Lysosomal Proteins as a Therapeutic Target in Neurodegeneration.

Annu Rev Med. 2017 Jan 14;68:445-458

Authors: Mc Donald JM, Krainc D

Abstract
Several proteins that are mutated in lysosomal storage diseases are linked to neurodegenerative disease. This review focuses on some of these lysosomal enzymes and transporters, as well as current therapies that have emerged from the lysosomal storage disease field. Given the deeper genetic understanding of lysosomal defects in neurodegeneration, we explore why some of these orphan disease drug candidates are also attractive targets in subpopulations of individuals with neurodegenerative disease.

PMID: 28099085 [PubMed - in process]

Managed care approach to the treatment of neurogenic orthostatic hypotension.

Am J Manag Care. 2015 Oct;21(13 Suppl):s258-68

Authors: Isaacson SH

Abstract
Neurogenic orthostatic hypotension (NOH) is an orphan disease that primarily affects patients with neurodegenerative disorders such as Parkinson's disease and multiple system atrophy. The first step in the management of NOH is to discontinue or minimize the use of drugs that lower blood pressure. Nonpharmacologic therapy for NOH includes physical countermaneuvers, compression abdominal binders and lower extremity stockings, recognition and avoidance of orthostatic stressors, hydration, and salt supplementation. The management of NOH should also include interventions to prevent falls. Pharmacotherapy for NOH includes the mineralocorticoid drug fludrocortisone to expand plasma volume and the sympathomimetic drugs midodrine and droxidopa. Clinical efficacy, tolerability, and the role of each drug in the treatment paradigm are reviewed here.

PMID: 26790110 [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 2017/01/18

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.

Postal recruitment and consent obtainment from index cases of narcolepsy.

BMC Med Ethics. 2016 Jan 16;17:6

Authors: Aliyu G, Mahmud SM

Abstract
BACKGROUND: Access to research volunteers may be hampered by low numbers of cases and few eligible participants for rare diseases in clinical settings.
METHODS: We recruited volunteers and obtained informed consent by mail from narcolepsy cases in a case-control study, and here in we report feasibility, response rate, timeliness and cost. We invited index cases into the study by mail through their care-giving physicians then mailed study information and consent forms to cases that indicated interest in the study.
RESULTS: Of the 33 index cases invited, 15 (45.0%) expressed interest in the study, and of those, 14 (93.3%) returned their signed informed consents by mail. The median number of days from invitation to consent return was 39, interquartile range = 45, and the cost per consent obtained from the recruited subjects was $ 23.61.
CONCLUSION: In this setting, postal recruitment for biomedical research on rare conditions is feasible and time and cost effective.

PMID: 26772982 [PubMed - indexed for MEDLINE]

Superficial morphea of the lips and gingiva.

Acta Dermatovenerol Croat. 2015;23(2):152-4

Authors: Vučićević Boras V, Gabrić D, Brailo V, Čikeš N, Velimir Vrdoljak D

PMID: 26228830 [PubMed - indexed for MEDLINE]

Subcutaneous cavernous angiolipoma: a new soft-tissue entity.

Acta Dermatovenerol Croat. 2015;23(2):144-5

Authors: Roncati L, Pusiol T, Piscioli F, Maiorana A

PMID: 26228827 [PubMed - indexed for MEDLINE]

Hypophosphatasia: Enzyme Replacement Therapy Brings New Opportunities and New Challenges.

J Bone Miner Res. 2017 Jan 13;:

Authors: Whyte MP

Abstract
At this time last year, 2015, our field achieved a milestone in the management of rickets and osteomalacia. Among the disorders that feature generalized impairment of hard tissue mineralization and its consequences, the final entity lacking a medical treatment acquired one sanctioned internationally by regulatory agencies. The holdout was hypophosphatasia (HPP), the inborn-error-of-metabolism identified in 1948 and caused by loss-of-function mutation(s) of the TNSALP (ALPL) gene that encodes the "tissue-nonspecific" isoenzyme of alkaline phosphatase (TNSALP). The therapy is asfotase alfa, a recombinant mineral-targeted ALP now approved for pediatric-onset HPP. This advance ended hopelessness for many HPP patients, and offers physicians successes in treating an orphan disease. However, as I will discuss, a number of challenges call for further progress and an especially thorough understanding of HPP, including its remarkably wide-ranging severity. Reviews concerning HPP, including comprehensive reports from testing this biologic in pediatric patients,have been published recently. This article is protected by copyright. All rights reserved.

PMID: 28084648 [PubMed - as supplied by publisher]

Alveolar echinococcosis - a rare disease with differential diagnostic problems.

Rozhl Chir. Summer 2016;95(6):240-4

Authors: Třeška V, Kolářová L, Mírka H, Daum O, Matějů J, Liška V, Koubová A, Sedláček D

Abstract
INTRODUCTION: Alveolar echinococcosis is a life-threatening zoonotic parasitic disease. Its incidence is rare. In some cases, the correct and timely diagnosis can be difficult.
CASE REPORT: The authors present the case of a young patient with liver, diaphragm and lung involvement. The suspicion of echinococcus infection was made on the basis of medical history, clinical symptoms, and a combination of ultrasonography, computed tomography, magnetic resonance imaging tests and serological methods. The patient underwent multimodal treatment with albendazole and en-bloc resection of the liver, lung and diaphragm. The definitive diagnosis of alveolar echinococcosis was determined from samples of the resected tissues using histopathology and polymerase chain reaction methods. The patient has been followed regularly and is on life-long treatment with albendazole.
CONCLUSION: The precise diagnosis and multimodal therapy of alveolar echinococcosis is fundamental from the point of view of patient long-term survival.
KEY WORDS: alveolar echinococcosis - diagnosis - multimodal treatment - follow-up.

PMID: 27410758 [PubMed - indexed for MEDLINE]

Establishment and Maintenance of Primary Fibroblast Repositories for Rare Diseases-Friedreich's Ataxia Example.

Biopreserv Biobank. 2016 Aug;14(4):324-9

Authors: Li Y, Polak U, Clark AD, Bhalla AD, Chen YY, Li J, Farmer J, Seyer L, Lynch D, Butler JS, Napierala M

Abstract
Friedreich's ataxia (FRDA) represents a rare neurodegenerative disease caused by expansion of GAA trinucleotide repeats in the first intron of the FXN gene. The number of GAA repeats in FRDA patients varies from approximately 60 to <1000 and is tightly correlated with age of onset and severity of the disease symptoms. The heterogeneity of Friedreich's ataxia stresses the need for a large cohort of patient samples to conduct studies addressing the mechanism of disease pathogenesis or evaluate novel therapeutic candidates. Herein, we report the establishment and characterization of an FRDA fibroblast repository, which currently includes 50 primary cell lines derived from FRDA patients and seven lines from mutation carriers. These cells are also a source for generating induced pluripotent stem cell (iPSC) lines by reprogramming, as well as disease-relevant neuronal, cardiac, and pancreatic cells that can then be differentiated from the iPSCs. All FRDA and carrier lines are derived using a standard operating procedure and characterized to confirm mutation status, as well as expression of FXN mRNA and protein. Consideration and significance of creating disease-focused cell line and tissue repositories, especially in the context of rare and heterogeneous disorders, are presented. Although the economic aspect of creating and maintaining such repositories is important, the benefits of easy access to a collection of well-characterized cell lines for the purpose of drug discovery or disease mechanism studies overshadow the associated costs. Importantly, all FRDA fibroblast cell lines collected in our repository are available to the scientific community.

PMID: 27002638 [PubMed - indexed for MEDLINE]

Hereditary Sensory Autonomic Neuropathy II, a rare disease in a large Pakistani family.

J Pak Med Assoc. 2015 Oct;65(10):1128-30

Authors: Arain FM, Chand P

Abstract
Hereditary Sensory Autonomic Neuropathy II (HSAN II) is a rare genetic disorder, characterized by severe loss of pain, temperature and touch sensation. Injuries in these patients can progress to necrosis and shedding of digits and limbs. Here we report two cases of HSAN II belonging to a Pakistani family. Individual 1, a forty five year old man, had complete loss of pain sensation since birth. Self-mutilation and complication of injuries resulted in the shedding of all the digits and right foot and surgical amputation of left leg. Individual 2, a five year old girl,had delay in healing of wounds and self-mutilation. Examination showed a complete lack of pain sensation throughout her body and hyporeflexia. As the genetic cause of HSAN II is unknown, identification of more patients will allow further research on this disease and possibly develop a cure.

PMID: 26440849 [PubMed - indexed for MEDLINE]

A curated gene list for reporting results of newborn genomic sequencing.

Genet Med. 2017 Jan 12;:

Authors: Ceyhan-Birsoy O, Machini K, Lebo MS, Yu TW, Agrawal PB, Parad RB, Holm IA, McGuire A, Green RC, Beggs AH, Rehm HL

Abstract
PURPOSE: Genomic sequencing (GS) for newborns may enable detection of conditions for which early knowledge can improve health outcomes. One of the major challenges hindering its broader application is the time it takes to assess the clinical relevance of detected variants and the genes they impact so that disease risk is reported appropriately.
METHODS: To facilitate rapid interpretation of GS results in newborns, we curated a catalog of genes with putative pediatric relevance for their validity based on the ClinGen clinical validity classification framework criteria, age of onset, penetrance, and mode of inheritance through systematic evaluation of published evidence. Based on these attributes, we classified genes to guide the return of results in the BabySeq Project, a randomized, controlled trial exploring the use of newborn GS (nGS), and used our curated list for the first 15 newborns sequenced in this project.
RESULTS: Here, we present our curated list for 1,514 gene-disease associations. Overall, 954 genes met our criteria for return in nGS. This reference list eliminated manual assessment for 41% of rare variants identified in 15 newborns.
CONCLUSION: Our list provides a resource that can assist in guiding the interpretive scope of clinical GS for newborns and potentially other populations.Genet Med advance online publication 12 January 2017Genetics in Medicine (2017); doi:10.1038/gim.2016.193.

PMID: 28079900 [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 2017/01/11

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 2017/01/10

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.

4-HYDROXYNONENAL PROTEIN ADDUCTS: KEY MEDIATOR IN RETT SYNDROME OXINFLAMMATION.

Free Radic Biol Med. 2017 Jan 04;:

Authors: Valacchi G, Pecorelli A, Cervellati C, Hayek J

Abstract
In the last 15 years a strong correlation between oxidative stress (OxS) and Rett syndrome (RTT), a rare neurodevelopmental disorder known to be caused in 95% of the cases, by a mutation in the methyl-CpG-binding protein 2 (MECP2) gene, has been well documented. Here, we revised, summarized and discussed the current knowledge on the role of lipid peroxidation byproducts, with special emphasis on 4-hydroxynonenal (4HNE), in RTT pathophysiology. The posttranslational modifications of proteins via 4HNE, known as 4HNE protein adducts (4NHE-PAs), causing detrimental effects on protein functions, appear to contribute to the clinical severity of the syndrome, since their levels increase significantly during the subsequent 4 clinical stages, reaching the maximum degree at stage 4, represented by a late motor deterioration. In addition, 4HNE-PA are only partially removed due to the compromised functionality of the proteasome activity, contributing therefore to the cellular damage in RTT. All this will lead to a characteristic subclinical inflammation, defined "OxInflammation", derived by a positive feedback loop between OxS byproducts and inflammatory mediators that in a long run further aggravates the clinical features of RTT patients. Therefore, in a pathology completely orphan of any therapy, aiming 4HNE as a  therapeutic target could represent a coadjuvant treatment with some beneficial impact in these patients.‬‬‬.

PMID: 28063942 [PubMed - as supplied by publisher]

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 2017/01/07

PubMed comprises more than 24 million 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.

Mouse Models for Drug Discovery. Can New Tools and Technology Improve Translational Power?

ILAR J. 2016 Dec;57(2):178-185

Authors: Zuberi A, Lutz C

Abstract
The use of mouse models in biomedical research and preclinical drug evaluation is on the rise. The advent of new molecular genome-altering technologies such as CRISPR/Cas9 allows for genetic mutations to be introduced into the germ line of a mouse faster and less expensively than previous methods. In addition, the rapid progress in the development and use of somatic transgenesis using viral vectors, as well as manipulations of gene expression with siRNAs and antisense oligonucleotides, allow for even greater exploration into genomics and systems biology. These technological advances come at a time when cost reductions in genome sequencing have led to the identification of pathogenic mutations in patient populations, providing unprecedented opportunities in the use of mice to model human disease. The ease of genetic engineering in mice also offers a potential paradigm shift in resource sharing and the speed by which models are made available in the public domain. Predictively, the knowledge alone that a model can be quickly remade will provide relief to resources encumbered by licensing and Material Transfer Agreements. For decades, mouse strains have provided an exquisite experimental tool to study the pathophysiology of the disease and assess therapeutic options in a genetically defined system. However, a major limitation of the mouse has been the limited genetic diversity associated with common laboratory mice. This has been overcome with the recent development of the Collaborative Cross and Diversity Outbred mice. These strains provide new tools capable of replicating genetic diversity to that approaching the diversity found in human populations. The Collaborative Cross and Diversity Outbred strains thus provide a means to observe and characterize toxicity or efficacy of new therapeutic drugs for a given population. The combination of traditional and contemporary mouse genome editing tools, along with the addition of genetic diversity in new modeling systems, are synergistic and serve to make the mouse a better model for biomedical research, enhancing the potential for preclinical drug discovery and personalized medicine.

PMID: 28053071 [PubMed - in process]

Familial florid osseous dysplasia: a report with review of the literature.

BMJ Case Rep. 2016 Mar 30;2016:

Authors: Kucukkurt S, Rzayev S, Baris E, Atac MS

Abstract
There are three types of osseous dysplasia: periapical cemental dysplasia (PCD), focal cemento-osseous dysplasia (FCD) and florid osseous dysplasia (FOD). While PCD is often observed in mandibular anterior teeth, FCD mainly affects mandibular posterior teeth. FOD, on the other hand, commonly involves both jaws. FOD is a type of sclerosing disease that is characterised by intense opaque masses and many areas with different densities. Genetic heritance of FOD is unusual, with only a few reported cases. We describe a case of FOD that affected three family members, discuss its clinical, radiological and histological characteristics, and review the literature.

PMID: 27030456 [PubMed - indexed for MEDLINE]

IgG4-related mastitis, a rare disease, can radiologically and histologically mimic malignancy.

BMJ Case Rep. 2016 Mar 23;2016:

Authors: Yamada R, Horiguchi S, Yamashita T, Kamisawa T

Abstract
IgG4-related disease (IgG4-RD) is characterised by high serum concentrations of IgG4, dense lymphoplasmacytic infiltrates, storiform fibrosis and increased IgG4-positive plasma cells in tissues. This systemic disease occurs in various organs metachronously, but IgG4-related mastitis appears extremely rare. We report a case of IgG4-related mastitis, radiologically considered to represent breast cancer mainly composed of intraductal component and requiring histological differentiation from mucosa-associated lymphoid tissue (MALT) lymphoma. The breast mass disappeared with steroid therapy. When patients have a breast mass, regardless of the presence or absence of IgG4-RD, IgG4-related mastitis should be considered in addition to breast cancer. If histological findings show dense lymphoplasmacytic infiltrates, IgG4-related mastitis should be suspected in addition to malignant lymphoma, and lack of monoclonality should be confirmed. To avoid unnecessary surgery or chemotherapy, knowledge and accurate diagnosis of the entity of IgG4-related mastitis is necessary.

PMID: 27009197 [PubMed - indexed for MEDLINE]

B-cell lymphoma of the heart: A rare diagnosis.

Rev Port Cardiol. 2014 Dec;33(12):803.e1-3

Authors: Matos AP, Palas J, Doulaptsis C, Ramalho M, Duarte S, Bogaert J

Abstract
We present a case of a primary cardiac lymphoma in a 60-year-old woman. The clinical presentation was non-specific and the diagnosis was suggested by its appearance on multidetector computed tomography. The final diagnosis was achieved by histopathological study and was corroborated by a decrease in tumor volume after targeted chemotherapy. A brief review of the appearance of primary cardiac lymphomas in imaging studies is presented.

PMID: 25459635 [PubMed - indexed for MEDLINE]

Sjögren-Larsson syndrome: a rare disease of the skin and central nervous system.

BMJ Case Rep. 2016 Apr 19;2016:10.1136/bcr-2016-215110

Authors: Roy U, Das U, Pandit A, Debnath A

Abstract
Sjögren-Larsson syndrome is a recessively inherited disease caused by a deficiency of fatty aldehyde dehydrogenase with presenting features of congenital ichthyosis, spastic diplegia or tetraplegia, and mental retardation. The basic pathogenic mechanism is deficiency of fatty aldehyde dehydrogenase, which may lead to an accumulation of long-chain fatty alcohols hampering cell membrane integrity, which further disrupts the barrier function of skin and white matter of the brain. MRI of the brain shows diffuse symmetrical white matter hyperintensities on T2-weighted sequences. Although there is no definitive cure for Sjögren-Larsson syndrome, most patients survive until adulthood and management involves therapies directed towards controlling specific problems. We present a case of Sjögren-Larsson syndrome with classical clinical and MRI features, including a few distinctly atypical characteristics in various attributes.

PMID: 27095813 [PubMed - indexed for MEDLINE]