The lysosomal disease caused by mutant VPS33A.

Hum Mol Genet. 2019 Apr 10;:

Authors: Pavlova EV, Shatunov A, Wartosch L, Moskvina AI, Nikolaeva LE, Bright NA, Tylee KL, Church HJ, Ballabio A, Luzio JP, Cox TM

Abstract
A rare lysosomal disease resembling a mucopolysaccharidosis with unusual systemic features, including renal disease and platelet dysfunction, caused by the defect in a conserved region of the VPS33A gene on human chromosome 12q24.31, occurs in Yakuts-a nomadic Turkic ethnic group of Southern Siberia. VPS33A is a core component of the class C core vacuole/endosome tethering (CORVET) and the homotypic fusion and protein sorting (HOPS) complexes, which have essential functions in the endocytic pathway. Here we show that cultured fibroblasts from patients with this disorder have morphological changes: vacuolation with disordered endosomal/lysosomal compartments and-common to sphingolipid diseases-abnormal endocytic trafficking of lactosylceramide. Urine glycosaminoglycan studies revealed a pathological excess of sialylated conjugates as well as dermatan and heparan sulphate. Lipidomic screening showed elevated β-D-galactosylsphingosine with unimpaired activity of cognate lysosomal hydrolases. The 3D crystal structure of human VPS33A predicts that replacement of arginine 498 by tryptophan will de-stabilize VPS33A folding. We observed that the missense mutation reduced the abundance of full-length VPS33A and other components of the HOPS and CORVET complexes. Treatment of HeLa cells stably expressing the mutant VPS33A with a proteasome inhibitor rescued the mutant protein from degradation. We propose that the disease is due to diminished intracellular abundance of intact VPS33A. Exposure of patient-derived fibroblasts to the clinically approved proteasome inhibitor, bortezomib, or inhibition of glucosylceramide synthesis with eliglustat, partially corrected the impaired lactosylceramide trafficking defect and immediately suggest therapeutic avenues to explore in this fatal orphan disease.

PMID: 31070736 [PubMed - as supplied by publisher]

Common genetic variants contribute to risk of rare severe neurodevelopmental disorders.

Nature. 2018 10;562(7726):268-271

Authors: Niemi MEK, Martin HC, Rice DL, Gallone G, Gordon S, Kelemen M, McAloney K, McRae J, Radford EJ, Yu S, Gecz J, Martin NG, Wright CF, Fitzpatrick DR, Firth HV, Hurles ME, Barrett JC

Abstract
There are thousands of rare human disorders that are caused by single deleterious, protein-coding genetic variants1. However, patients with the same genetic defect can have different clinical presentations2-4, and some individuals who carry known disease-causing variants can appear unaffected5. Here, to understand what explains these differences, we study a cohort of 6,987 children assessed by clinical geneticists to have severe neurodevelopmental disorders such as global developmental delay and autism, often in combination with abnormalities of other organ systems. Although the genetic causes of these neurodevelopmental disorders are expected to be almost entirely monogenic, we show that 7.7% of variance in risk is attributable to inherited common genetic variation. We replicated this genome-wide common variant burden by showing, in an independent sample of 728 trios (comprising a child plus both parents) from the same cohort, that this burden is over-transmitted from parents to children with neurodevelopmental disorders. Our common-variant signal is significantly positively correlated with genetic predisposition to lower educational attainment, decreased intelligence and risk of schizophrenia. We found that common-variant risk was not significantly different between individuals with and without a known protein-coding diagnostic variant, which suggests that common-variant risk affects patients both with and without a monogenic diagnosis. In addition, previously published common-variant scores for autism, height, birth weight and intracranial volume were all correlated with these traits within our cohort, which suggests that phenotypic expression in individuals with monogenic disorders is affected by the same variants as in the general population. Our results demonstrate that common genetic variation affects both overall risk and clinical presentation in neurodevelopmental disorders that are typically considered to be monogenic.

PMID: 30258228 [PubMed - indexed for MEDLINE]

Rare advances for rare diseases.

Lancet Neurol. 2017 01;16(1):1

Authors: The Lancet Neurology

PMID: 27979337 [PubMed - indexed for MEDLINE]

Revisiting the NIH Taskforce on the Research needs of Eosinophil-Associated Diseases (RE-TREAD).

J Leukoc Biol. 2018 07;104(1):69-83

Authors: Khoury P, Akuthota P, Ackerman SJ, Arron JR, Bochner BS, Collins MH, Kahn JE, Fulkerson PC, Gleich GJ, Gopal-Srivastava R, Jacobsen EA, Leiferman KM, Francesca LS, Mathur SK, Minnicozzi M, Prussin C, Rothenberg ME, Roufosse F, Sable K, Simon D, Simon HU, Spencer LA, Steinfeld J, Wardlaw AJ, Wechsler ME, Weller PF, Klion AD

Abstract
Eosinophil-associated diseases (EADs) are rare, heterogeneous disorders characterized by the presence of eosinophils in tissues and/or peripheral blood resulting in immunopathology. The heterogeneity of tissue involvement, lack of sufficient animal models, technical challenges in working with eosinophils, and lack of standardized histopathologic approaches have hampered progress in basic research. Additionally, clinical trials and drug development for rare EADs are limited by the lack of primary and surrogate endpoints, biomarkers, and validated patient-reported outcomes. Researchers with expertise in eosinophil biology and eosinophil-related diseases reviewed the state of current eosinophil research, resources, progress, and unmet needs in the field since the 2012 meeting of the NIH Taskforce on the Research of Eosinophil-Associated Diseases (TREAD). RE-TREAD focused on gaps in basic science, translational, and clinical research on eosinophils and eosinophil-related pathogenesis. Improved recapitulation of human eosinophil biology and pathogenesis in murine models was felt to be of importance. Characterization of eosinophil phenotypes, the role of eosinophil subsets in tissues, identification of biomarkers of eosinophil activation and tissue load, and a better understanding of the role of eosinophils in human disease were prioritized. Finally, an unmet need for tools for use in clinical trials was emphasized. Histopathologic scoring, patient- and clinician-reported outcomes, and appropriate coding were deemed of paramount importance for research collaborations, drug development, and approval by regulatory agencies. Further exploration of the eosinophil genome, epigenome, and proteome was also encouraged. Although progress has been made since 2012, unmet needs in eosinophil research remain a priority.

PMID: 29672914 [PubMed - indexed for MEDLINE]

[25 Years of ESPED as a Surveillance Tool for Rare Diseases in Children in Germany: A Critical Analysis].

Klin Padiatr. 2018 Jul;230(4):215-224

Authors: Ebrahimi-Fakhari D, Zemlin M, Sauer H, Poryo M, Graf N, Meyer S

Abstract
BACKGROUND: The German Paediatric Surveillance Unit (ESPED) was founded in 1992 to generate incidence data and detailed clinical descriptions of rare, childhood-onset diseases.
METHODS: Retrospective analysis of the ESPED epidemiological data collection from 1992-2017, and analysis of all published national and international publications originating from ESPED surveys. Center of Disease Control and Prevention (CDC) criteria for evaluating surveillance systems (simplicity, flexibility, timeliness, usefulness, data quality, representativeness, stability and acceptability) were adopted and applied to available ESPED data.
RESULTS: Between 1992 and 2017 ESPED completed 96 prospective studies on rare diseases in children. The 3 most frequent clinical entities were: Infectious/communicable disease (n=30), neurological diseases (n = 14) and hematologic diseases (n=10). Studies resulted in 337 publications in national and international journals. The median impact factor of the 192 journal publications with (impact factor) was 2,587 (range 0,032-28,409). The highest impact factors were seen in the fields of endocrinology/metabolism (n=130; median IF=3,534), infectious diseases (n=83; median IF=3,131) and hematology (n=37; median IF=2,497). Our analysis indicates that ESPED surveys meet CDC quality standards.
CONCLUSION: ESPED surveys are an important contributor in the field of clinical epidemiology in children with rare diseases. The high quality of ESPED surveys is reflected by high-impact publications in both national and international journals.

PMID: 29614515 [PubMed - indexed for MEDLINE]

Trajectory Algorithms to Infer Stem Cell Fate Decisions.

Methods Mol Biol. 2019;1975:193-209

Authors: Lummertz da Rocha E, Malleshaiah M

Abstract
Single-cell trajectory analysis is an active research area in single-cell genomics aiming at developing sophisticated algorithms to reconstruct complex cell-state transition trajectories. Here, we present a step-by-step protocol to use CellRouter, a multifaceted single-cell analysis platform that integrates subpopulation identification, gene regulatory networks, and trajectory inference to precisely and flexibly reconstruct complex single-cell trajectories. Subpopulations are either user-defined or identified by a graph-clustering approach in which a k-nearest neighbor graph (kNN) is created from cell-to-cell distances in a low-dimensional embedding. Edges in this graph are weighted by network similarity metrics (e.g., Jaccard index) to robustly encode phenotypic relatedness, creating a representation of single-cell transcriptomes suitable for community detection algorithms to identify clusters of densely connected cells. This subpopulation structure represents a map of putative cell-state transitions. CellRouter implements a flow network algorithm to explore this map and reconstruct cell-state transitions in complex single-cell, multidimensional omics datasets. We describe a step-by-step application of CellRouter to hematopoietic stem and progenitor cell differentiation toward four major lineages-erythrocytes, megakaryocytes, monocytes, and granulocytes-to demonstrate key components of CellRouter for single-cell trajectory analysis.

PMID: 31062311 [PubMed - in process]

Rare Presentation of Dercum's Disease in a Child with Abnormalities in Lipoprotein Metabolism.

Arq Bras Cardiol. 2018 11;111(5):755-757

Authors: Izar MCO, Fonseca HARD, França CN, Machado VA, Ferreira CEDS, Fonseca FAH

PMID: 30484519 [PubMed - indexed for MEDLINE]

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Treatable inherited rare movement disorders.

Mov Disord. 2018 01;33(1):21-35

Authors: Jinnah HA, Albanese A, Bhatia KP, Cardoso F, Da Prat G, de Koning TJ, Espay AJ, Fung V, Garcia-Ruiz PJ, Gershanik O, Jankovic J, Kaji R, Kotschet K, Marras C, Miyasaki JM, Morgante F, Munchau A, Pal PK, Rodriguez Oroz MC, Rodríguez-Violante M, Schöls L, Stamelou M, Tijssen M, Uribe Roca C, de la Cerda A, Gatto EM, International Parkinson's Disease Movement Disorders Society Task Force on Rare Movement Disorders

Abstract
There are many rare movement disorders, and new ones are described every year. Because they are not well recognized, they often go undiagnosed for long periods of time. However, early diagnosis is becoming increasingly important. Rapid advances in our understanding of the biological mechanisms responsible for many rare disorders have enabled the development of specific treatments for some of them. Well-known historical examples include Wilson disease and dopa-responsive dystonia, for which specific and highly effective treatments have life-altering effects. In recent years, similarly specific and effective treatments have been developed for more than 30 rare inherited movement disorders. These treatments include specific medications, dietary changes, avoidance or management of certain triggers, enzyme replacement therapy, and others. This list of treatable rare movement disorders is likely to grow during the next few years because a number of additional promising treatments are actively being developed or evaluated in clinical trials. © 2017 International Parkinson and Movement Disorder Society.

PMID: 28861905 [PubMed - indexed for MEDLINE]

Future of Rare Diseases Research 2017-2027: An IRDiRC Perspective.

Clin Transl Sci. 2018 01;11(1):21-27

Authors: Austin CP, Cutillo CM, Lau LPL, Jonker AH, Rath A, Julkowska D, Thomson D, Terry SF, de Montleau B, Ardigò D, Hivert V, Boycott KM, Baynam G, Kaufmann P, Taruscio D, Lochmüller H, Suematsu M, Incerti C, Draghia-Akli R, Norstedt I, Wang L, Dawkins HJS, International Rare Diseases Research Consortium (IRDiRC)

PMID: 28796445 [PubMed - indexed for MEDLINE]

Progress in Rare Diseases Research 2010-2016: An IRDiRC Perspective.

Clin Transl Sci. 2018 01;11(1):11-20

Authors: Dawkins HJS, Draghia-Akli R, Lasko P, Lau LPL, Jonker AH, Cutillo CM, Rath A, Boycott KM, Baynam G, Lochmüller H, Kaufmann P, Le Cam Y, Hivert V, Austin CP, International Rare Diseases Research Consortium (IRDiRC)

PMID: 28796411 [PubMed - indexed for MEDLINE]

Fibro Dysplasia Ossificans Progressiva.

J Ayub Med Coll Abbottabad. 2019 Jan-Mar;31(1):123-126

Authors: Ahmed W, Safdar A, Ahmed I, Ahmed N

Abstract
We present a case of 7 years old boy with a very rare debilitating autosomal dominant disorder characterized by heterotopic ossification. Fibro dysplasia ossificans progressiva affects 1 in 2 million individuals with only 2 previous cases reported from this region. The disease manifests as multiple foci of bone formation in muscles, fasciae, tendons and ligaments often triggered by trauma. The child was born with bilateral short hallux valgus and aplasia of distal phalanges of both thumbs. In the last 3 years he had developed hard bony swellings in the scalp, followed by limitation of neck mobility. He developed palpable nodules on the right lateral thoracic cage over the last 1 year following trauma. Heterotopic bone formation was also seen in both tibias. FOP causes irreversible lesions of ossification thus early institution of prophylactic measures, counselling regarding avoidance of trauma and surgery can significantly reduce acute exacerbations of this rare disease.

PMID: 30868796 [PubMed - in process]

Oncocytic cyst of the larynx: a rare finding.

BMJ Case Rep. 2019 Jan 18;12(1):

Authors: Baird S, Mann H, Salinas-La Rosa CM, Ozdemir H

Abstract
A 75-year-old woman presented with an 18-month history of severe, slowly worsening dysphonia. She was a smoker and known to have multiple benign cystic thyroid lesions. She reported no associated symptoms and other medical and social history was unremarkable. Fibreoptic nasendoscopy revealed a right-sided supraglottic cyst appearing to arise from the right false vocal cord. Further bedside examination was unremarkable. She underwent microlaryngoscopy and biopsy which showed a cyst originating from the right anterior ventricle, successfully removed without rupture using cold steel. Formal histopathology revealed a 14×10×7 mm unilocular, completely excised cyst lined by oncocytic epithelium and composed of columnar cells with darkly stained nuclei and abundant granular, eosinophilic cytoplasm. Three weeks postoperatively the patient's voice had returned to normal. To date, 11 months postoperatively, there is no evidence of recurrence, and she will continue long-term follow-up.

PMID: 30661046 [PubMed - in process]

SSEv: A New Small Samples Evaluator Based on Modified Survival Curves.

Adv Exp Med Biol. 2017;989:265-270

Authors: Geronikolou S, Zimeras S

Abstract
Rare diseases, either of genetic or epigenetic origin, either proliferative or degenerative, are hard to be studied credibly, because of sparse prevalence, thus, small sampling. In addition, biological or translational experimentation either with animal models, or in vitro studies share small sampling-often due to lack of financial support or due to mannered and costly techniques. Pilot or feasibility studies been performed, before expensive clinical trials are decided, focus on small samples. Small Samples Evaluator (SSEv) is a useful tool based on a modification of survival curves. The technique can be applied to repeated measures, as well as to case-control or cross-sectional designed studies. A web-based application of SSEv is created and presented herein. The application is freely accessible at: https://ssev.eu .

PMID: 28971434 [PubMed - in process]

Susac syndrome presenting with acute hemibody paraesthesia.

JRSM Cardiovasc Dis. 2019 Jan-Dec;8:2048004019844687

Authors: Campbell P, Kaski D, Saifee TA

Abstract
Susac syndrome is an orphan disease characterised by encephalopathy, branch retinal artery occlusion and sensorineural hearing loss. As the clinical triad is rarely present at symptom onset, it is often initially misdiagnosed and appropriate treatment is often delayed. Herewith, we report a case of Susac syndrome in a 47-year-old man presenting with acute hemisensory loss and highlight the challenges of early diagnosis, particularly relevant in the era of hyperacute stroke management.

PMID: 31041097 [PubMed]

Aggregatibacter actinomycetemcomitans (Aa) Under the Radar: Myths and Misunderstandings of Aa and Its Role in Aggressive Periodontitis.

Front Immunol. 2019;10:728

Authors: Fine DH, Patil AG, Velusamy SK

Abstract
Aggregatibacter actinomycetemcomitans (Aa) is a low-abundance Gram-negative oral pathobiont that is highly associated with a silent but aggressive orphan disease that results in periodontitis and tooth loss in adolescents of African heritage. For the most part Aa conducts its business by utilizing strategies allowing it to conceal itself below the radar of the host mucosal immune defense system. A great deal of misinformation has been conveyed with respect to Aa biology in health and disease. The purpose of this review is to present misconceptions about Aa and the strategies that it uses to colonize, survive, and evade the host. In the process Aa manages to undermine host mucosal defenses and contribute to disease initiation. This review will present clinical observational, molecular, and interventional studies that illustrate genetic, phenotypic, and biogeographical tactics that have been recently clarified and demonstrate how Aa survives and suppresses host mucosal defenses to take part in disease pathogenesis. At one point in time Aa was considered to be the causative agent of Localized Aggressive Periodontitis. Currently, it is most accurate to look at Aa as a community activist and necessary partner of a pathogenic consortium that suppresses the initial host response so as to encourage overgrowth of its partners. The data for Aa's activist role stems from molecular genetic studies complemented by experimental animal investigations that demonstrate how Aa establishes a habitat (housing), nutritional sustenance in that habitat (food), and biogeographical mobilization and/or relocation from its initial habitat (transportation). In this manner Aa can transfer to a protected but vulnerable domain (pocket or sulcus) where its community activism is most useful. Aa's "strategy" includes obtaining housing, food, and transportation at no cost to its partners challenging the economic theory that "there ain't no such thing as a free lunch." This "strategy" illustrates how co-evolution can promote Aa's survival, on one hand, and overgrowth of community members, on the other, which can result in local host dysbiosis and susceptibility to infection.

PMID: 31040843 [PubMed - in process]

Metastatic choroidal melanoma to the contralateral eye: a rare case.

Arq Bras Oftalmol. 2018 Nov./Dec.;81(6):517-519

Authors: Belfort RN, Müller MS, Isenberg J, Ferraz P, Szejnfeld D

Abstract
Uveal melanoma is the most common adult primary intraocular cancer. Although liver metastasis is common to the natural history of the disease, metastasis to the fellow eye is extremely rare. Here we report the case of a 59-year-old man with choroidal melanoma in his right eye who underwent enucleation at a different center. The patient was referred to our service 21 months postoperatively, complaining of decreased vision. He was found to have a new pigmented choroidal tumor in his left eye associated with liver disease. Ocular ultrasonography and liver biopsy with histopathological and immunohistochemical analysis were performed and confirmed the diagnosis. Few similar cases have been described in the literature. The differential diagnosis included primary bilateral choroidal melanoma and metastatic choroidal tumor from a primary skin melanoma.

PMID: 30328940 [PubMed - indexed for MEDLINE]

Use of a rare disease patient registry in long-term post-authorisation drug studies: a model for collaboration with industry.

Lancet Respir Med. 2018 07;6(7):495-496

Authors: Bilton D, Caine N, Cunningham S, Simmonds NJ, Cosgriff R, Carr SB

PMID: 29735358 [PubMed - indexed for MEDLINE]

Rare left ventricular metastasis from uveal melanoma.

Cardiol J. 2017;24(6):712-714

Authors: Zardi EM, Cacioli G, Giorgi C, Rafano Carnà EP, Zardi DM

PMID: 29297586 [PubMed - indexed for MEDLINE]

Blastic Plasmacytoid Dendritic Cell Neoplasm: State of the Art and Prospects.

Cancers (Basel). 2019 Apr 28;11(5):

Authors: Sapienza MR, Pileri A, Derenzini E, Melle F, Motta G, Fiori S, Calleri A, Pimpinelli N, Tabanelli V, Pileri S

Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an extremely rare tumour, which usually affects elderly males and presents in the skin with frequent involvement of the bone-marrow, peripheral blood and lymph nodes. It has a dismal prognosis, with most patients dying within one year when treated by conventional chemotherapies. The diagnosis is challenging, since neoplastic cells can resemble lymphoblasts or small immunoblasts, and require the use of a large panel of antibodies, including those against CD4, CD56, CD123, CD303, TCL1, and TCF4. The morphologic and in part phenotypic ambiguity explains the uncertainties as to the histogenesis of the neoplasm that led to the use of various denominations. Recently, a series of molecular studies based on karyotyping, gene expression profiling, and next generation sequencing, have largely unveiled the pathobiology of the tumour and proposed the potentially beneficial use of new drugs. The latter include SL-401, anti-CD123 immunotherapies, venetoclax, BET-inhibitors, and demethylating agents. The epidemiologic, clinical, diagnostic, molecular, and therapeutic features of BPDCN are thoroughly revised in order to contribute to an up-to-date approach to this tumour that has remained an orphan disease for too long.

PMID: 31035408 [PubMed]