Targeting Glucosylceramide Synthesis in the Treatment of Rare and Common Renal Disease.

Semin Nephrol. 2018 03;38(2):183-192

Authors: Shayman JA

Abstract
Sphingolipids, including ceramides, glycosphingolipids, sphingomyelin, and sphingosine-1-phosphate, have been recognized as important molecules that regulate critical cellular functions. Although originally studied in the context of lysosomal storage diseases, the roles of these compounds in more common disorders involving metabolism, vascular disease, and aberrant growth has been the focus of recent studies, including in disorders that affect the kidneys. These efforts have led to new insights into Fabry disease, a classic disorder of lysosomal function that results in renal failure as well as in more common renal diseases including diabetic nephropathy and polycystic kidney disease. Pathways for glycosphingolipid synthesis can be targeted with orally available small-molecule inhibitors, creating new opportunities for the treatment of both rare and common kidney diseases.

PMID: 29602400 [PubMed - indexed for MEDLINE]

Urine cell-free DNA is a biomarker for nephroblastomatosis or Wilms tumor in PIK3CA-related overgrowth spectrum (PROS).

Genet Med. 2018 09;20(9):1077-1081

Authors: Biderman Waberski M, Lindhurst M, Keppler-Noreuil KM, Sapp JC, Baker L, Gripp KW, Adams DM, Biesecker LG

Abstract
PURPOSE: We set out to facilitate the molecular diagnosis of patients with PIK3CA-related overgrowth spectrum (PROS), a heterogeneous somatic disorder characterized by variable presentations of segmental overgrowth, vascular malformations, skin lesions, and nephroblastomatosis, rare precursor lesions to Wilms tumor. Molecular diagnosis of PROS is challenging due to its mosaic nature, often requiring invasive biopsies.
METHODS: Digital droplet polymerase chain reaction (ddPCR) was used to analyze tissues including urine, saliva, buccal cells, and blood, from eight patients with PROS. Further analyses were performed on plasma and urine cell-free DNA (cfDNA).
RESULTS: PIK3CA variants were detected in plasma cfDNA at levels up to 0.5% in 50% of tested samples. In addition, high levels of PIK3CA variants in urine cfDNA correlated with a history of nephroblastomatosis compared with patients without renal involvement (P < 0.05).
CONCLUSION: Digital droplet PCR is a sensitive molecular tool that enables low-level variant detection of PIK3CA in various tissue types, providing an alternative diagnostic method. Furthermore, urine cfDNA is a candidate biomarker for nephroblastomatosis in PROS, which may be useful to refine screening guidelines for tumor risk in these patients.

PMID: 29300373 [PubMed - indexed for MEDLINE]

Ribosome Levels Selectively Regulate Translation and Lineage Commitment in Human Hematopoiesis.

Cell. 2018 03 22;173(1):90-103.e19

Authors: Khajuria RK, Munschauer M, Ulirsch JC, Fiorini C, Ludwig LS, McFarland SK, Abdulhay NJ, Specht H, Keshishian H, Mani DR, Jovanovic M, Ellis SR, Fulco CP, Engreitz JM, Schütz S, Lian J, Gripp KW, Weinberg OK, Pinkus GS, Gehrke L, Regev A, Lander ES, Gazda HT, Lee WY, Panse VG, Carr SA, Sankaran VG

Abstract
Blood cell formation is classically thought to occur through a hierarchical differentiation process, although recent studies have shown that lineage commitment may occur earlier in hematopoietic stem and progenitor cells (HSPCs). The relevance to human blood diseases and the underlying regulation of these refined models remain poorly understood. By studying a genetic blood disorder, Diamond-Blackfan anemia (DBA), where the majority of mutations affect ribosomal proteins and the erythroid lineage is selectively perturbed, we are able to gain mechanistic insight into how lineage commitment is programmed normally and disrupted in disease. We show that in DBA, the pool of available ribosomes is limited, while ribosome composition remains constant. Surprisingly, this global reduction in ribosome levels more profoundly alters translation of a select subset of transcripts. We show how the reduced translation of select transcripts in HSPCs can impair erythroid lineage commitment, illuminating a regulatory role for ribosome levels in cellular differentiation.

PMID: 29551269 [PubMed - indexed for MEDLINE]

Colorectal follicular lymphoma: A case report.

Medicine (Baltimore). 2019 Jan;98(3):e13985

Authors: Wang ML, Chang J, Huang H, Fu W, Niu YC, Lu ML, Shrestha S

Abstract
RATIONALE: Considering the low incidence of colorectal follicular lymphoma (FL) and its clinical features in endoscopic views, only a few studies have described the pathological diagnosis and treatment of this disease. This study aimed to reveal the overall process of clinical diagnosis and treatment of colorectal FL by conducting a case review.
PATIENT CONCERNS: A 27-year-old female presented to our department because of "severe bloody stool" lasting for more than 1 month. Her primary symptom was melena. Colonoscopy revealed widespread flat polyps with various immunophenotypes (CD10+, BCL2+, BCL6+, cyclin D1-, CD5-) in the colorectal area.
DIAGNOSIS: In accordance with manifestations on positron emission tomography-computed tomography (PET/CT), the patient was diagnosed with stage IV colorectal FL.
INTERVENTIONS: PET/CT reexamination after 2 courses of rituximab, cyclophosphamide, liposomal doxorubicin, vincristine sulfate, and hydroprednisone (R-CHOP) regimen and 3 courses of R-CHOP plus etoposide regimen for chemotherapy indicated a significant reduction in tumor burden. Subsequently, rituximab was administered alone in 2 treatment courses.
OUTCOMES: Lesions on PET/CT disappeared after reexamination. No recurrence was observed within the 12-month follow-up period.
LESSONS: Colorectal FL is a rare disease with an inert clinical course and is common in the ileocecal area. Endoscopic views show multiple polyps. Interventional treatment is usually provided after observation of clinical symptoms or during disease progression. The disease has a relatively good prognosis.

PMID: 30653103 [PubMed - indexed for MEDLINE]

[Implementing a population-based rare diseases registry in Spain: the Navarre´s experience].

Rev Esp Salud Publica. 2018 Nov 19;92:

Authors: Vicente E, Guevara M, Lasanta MJ, Ramos-Arroyo MA, Ardanaz E

Abstract
In 2012, the Spanish Rare Disease Registries Research Network (Spain-RDR) was consolidated with the aim of creating a Spanish population-based Rare Diseases Registry. In order to achieve this, each of the 17 Spanish Regions had to develop its own regional registry with a common agreed methodology. The Population-based Rare Disease Registry of Navarre was created in 2013 and, since then, its implementation is been carried out. Navarre assumed the agreed list within the Spanish Network, which included 934 codes of the International Classification of Diseases, 9th Revision, Clinical Modification. Initially, the main data source used to capture cases was the Assisted Morbidity Registry of Navarre, which includes the Minimum Basic Data Set of every regional hospital discharges (both public and private). Afterwards, new data sources were been added and ongoing validation studies of captured cases were been developed. Population-based rare diseases registries are fundamental for the study and quantification of this type of diseases since the classification and coding systems used in the current healthcare information systems are very nonspecific. The analysis and cross-referencing of data among multiple data sources is essential to maximize case detection capacity. Due to the low prevalence of these diseases, a high false positives rate among the detected cases greatly affects the estimation of epidemiological indicators, which makes it necessary to validate the cases by verifying the diagnoses.

PMID: 30442882 [PubMed - indexed for MEDLINE]

Isavuconazole treatment for rare fungal diseases and for invasive aspergillosis in patients with renal impairment: Challenges and lessons of the VITAL trial.

Mycoses. 2018 Jul;61(7):420-429

Authors: Perfect JR, Cornely OA, Heep M, Ostrosky-Zeichner L, Mullane KM, Maher R, Croos-Dabrera R, Lademacher C, Engelhardt M, Chen C, Marty FM

Abstract
Invasive fungal disease (IFD) confers a substantial risk for morbidity and mortality to immunocompromised patients. Invasive aspergillosis (IA) is the most common IFD caused by moulds but the prevalence of other rare mould diseases, such as mucormycosis, hyalohyphomycosis and phaeohyphomycosis, may be increasing. Treatments are available for IA, but evidence to support efficacy and safety of antifungal agents for rare IFDs, or for IFDs in special patient populations, is limited or lacking. The VITAL trial was conducted to assess the efficacy and safety of isavuconazole for the treatment of patients with IA and renal impairment, or with IFDs caused by rare moulds, yeasts or dimorphic fungi. These patients stand to benefit most from a new treatment option but are unlikely to be included in a randomised, controlled trial. In this article, we review the challenges faced in the design and conduct of the VITAL trial. We also review the findings of VITAL, which included evidence of the efficacy and safety of isavuconazole. Finally, we consider the importance of trials such as VITAL to inform therapeutic decision making for clinicians faced with the challenge of treating patients with rare IFDs and as one paradigm of how to determine efficacy and safety of new drugs for rare and resistant infections without a suitable comparator.

PMID: 29570857 [PubMed - indexed for MEDLINE]

Quantitative natural history characterization in a cohort of 142 published cases of patients with galactosialidosis-A cross-sectional study.

J Inherit Metab Dis. 2018 Dec 27;:

Authors: Sláma T, Garbade SF, Kölker S, Hoffmann GF, Ries M

Abstract
Galactosialidosis (GS; OMIM #256540) is a rare multisystemic inborn glycoprotein storage disease caused by biallelic mutations in the cathepsin A gene resulting in combined deficiency of the lysosomal enzymes β-galactosidase and α-neuraminidase. The precise understanding of the natural course of the disease is limited. Development of enzyme replacement therapy is at the preclinical stage. The purpose of this research project was to quantitatively characterize the natural history of the condition. Quantitative analysis of all published cases in the literature with sufficient data (N = 142 patients) was carried out. Main outcome variables were survival, diagnostic delay, description of symptoms, biomarker-phenotype associations, and radiological findings. STROBE criteria were respected. Median survival age of the cohort was 48 years. Median age of onset was 4.25 years with interquartile range (IQR) 1 to 16 years. Median age at diagnosis was 19 (IQR: 8.92-29) years, with median diagnostic delay of 8 (IQR: 4-12) years. Patients with residual β-galactosidase activity of more than 8.6% (leukocytes) survived significantly longer than patients with lower enzyme activities.

PMID: 30693535 [PubMed - as supplied by publisher]

IMP2 increases mouse skeletal muscle mass and voluntary activity by enhancing autocrine IGF2 production and optimizing muscle metabolism.

Mol Cell Biol. 2019 Jan 28;:

Authors: Regué L, Ji F, Flicker D, Kramer D, Pierce W, Davidoff T, Widrick JJ, Houstis N, Minichiello L, Dai N, Avruch J

Abstract
The IGF2 mRNA binding protein2/IMP2 was selectively deleted from adult mouse muscle; two phenotypes were observed: decreased accrual of skeletal muscle mass after weaning and reduced wheel running activity but normal forced treadmill performance. Reduced wheel running occurs when fed a high fat diet but is normalized consuming standard chow. The two phenotypes are due to altered abundance of different IMP2 client mRNAs. The reduced fiber size of IMP2 deficient muscle is attributable, in part, to diminished autocrine Igf2 production; basal tyrosine phosphorylation of the Insulin and IGF1 receptors is diminished and Akt1 activation is selectively reduced. Gsk3α is disinhibited and eIF2Bϵ[lsqb]S536[rsqb] hyperphosphorylated. Protein synthesis is reduced despite unaltered MTOR complex1 activity. The diet dependent reduction in voluntary exercise is likely due to altered muscle metabolism, as contractile function is normal. IMP2-deficient muscle exhibits reduced fatty acid oxidation, due to reduced abundance of PPARα mRNA, an IMP2 client, and PPARα protein. IMP2 deficient muscle fibers treated with mitochondrial uncoupler to increase electron flux, as occurs with exercise, exhibit reduced oxygen consumption from fatty acids with higher oxygen consumption from glucose. The greater dependence on muscle glucose metabolism during increased oxygen demand may promote central fatigue and thereby diminish voluntary activity.

PMID: 30692269 [PubMed - as supplied by publisher]

Development of a novel observer reported outcome tool as the primary efficacy outcome measure for a rare disease randomized controlled trial.

Mitochondrion. 2018 09;42:59-63

Authors: Stacpoole PW, Shuster J, Thompson JLPS, Prather RA, Lawson LA, Zou B, Buchsbaum R, Nixon SJ

Abstract
We developed an Observer-Reported Outcome (ObsRO) survey instrument to be applied in a multicenter, placebo-controlled, crossover randomized controlled trial of dichloroacetate in children with pyruvate dehydrogenase complex deficiency. The instrument quantifies a subject's at-home level of functionality, as reported by a parent/caregiver, who were instrumental in providing the clinical descriptors and domains that formed the instrument's content. Feasibility testing of the ObsRO tool showed it to be easy to use and comprehensive in capturing the major clinical functional limitations of affected children and requires less than 5min for a parent/caregiver to complete daily.

PMID: 29129554 [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 2019/01/29

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.

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 2019/01/27

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.

Pleural effusion in AA amyloidosis - A rare involvement of a rare disease.

Rev Port Pneumol (2006). 2017 Jul - Aug;23(4):234-236

Authors: Dias C, Tavares I, Magalhães A, Melo N

PMID: 28427884 [PubMed - indexed for MEDLINE]

Mastocytosis.

Gastroenterol Nurs. 2018 Sep/Oct;41(5):380-387

Authors: Birn CS

Abstract
Mastocytosis is a rare and underdiagnosed disorder characterized by mast cell proliferation in the tissues and organs of the body. The gastrointestinal manifestations of the disease can be noted in approximately 70%-80% of those patients diagnosed with the disorder. Symptomatic manifestations of systemic mastocytosis can either be triggered spontaneously or be precipitated by a variety of situations, stimuli, and exposures. Common gastrointestinal complaints include abdominal pain, diarrhea, nausea, vomiting, and gastrointestinal reflux disease. Substantial numbers of mast cells have been noted in patients who have been diagnosed with gastritis, ulcerative colitis, and Crohn disease. Irreversible, with symptoms that run the gamut from the merely annoying to the severely life-threatening, mastocytosis is a disease that prevents an individual from leading a normal life. As the prevalence of gastrointestinal symptomatology in those patients who have been diagnosed with mastocytosis is so significant, it is an important and relevant disease of which gastroenterology nurses should be cognizant.

PMID: 30272600 [PubMed - indexed for MEDLINE]

Linear IgA dermatosis: An atypical manifestation of a rare disease.

Pediatr Neonatol. 2018 06;59(3):324-325

Authors: Ferreira H, Vilarinho C

PMID: 29274682 [PubMed - indexed for MEDLINE]

Utility of Bayesian Single-Arm Design in New Drug Application for Rare Cancers in Japan: A Case Study of Phase 2 Trial for Sarcoma.

Ther Innov Regul Sci. 2018 05;52(3):334-338

Authors: Hirakawa A, Nishikawa T, Yonemori K, Shibata T, Nakamura K, Ando M, Ueda T, Ozaki T, Tamura K, Kawai A, Fujiwara Y

Abstract
Investigational drugs for rare cancers are often approved based solely on a single-arm phase II trial that primarily evaluates response rate in Japan. Such trials typically use a fixed sample size determined on the basis of the frequentist manner. However, since predicting the speed of patient enrollment is challenging because of the disease rarity, the time needed to complete the enrollment of the fixed number of patients is prolonged in some cases. A Bayesian design without fixing the sample size is useful for single-arm phase II trials of rare cancers. However, the arbitrariness of prior distribution specifications and the frequentist operating characteristics are regulatory issues. We recently started a Bayesian single-arm phase II trial of nivolumab in patients with sarcoma for new drug application in Japan and examined the statistical rationale and design consideration. In the Bayesian design, we specify the minimum and maximum numbers of enrolled patients during the enrollment period and the prior distributions of response rates. Considering these parameters, we obtain the minimum number of responders needed for the positive conclusion of the efficacy of nivolumab for each sample size. Simulation studies demonstrated that the operating characteristics of this design would be acceptable from the frequentist view. The Bayesian design provided an adaptive decision rule for efficacy conclusion for the drug without fixing the sample size. We hope our trial's success will provide a new drug development option for rare cancers in Japan.

PMID: 29714533 [PubMed - indexed for MEDLINE]

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 2019/01/23

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.

Whipple's Disease: A Well-Done Outcome to a Rare Disease.

Dig Dis Sci. 2019 01;64(1):9-11

Authors: Sellin J, Beales ILP

Abstract

PMID: 30406860 [PubMed - indexed for MEDLINE]

Rare Diseases Inform Myocardial Phenotypes for Precision Medicine.

J Card Fail. 2018 10;24(10):680-681

Authors: Macrae CA

PMID: 30218700 [PubMed - indexed for MEDLINE]

Evaluating The Impact Of The Orphan Drug Act's Seven-Year Market Exclusivity Period.

Health Aff (Millwood). 2018 05;37(5):732-737

Authors: Sarpatwari A, Beall RF, Abdurrob A, He M, Kesselheim AS

Abstract
For thirty-five years the Orphan Drug Act of 1983 has provided incentives for pharmaceutical manufacturers to develop drugs to treat rare diseases-conditions that affect fewer than 200,000 people in the US. One key statutory incentive is an exclusive seven-year marketing right for the rare disease indication, which has been heralded as driving a dramatic increase in the number of rare disease treatments. However, most new drugs are also protected by patents. In this study we assessed all new small-molecule drugs approved in the period 1985-2014 that had at least one indication for an orphan-designated disease as of January 1, 2017. We found that orphan drug exclusivity outlasted the last expiring patent in 33 percent of cases overall, and in a smaller percentage of cases for each successive ten-year drug cohort: from 50 percent for drugs approved in 1985-94 to 35 percent for those approved in 1995-2004 and 18 percent for those approved in 2005-14. The Orphan Drug Act's market exclusivity incentive has played an increasingly smaller role in protecting rare disease drugs from competition, while rare disease drugs have substantially increased as a fraction of all new drug approvals.

PMID: 29733729 [PubMed - indexed for MEDLINE]

Embolization of a large progressive symptomatic desmoid tumor in the rectus muscle of a female patient with multiple sclerosis: a case report.

Acta Chir Belg. 2018 Jun;118(3):192-195

Authors: Diebels I, Blockhuys M, Willemsen P, Pirenne Y

Abstract
INTRODUCTION: Desmoid tumors are benign tumors, yet can lead to significant morbidity due to aggressive local expansions. Treatment starts with a wait-and-see policy, however, more aggressive treatments like broad margin resection surgery might be necessary in case of tumor progression.
PATIENTS AND METHODS: We report the case of a 26-year-old female with a symptomatic desmoid tumor in the left rectus muscle. The initial wait-and-see policy led to an increase in tumor size and progression of symptoms. Computed tomography (CT) angiography revealed a dominant arterial blood supply via a branch of the inferior epigastric artery. We then performed a super selective embolization of the dominant arterial blood supply, to avoid the need for broad margin resection.
RESULTS: At three months follow-up, the patient was asymptomatic and magnetic resonance imaging (MRI) showed no residual tumor. At nine months follow-up, MRI scan reconfirmed the successful outcome.
CONCLUSIONS: Embolization of a primary supplying vessel of a desmoid tumor is a viable treatment option. However, scientific evidence remains limited and further research is mandatory for inclusion in evidence based treatment algorithms.

PMID: 28641503 [PubMed - indexed for MEDLINE]