at baseline and was 2.50 (95% credible interval [CrI], 1.77-3.24) during the mexiletine period and 5.56 (95% CrI, 4.73-6.39) during the placebo period; difference in symptom score reduction, 3.06 (95% CrI, 1.96-4.15; n = 27) favoring mexiletine. The most common adverse event was gastrointestinal discomfort (21 mexiletine [70%], 1 placebo [3%]). One serious adverse event occurred (1 mexiletine [3%]; allergic skin reaction). Using frequentist reanalysis, mexiletine compared with placebo resulted in a mean reduction in daily-reported muscle stiffness of 3.12 (95% CI, 2.46-3.78), consistent with the previous RCT treatment effect of 2.69 (95% CI, 2.12-3.26).
Conclusions and Relevance: In a series of N-of-1 trials of mexiletine vs placebo in patients with nondystrophic myotonia, there was a reduction in mean daily-reported muscle stiffness that was consistent with the treatment effect in a previous randomized clinical trial. These findings support the efficacy of mexiletine for treatment of nondystrophic myotonia as well as the feasibility of N-of-1 trials for assessing interventions in some chronic rare diseases.
Trial Registration: ClinicalTrials.gov Identifier: NCT02045667.

PMID: 30535218 [PubMed - indexed for MEDLINE]

Becker's nevus syndrome: a report of a rare disease with unusual associations.

Int J Dermatol. 2017 Apr;56(4):458-460

Authors: Ghosh SK, Majumder B, Agarwal M

PMID: 27655000 [PubMed - indexed for MEDLINE]

Characteristics of undiagnosed diseases network applicants: implications for referring providers.

BMC Health Serv Res. 2018 Aug 22;18(1):652

Authors: Walley NM, Pena LDM, Hooper SR, Cope H, Jiang YH, McConkie-Rosell A, Sanders C, Schoch K, Spillmann RC, Strong K, McCray AT, Mazur P, Esteves C, LeBlanc K, Undiagnosed Diseases Network, Wise AL, Shashi V

Abstract
BACKGROUND: The majority of undiagnosed diseases manifest with objective findings that warrant further investigation. The Undiagnosed Diseases Network (UDN) receives applications from patients whose symptoms and signs have been intractable to diagnosis; however, many UDN applicants are affected primarily by subjective symptoms such as pain and fatigue. We sought to characterize presenting symptoms, referral sources, and demographic factors of applicants to the UDN to identify factors that may determine application outcome and potentially differentiate between those with undiagnosed diseases (with more objective findings) and those who are less likely to have an undiagnosed disease (more subjective symptoms).
METHODS: We used a systematic retrospective review of 151 consecutive Not Accepted and 50 randomly selected Accepted UDN applications. The primary outcome was whether an applicant was Accepted, or Not Accepted, and, if accepted, whether or not a diagnosis was made. Objective and subjective symptoms and information on prior specialty consultations were collected from provider referral letters. Demographic data and decision data on network acceptance were gathered from the UDN online portal.
RESULTS: Fewer objective findings and more subjective symptoms were found in the Not Accepted applications. Not Accepted referrals also were from older individuals, reported a shorter period of illness, and were referred to the UDN by their primary care physicians. All of these differences reached statistical significance in comparison with Accepted applications. The frequency of subspecialty consults for diagnostic purposes prior to UDN application was similar in both groups.
CONCLUSIONS: The preponderance of subjective and lack of objective findings in the Not Accepted applications distinguish these from applicants that are accepted for evaluation and diagnostic efforts through the UDN. Not Accepted applicants are referred primarily by their primary care providers after multiple specialist consultations fail to yield answers. Distinguishing between patients with undiagnosed diseases with objective findings and those with primarily subjective findings can delineate patients who would benefit from further diagnostic processes from those who may have functional disorders and need alternative pathways for management of their symptoms.
TRIAL REGISTRATION: clinicaltrials.gov NCT02450851 , posted May 21st 2015.

PMID: 30134969 [PubMed - indexed for MEDLINE]

Rare disease prevention and treatment: the need for a level playing field.

Pharmacogenomics. 2018 02;19(3):243-247

Authors: Hughes DA, Plumpton CO

Abstract
Pharmacogenetic tests are being used increasingly to prevent rare and potentially life-threatening adverse drug reactions. For many tests, however, cost-effectiveness is hard to demonstrate, and with the exception of a few cases, widespread implementation remains a distant prospect. Many orphan drugs for rare diseases are also not cost effective but are nonetheless normally reimbursed. In this article, we argue that the health technology assessment of pharmacogenetic tests aimed to prevent rare but severe adverse drug reactions should be on a level playing field with orphan drugs. This is supported by a number of arguments, concerning the severity, rarity and iatrogenic nature of adverse drug reactions, the distribution of benefits and costs and societal preference towards prevention over treatment.

PMID: 29327657 [PubMed - indexed for MEDLINE]

Bumps in the Road for Commercial Gene Therapy for Rare Diseases.

Mol Ther. 2017 10 04;25(10):2225

Authors: Ylä-Herttuala S

PMID: 28939088 [PubMed - indexed for MEDLINE]