A Rare Decade Where Magic Could Happen.

PDA J Pharm Sci Technol. 2016 May-Jun;70(3):189-90

Authors: Kondragunta B

PMID: 27252365 [PubMed - indexed for MEDLINE]

Total pericardium agenesis mistaken for arrhythmogenic right ventricular cardiomyopathy.

Eur Heart J Cardiovasc Imaging. 2018 01 01;19(1):120

Authors: Laredo M, Duthoit G, Gandjbakhch E, Redheuil A, Hébert JL

PMID: 29040463 [PubMed - indexed for MEDLINE]

The Role of Real-World Evidence in UK Reimbursement: Case Study of Lenalidomide in Myelodysplastic Syndrome Deletion 5q.

Pharmacoecon Open. 2018 Dec 14;:

Authors: Lee D, Brereton N, Dhanasiri S, Kulasekararaj A

Abstract
BACKGROUND: Uncertainty within cost-effectiveness analysis, often driven by lack of mature data from large clinical trials, plays a key role in decisions made by the National Institute for Health and Care Excellence (NICE), particularly for early access medicines and orphan drugs.
OBJECTIVES: In this case study, we used real-world evidence to address the uncertainty in the cost-effectiveness case for lenalidomide in transfusion-dependent low- and intermediate-1-risk myelodysplastic syndrome (MDS) deletion 5q [del(5q)], affecting a small but unique subpopulation with an orphan disease.
METHODS: As part of a submission to NICE, we developed a cost-effectiveness model for lenalidomide, resulting in eventual recommendation.
RESULTS: Due to data limitations within the trial evidence available, the model was based on surrogate outcomes supported by a disease-wide literature review. The validity of modelled estimates for critical long-term outcomes in terms of time on treatment (32% reaching 26 cycles when the patient access scheme applied in the model vs. 28% in the real-world data) and survival was confirmed using real-world evidence (projected median survival for best supportive care of 4.3 years vs. real-world evidence showing median survival with low- and intermediate-1-risk MDS of 5.7 and 3.5 years, respectively).
CONCLUSION: This case study demonstrates the usefulness and relevance of the application of real-world data when trial data are limited.

PMID: 30552652 [PubMed - as supplied by publisher]

Novel variants in SPTAN1 without epilepsy: An expansion of the phenotype.

Am J Med Genet A. 2018 Dec 11;:

Authors: Gartner V, Markello TC, Macnamara E, De Biase A, Thurm A, Joseph L, Beggs A, Schmahmann JD, Berry GT, Anselm I, Boslet E, Tifft CJ, Gahl WA, Lee PR

Abstract
We describe two unrelated children with de novo variants in the non-erythrocytic alpha-II-spectrin (SPTAN1) gene who have hypoplastic brain structures, intellectual disability, and both fine and gross motor impairments. Using agnostic exome sequencing, we identified a nonsense variant creating a premature stop codon in exon 21 of SPTAN1, and in a second patient we identified an intronic substitution in SPTAN1 prior to exon 50 creating a new donor acceptor site. Neither of these variants has been described previously. Although some of these patients' features are consistent with the known SPTAN1 encephalopathy phenotype, these two children do not have epilepsy, in contrast to reports about nearly every other patient with heterozygous SPTAN1 variants and in all patients with a variant near the C-terminal coding region. Moreover, both children have abnormal thyroid function, which has not been previously reported in association with SPTAN1 variant. We present a detailed discussion of the clinical manifestations of these two unique SPTAN1 variants and provide evidence that both variants result in reduced mRNA expression despite different locations within the gene and clinical phenotypes. These findings expand the motor, cognitive, and behavioral spectrum of the SPTAN1-associated phenotype and invite speculation about underlying pathophysiologies.

PMID: 30548380 [PubMed - as supplied by publisher]

COEXISTENCE OF GASTRIC DIVERTICULUM AND GASTRIC CANCER.

Gastroenterol Nurs. 2018 Mar/Apr;41(2):166-168

Authors: Ölmez S, Aslan M, Yavuz A, Sarıtaş B

PMID: 29596131 [PubMed - indexed for MEDLINE]

Polyamine Homeostasis in Snyder-Robinson Syndrome.

Med Sci (Basel). 2018 Dec 07;6(4):

Authors: Murray-Stewart T, Dunworth M, Foley JR, Schwartz CE, Casero RA

Abstract
Loss-of-function mutations of the spermine synthase gene (SMS) result in Snyder-Robinson Syndrome (SRS), a recessive X-linked syndrome characterized by intellectual disability, osteoporosis, hypotonia, speech abnormalities, kyphoscoliosis, and seizures. As SMS catalyzes the biosynthesis of the polyamine spermine from its precursor spermidine, SMS deficiency causes a lack of spermine with an accumulation of spermidine. As polyamines, spermine, and spermidine play essential cellular roles that require tight homeostatic control to ensure normal cell growth, differentiation, and survival. Using patient-derived lymphoblast cell lines, we sought to comprehensively investigate the effects of SMS deficiency on polyamine homeostatic mechanisms including polyamine biosynthetic and catabolic enzymes, derivatives of the natural polyamines, and polyamine transport activity. In addition to decreased spermine and increased spermidine in SRS cells, ornithine decarboxylase activity and its product putrescine were significantly decreased. Treatment of SRS cells with exogenous spermine revealed that polyamine transport was active, as the cells accumulated spermine, decreased their spermidine level, and established a spermidine-to-spermine ratio within the range of wildtype cells. SRS cells also demonstrated elevated levels of tissue transglutaminase, a change associated with certain neurodegenerative diseases. These studies form a basis for further investigations into the leading biochemical changes and properties of SMS-mutant cells that potentially represent therapeutic targets for the treatment of Snyder-Robinson Syndrome.

PMID: 30544565 [PubMed]

Novel CHM mutations in Polish patients with choroideremia - an orphan disease with close perspective of treatment.

Orphanet J Rare Dis. 2018 Dec 12;13(1):221

Authors: Skorczyk-Werner A, Wawrocka A, Kochalska N, Krawczynski MR

Abstract
BACKGROUND: Choroideremia (CHM) is a rare X-linked recessive retinal dystrophy characterized by progressive chorioretinal degeneration in the males affected. The symptoms include night blindness in childhood, progressive peripheral vision loss and total blindness in the late stages. The disease is caused by mutations in the CHM gene encoding Rab Escort Protein 1 (REP-1). The aim of the study was to identify the molecular basis of choroideremia in five families of Polish origin.
METHODS: Six male patients from five unrelated families of Polish ethnicity, who were clinically diagnosed with choroideremia, were examined in this study. An ophthalmologic examination performed in all the probands included: best-corrected visual acuity, slit-lamp examination, funduscopy, fluorescein angiography and perimetry. The entire coding region encompassing 15 exons and the flanking intronic sequences of the CHM gene were amplified with PCR and directly sequenced in all the patients.
RESULTS: Five variants in the CHM gene were identified in the five families examined. Two of the variants were new: c.1175dupT and c.83C > G, while three had been previously reported.
CONCLUSIONS: This study provides the first molecular genetic characteristics of patients with choroideremia from the previously unexplored Polish population.

PMID: 30541579 [PubMed - in process]

A rare cause of blanching red legs: cutaneous collagenous vasculopathy.

Int J Dermatol. 2018 Mar;57(3):349-350

Authors: Roy SF, Ghazawi FM, Veilleux B, Bouffard D, Bélisle A

PMID: 29359327 [PubMed - indexed for MEDLINE]

Nonspecific diffuse alopecia as a single manifestation of syphilis infection: clinical and trichoscopic features.

Int J Dermatol. 2018 May;57(5):593-595

Authors: Costa MC, Peres AS, Queiróz AJR, Souza Medeiros N, Costa IMC

PMID: 29336022 [PubMed - indexed for MEDLINE]

Generalized eruptive histiocytosis diagnosed in light of dermoscopic findings.

Int J Dermatol. 2018 Mar;57(3):355-357

Authors: Kaçar N, Demirkan N, Duygulu Ş

PMID: 29243820 [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 2018/12/13

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 2018/12/13

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.

57 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 2018/12/12

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.

Gender Alters the MHC Class I HLA-A Association with Polyglandular Autoimmunity.

J Clin Endocrinol Metab. 2018 Dec 05;:

Authors: Flesch BK, König J, Frommer L, Hansen MP, Kahaly GJ

Abstract
Context: The Major Histocompatibility Complex (MHC) strongly contributes to the development of polyglandular autoimmunity (PGA).
Objective: To evaluate the impact of gender on human leukocyte antigen (HLA) association with PGA for the first time.
Design: Cross-sectional immunogenetic study.
Setting: Academic, tertiary referral, orphan disease center for PGA (ORPHA 282196) and immunogenetics laboratory.
Subjects: 158 patients with coexistent type 1 diabetes and autoimmune thyroid disease (adult type three PGA, ORPHA 227982) and 479 unrelated healthy controls.
Methods: All 637 Caucasian subjects were typed for HLA-A, -B, DRB1, -DQA1, and -DQB1 alleles at a two-field level.
Main outcome measure: Modification of the gene-disease association by gender.
Results: MHC class I HLA-A association was gender-related to both the total Caucasian adult type three PGA collective (n=158, p=0.0065) as well as in PGA patients with autoimmune Hashimoto's thyroiditis (n=91, p=0.010). Compared to HLA-A*02:01, A*11:01 was overrepresented in male patients, yet underrepresented in females (OR 1.49, 95% CI 0.55-3.88 vs. 0.42, 0.12-1.17). A*24:02 was underrepresented in males but not in female patients (OR 0.37, 95% CI 0.111.04 vs. 1.19, 0.65-2.15). Excluding the five most frequent alleles (A*01:01, A*02:01, A*03:01, A*11:01, and A*24:02), the sum of all other identified alleles was underrepresented in male patients (OR 0.37, 0.18-0.72, p=0.0046). The strong MHC HLA-B association with PGA (p<0.0001) was not gender-related (p=0.55). Further, no interaction with gender was observed for the MHC class II HLA-DRB1, DQA1, and DQB1 alleles.
Conclusion: MHC class I HLA-A association with type three PGA is significantly affected by gender.

PMID: 30520966 [PubMed - as supplied by publisher]

Chromosomal microarray and whole exome sequencing identify genetic causes of congenital hypothyroidism with extra-thyroidal congenital malformations.

Clin Chim Acta. 2018 Nov 30;:

Authors: Fu C, Luo S, Zhang Y, Fan X, D'Gama AM, Zhang X, Zheng H, Su J, Li C, Luo J, Agrawal PB, Li Q, Chen S

Abstract
BACKGROUND: Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder. Although most patients present with isolated CH, some patients present with CH and extra-thyroidal congenital malformations (ECMs), for which less is known about the underlying genetics. The aim of this study was to investigate the genetic mechanisms in patients with CH and ECMs using chromosomal microarray (CMA) and whole exome sequencing (WES).
METHODS: Peripheral venous blood samples were collected from 16 patients with CH and ECMs. Genomic DNA was extracted from peripheral blood leukocytes. CMA and WES were performed to detect copy number and single nucleotide variants.
RESULTS: CMA identified clinically significant copy number variants in 7 patients consistent with their phenotypes. For 6 of them, the genotype and phenotype suggested a syndromic diagnosis, and the remaining patient carried a pathogenic microdeletion and microduplication including GLIS3. WES analysis identified 9 different variants in 7 additional patients. The variants included 2 known mutations (c.1096C>T (p.Arg366Trp) in KCNQ1 and c.848C>A (p.Pro283Gln) in NKX2-5) and 7 novel variants: one nonsense mutation (c.4330C>T (p.Arg1444*) in ASXL3), one frameshift mutation (c.1253_1259delACTCTGG (p.Asp418fs) in TG), three missense variants (c.1472C>T (p.Thr491Ile) in TG, c.4604A>G (p.Asp1535Gly) in TG, and c.2139G>T (p.Glu713Asp) in DUOX2, and two splice site variants (c.944-1G>C and c.3693 + 1G>T) in DUOX2.
CONCLUSIONS: We report the first genetic study of CH patients with ECMs using CMA and WES. Overall, our detection rate for pathogenic and possibly pathogenic variants was 87.5% (14/16). We report 7 novel variants, expanding the mutational spectrum of TG, DUOX2, and ASXL3.

PMID: 30508507 [PubMed - as supplied by publisher]

The Genetic Landscape of Diamond-Blackfan Anemia.

Am J Hum Genet. 2018 Nov 21;:

Authors: Ulirsch JC, Verboon JM, Kazerounian S, Guo MH, Yuan D, Ludwig LS, Handsaker RE, Abdulhay NJ, Fiorini C, Genovese G, Lim ET, Cheng A, Cummings BB, Chao KR, Beggs AH, Genetti CA, Sieff CA, Newburger PE, Niewiadomska E, Matysiak M, Vlachos A, Lipton JM, Atsidaftos E, Glader B, Narla A, Gleizes PE, O'Donohue MF, Montel-Lehry N, Amor DJ, McCarroll SA, O'Donnell-Luria AH, Gupta N, Gabriel SB, MacArthur DG, Lander ES, Lek M, Da Costa L, Nathan DG, Korostelev AA, Do R, Sankaran VG, Gazda HT

Abstract
Diamond-Blackfan anemia (DBA) is a rare bone marrow failure disorder that affects 7 out of 1,000,000 live births and has been associated with mutations in components of the ribosome. In order to characterize the genetic landscape of this heterogeneous disorder, we recruited a cohort of 472 individuals with a clinical diagnosis of DBA and performed whole-exome sequencing (WES). We identified relevant rare and predicted damaging mutations for 78% of individuals. The majority of mutations were singletons, absent from population databases, predicted to cause loss of function, and located in 1 of 19 previously reported ribosomal protein (RP)-encoding genes. Using exon coverage estimates, we identified and validated 31 deletions in RP genes. We also observed an enrichment for extended splice site mutations and validated their diverse effects using RNA sequencing in cell lines obtained from individuals with DBA. Leveraging the size of our cohort, we observed robust genotype-phenotype associations with congenital abnormalities and treatment outcomes. We further identified rare mutations in seven previously unreported RP genes that may cause DBA, as well as several distinct disorders that appear to phenocopy DBA, including nine individuals with biallelic CECR1 mutations that result in deficiency of ADA2. However, no new genes were identified at exome-wide significance, suggesting that there are no unidentified genes containing mutations readily identified by WES that explain >5% of DBA-affected case subjects. Overall, this report should inform not only clinical practice for DBA-affected individuals, but also the design and analysis of rare variant studies for heterogeneous Mendelian disorders.

PMID: 30503522 [PubMed - as supplied by publisher]

ClinPhen extracts and prioritizes patient phenotypes directly from medical records to expedite genetic disease diagnosis.

Genet Med. 2018 Dec 05;:

Authors: Deisseroth CA, Birgmeier J, Bodle EE, Kohler JN, Matalon DR, Nazarenko Y, Genetti CA, Brownstein CA, Schmitz-Abe K, Schoch K, Cope H, Signer R, Undiagnosed Diseases Network, Martinez-Agosto JA, Shashi V, Beggs AH, Wheeler MT, Bernstein JA, Bejerano G

Abstract
PURPOSE: Diagnosing monogenic diseases facilitates optimal care, but can involve the manual evaluation of hundreds of genetic variants per case. Computational tools like Phrank expedite this process by ranking all candidate genes by their ability to explain the patient's phenotypes. To use these tools, busy clinicians must manually encode patient phenotypes from lengthy clinical notes. With 100 million human genomes estimated to be sequenced by 2025, a fast alternative to manual phenotype extraction from clinical notes will become necessary.
METHODS: We introduce ClinPhen, a fast, high-accuracy tool that automatically converts clinical notes into a prioritized list of patient phenotypes using Human Phenotype Ontology (HPO) terms.
RESULTS: ClinPhen shows superior accuracy and 20× speedup over existing phenotype extractors, and its novel phenotype prioritization scheme improves the performance of gene-ranking tools.
CONCLUSION: While a dedicated clinician can process 200 patient records in a 40-hour workweek, ClinPhen does the same in 10 minutes. Compared with manual phenotype extraction, ClinPhen saves an additional 3-5 hours per Mendelian disease diagnosis. Providers can now add ClinPhen's output to each summary note attached to a filled testing laboratory request form. ClinPhen makes a substantial contribution to improvements in efficiency critically needed to meet the surging demand for clinical diagnostic sequencing.

PMID: 30514889 [PubMed - as supplied by publisher]

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 2018/12/04

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.

[Pathogenesis and epidemiology of neurotrophic keratopathy].

Ophthalmologe. 2018 Nov 26;:

Authors: Mertsch S, Alder J, Dua HS, Geerling G

Abstract
Neurotrophic keratopathy (NK) is a degenerative corneal disease that is based on an impairment of the corneal innervation. The damage to the sensory innervation, which is delivered through the 1st branch of the trigeminal nerve (ophthalmic nerve), can occur throughout the entire length of the nerve from the nucleus in the brainstem, e.g. caused by brain tumors, to the terminal nerve fibers in the cornea, caused for example by refractive corneal surgery (e. g. LASIK). Due to the loss of the sensory innervation, a reduced lacrimation and a reduction in the secretion of trophic factors occur. This in turn inhibits the regeneration potential of the corneal epithelium. In the most severe cases of the disease, the reduction or loss of lacrimation, together with the impaired regeneration potential of the epithelial cells, can lead to persistent epithelial defects, ulcers and corneal perforation. The NK has a prevalence of 5 or fewer individuals per 10,000 and is classified as a rare, i. e. orphan disease (ORPHA137596). A fundamental understanding of the pathogenesis and epidemiology of NK supports the early diagnosis and therefore the initiation of a specific treatment.

PMID: 30478498 [PubMed - as supplied by publisher]

Arginine does not rescue p.Q188R mutation deleterious effect in classic galactosemia.

Orphanet J Rare Dis. 2018 Nov 26;13(1):212

Authors: Haskovic M, Derks B, van der Ploeg L, Trommelen J, Nyakayiru J, van Loon LJC, Mackinnon S, Yue WW, Peake RWA, Zha L, Demirbas D, Qi W, Huang X, Berry GT, Achten J, Bierau J, Rubio-Gozalbo ME, Coelho AI

Abstract
BACKGROUND: Classic galactosemia is a rare genetic metabolic disease with an unmet treatment need. Current standard of care fails to prevent chronically-debilitating brain and gonadal complications. Many mutations in the GALT gene responsible for classic galactosemia have been described to give rise to variants with conformational abnormalities. This pathogenic mechanism is highly amenable to a therapeutic strategy based on chemical/pharmacological chaperones. Arginine, a chemical chaperone, has shown beneficial effect in other inherited metabolic disorders, as well as in a prokaryotic model of classic galactosemia. The p.Q188R mutation presents a high prevalence in the Caucasian population, making it a very clinically relevant mutation. This mutation gives rise to a protein with lower conformational stability and lower catalytic activity. The aim of this study is to assess the potential therapeutic role of arginine for this mutation.
METHODS: Arginine aspartate administration to four patients with the p.Q188R/p.Q188R mutation, in vitro studies with three fibroblast cell lines derived from classic galactosemia patients as well as recombinant protein experiments were used to evaluate the effect of arginine in galactose metabolism. This study has been registered at https://clinicaltrials.gov (NCT03580122) on 09 July 2018. Retrospectively registered.
RESULTS: Following a month of arginine administration, patients did not show a significant improvement of whole-body galactose oxidative capacity (p = 0.22), erythrocyte GALT activity (p = 0.87), urinary galactose (p = 0.52) and urinary galactitol levels (p = 0.41). Patients' fibroblasts exposed to arginine did not show changes in GALT activity. Thermal shift analysis of recombinant p.Q188R GALT protein in the presence of arginine did not exhibit a positive effect.
CONCLUSIONS: This short pilot study in four patients homozygous for the p.Q188R/p.Q188R mutation reveals that arginine has no potential therapeutic role for galactosemia patients homozygous for the p.Q188R mutation.

PMID: 30477550 [PubMed - in process]