The primitive extratesticular seminoma: diagnosis of a rare pathology.

Acta Biomed. 2017 Apr 28;88(1):82-85

Authors: Saba L

Abstract
 Background: The Primitive Extratesticular Seminoma is a very rare condition and represents 3% of germ cell tumors; it is an indeterminate origin disease, whose diagnosis is often complicated by a nonspecific and highly variable clinical finding.
CASE PRESENTATION: A caucasian 55 years old male, non-smoker, arrived to our centre with cough, severe respiratory distress and dysphagia, in a context of the superior vena cava syndrome. A Computed Tomography was performed, which shows the presence of a mediastinal anterior mass with aorto-pulmonary window and left paracardiac invasion. A biopsy of the mediastinal mass was performed with mediastinoscopy; the hystological diagnosis was seminoma. After, first of all the 18FDG PET-CT is performed, which shows the presence of an intense hypermetabolism (SUV max=20.3 and metabolic volume 867 cc) at the level of bulky mediastinal mass, with paratracheal, aorto-pulmonary window and left paracardiac invasion. The mass presents also a sternal manubrium invasion. There were no other detectable tissue metabolic alterations with the 18FDG PET-CT and, in particular, the testicles examination was negative. A bilateral testicular ultrasound (US) was executed, which confirms the absence of testicular germ tumor. Clinical laboratory tests show a significant increase of beta-HCG (123 IU/L); AFP is negative. A final diagnosis of primitive extratesticular seminoma was carried.
CONCLUSIONS: The Primitive Extratesticolar Seminoma is a rare patology, and, for its massive size at the onset diagnosis, curable in early stage often only with radiochemotherapy. The Diagnostic Imaging and Nuclear Medicine, as Testicular Ultrasound, the CT with contrast medium and the 18FDG PET-CT total body examination, are fundamental to the staging and localisation. MRI sometimes is useful for testicular evaluation. The biopsy is needed for tissue characterization.

PMID: 28467339 [PubMed - indexed for MEDLINE]

Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features.

Proc Natl Acad Sci U S A. 2016 09 20;113(38):E5598-607

Authors: Ouyang Q, Nakayama T, Baytas O, Davidson SM, Yang C, Schmidt M, Lizarraga SB, Mishra S, Ei-Quessny M, Niaz S, Gul Butt M, Imran Murtaza S, Javed A, Chaudhry HR, Vaughan DJ, Hill RS, Partlow JN, Yoo SY, Lam AT, Nasir R, Al-Saffar M, Barkovich AJ, Schwede M, Nagpal S, Rajab A, DeBerardinis RJ, Housman DE, Mochida GH, Morrow EM

Abstract
Mutations that cause neurological phenotypes are highly informative with regard to mechanisms governing human brain function and disease. We report autosomal recessive mutations in the enzyme glutamate pyruvate transaminase 2 (GPT2) in large kindreds initially ascertained for intellectual and developmental disability (IDD). GPT2 [also known as alanine transaminase 2 (ALT2)] is one of two related transaminases that catalyze the reversible addition of an amino group from glutamate to pyruvate, yielding alanine and α-ketoglutarate. In addition to IDD, all affected individuals show postnatal microcephaly and ∼80% of those followed over time show progressive motor symptoms, a spastic paraplegia. Homozygous nonsense p.Arg404* and missense p.Pro272Leu mutations are shown biochemically to be loss of function. The GPT2 gene demonstrates increasing expression in brain in the early postnatal period, and GPT2 protein localizes to mitochondria. Akin to the human phenotype, Gpt2-null mice exhibit reduced brain growth. Through metabolomics and direct isotope tracing experiments, we find a number of metabolic abnormalities associated with loss of Gpt2. These include defects in amino acid metabolism such as low alanine levels and elevated essential amino acids. Also, we find defects in anaplerosis, the metabolic process involved in replenishing TCA cycle intermediates. Finally, mutant brains demonstrate misregulated metabolites in pathways implicated in neuroprotective mechanisms previously associated with neurodegenerative disorders. Overall, our data reveal an important role for the GPT2 enzyme in mitochondrial metabolism with relevance to developmental as well as potentially to neurodegenerative mechanisms.

PMID: 27601654 [PubMed - indexed for MEDLINE]

Risk of Human Papillomavirus Infection in Cancer-Prone Individuals: What We Know.

Viruses. 2018 Jan 20;10(1):

Authors: Khoury R, Sauter S, Butsch Kovacic M, Nelson AS, Myers KC, Mehta PA, Davies SM, Wells SI

Abstract
Human papillomavirus (HPV) infections cause a significant proportion of cancers worldwide, predominantly squamous cell carcinomas (SCC) of the mucosas and skin. High-risk HPV types are associated with SCCs of the anogenital and oropharyngeal tract. HPV oncogene activities and the biology of SCCs have been intensely studied in laboratory models and humans. What remains largely unknown are host tissue and immune-related factors that determine an individual's susceptibility to infection and/or carcinogenesis. Such susceptibility factors could serve to identify those at greatest risk and spark individually tailored HPV and SCC prevention efforts. Fanconi anemia (FA) is an inherited DNA repair disorder that is in part characterized by extreme susceptibility to SCCs. An increased prevalence of HPV has been reported in affected individuals, and molecular and functional connections between FA, SCC, and HPV were established in laboratory models. However, the presence of HPV in some human FA tumors is controversial, and the extent of the etiological connections remains to be established. Herein, we discuss cellular, immunological, and phenotypic features of FA, placed into the context of HPV pathogenesis. The goal is to highlight this orphan disease as a unique model system to uncover host genetic and molecular HPV features, as well as SCC susceptibility factors.

PMID: 29361695 [PubMed - in process]

Cerebral cortical neuron diversity and development at single-cell resolution.

Curr Opin Neurobiol. 2017 Feb;42:9-16

Authors: Johnson MB, Walsh CA

Abstract
Over a century of efforts to categorize the astonishing diversity of cortical neurons has relied on criteria of morphology, electrophysiology, ontology, and the expression of a few transcripts and proteins. The rapid development of single-cell RNA sequencing (scRNA-seq) adds genome-wide gene expression patterns to this list of criteria, and promises to reveal new insights into the transitions that establish neuronal identity during development, differentiation, activity, and disease. Comparing single neuron data to reference atlases constructed from hundreds of thousands of single-cell transcriptomes will be critical to understanding these transitions and the molecular mechanisms that drive them. We review early efforts, and discuss future challenges and opportunities, in applying scRNA-seq to the elucidation of neuronal subtypes and their development.

PMID: 27888678 [PubMed - indexed for MEDLINE]

Rare Disease: Lobar Holoprosencephaly With a Median Cleft Lip-Case Report.

Cleft Palate Craniofac J. 2016 Jan;53(1):109-17

Authors: Radojicic J, Tanic T, Pesic Z, Jovic N, Cutovic T, Filipovic G

Abstract
Holoprosencephaly is a complex malformation of the brain associated with the median facial defects. Variability of the clinical picture is the characteristic of this anomaly. In most cases, the degree of severity of the facial anomaly correlates with the degree of damage to the brain. This article aims to present a rare case of child with a milder form of brain anomaly combined with a severe form of facial anomaly. The article also presents the application of a feeding stimulator to improve the child's quality of life. The anomaly was diagnosed by postnatal sonography of the brain, magnetic resonance imaging of the endocranium, and three-dimensional computed tomography of the craniofacial skeleton.

PMID: 25291088 [PubMed - indexed for MEDLINE]

Early Recognition and Management of Rare Kidney Stone Disorders.

Urol Nurs. 2017 Mar-Apr;37(2):81-9, 102

Authors: Goldstein B, Goldfarb DS

Abstract
Kidney stones, especially those that present in childhood/adolescence, may be due to rare inherited disorders such as cystinuria. Early recognition and prompt treatment can help reduce or even prevent the serious long-term complications of these rare stone disorders.

PMID: 29240373 [PubMed - indexed for MEDLINE]

Anaesthesia and orphan disease: Hutchinson-Gilford progeria syndrome, a case report and summary of previous cases.

Eur J Anaesthesiol. 2016 11;33(11):869-872

Authors: Vreeswijk SJ, Claahsen HL, Borstlap WA, Hendriks MP

PMID: 27749465 [PubMed - indexed for MEDLINE]

Anaesthesia and orphan disease: sedation with ketofol in two patients with Joubert syndrome.

Eur J Anaesthesiol. 2016 11;33(11):868-869

Authors: Atalay YO, Soylu AI, Tekcan D

PMID: 27326823 [PubMed - indexed for MEDLINE]

Cysticercosis of the tongue.

J Nepal Health Res Counc. 2014 May-Aug;12(27):147-9

Authors: Sharma BP, Gaunt F, Sigdel B

Abstract
Cysticercosis is a condition in which a human being acts as the intermediate host of Taenia solium, a pork tape worm. The oral mucosa is an uncommonly involved site. A rurally living 35 year old vegetarian female presented with a swelling over the right side of her tongue of seven months duration. Histopathology of excisional biopsy revealed it to be cysticercosis. Diagnosis of cysticercosis was clinically unsuspected. The patient was referred to the general medical clinic for further treatment.

PMID: 25575011 [PubMed - indexed for MEDLINE]

Pyridostigmine bromide versus fludrocortisone in the treatment of orthostatic hypotension in Parkinson's disease - reply.

Eur J Neurol. 2018 Feb;25(2):e27-e28

Authors: Schreglmann SR, Büchele F, Kägi G, Baumann CR, study authors

PMID: 29356263 [PubMed - in process]

An overview of the impact of rare disease characteristics on research methodology.

Orphanet J Rare Dis. 2018 Jan 19;13(1):14

Authors: Whicher D, Philbin S, Aronson N

Abstract
BACKGROUND: About 30 million individuals in the United States are living with a rare disease, which by definition have a prevalence of 200,000 or fewer cases in the United States ([National Organization for Rare Disorders], [About NORD], [2016]). Disease heterogeneity and geographic dispersion add to the difficulty of completing robust studies in small populations. Improving the ability to conduct research on rare diseases would have a significant impact on population health. The purpose of this paper is to raise awareness of methodological approaches that can address the challenges to conducting robust research on rare diseases.
APPROACH: We conducted a landscape review of available methodological and analytic approaches to address the challenges of rare disease research. Our objectives were to: 1. identify algorithms for matching study design to rare disease attributes and the methodological approaches applicable to these algorithms; 2. draw inferences on how research communities and infrastructure can contribute to the efficiency of research on rare diseases; and 3. to describe methodological approaches in the rare disease portfolio of the Patient-Centered Outcomes Research Institute (PCORI), a funder promoting both rare disease research and research infrastructure.
RESULTS: We identified three algorithms for matching study design to rare disease or intervention characteristics (Gagne, et.al, BMJ 349:g6802, 2014); (Gupta, et.al, J Clin Epidemiol 64:1085-1094, 2011); (Cornu, et. al, Orphet J Rare Dis 8:48,2012) and summarized the applicable methodological and analytic approaches. From this literature we were also able to draw inferences on how an effective research infrastructure can set an agenda, prioritize studies, accelerate accrual, catalyze patient engagement and terminate poorly performing studies. Of the 24 rare disease projects in the PCORI portfolio, 11 are randomized controlled trials (RCTs) using standard designs. Thirteen are observational studies using case-control, prospective cohort, or natural history designs. PCORI has supported the development of 9 Patient-Powered Research Networks (PPRNs) focused on rare diseases.
CONCLUSION: Matching research design to attributes of rare diseases and interventions can facilitate the completion of RCTs that are adequately powered. An effective research infrastructure can improve efficiency and avoid waste in rare disease research. Our review of the PCORI research portfolio demonstrates that it is feasible to conduct RCTs in rare disease. However, most of these studies are using standard RCT designs. This suggests that use of a broader array of methodological approaches to RCTs --such as adaptive trials, cross-over trials, and early escape designs can improve the productivity of robust research in rare diseases.

PMID: 29351763 [PubMed - in process]

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 2018/01/20

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.

Accelerating Scientific Advancement for Pediatric Rare Lung Disease Research. Report from a National Institutes of Health-NHLBI Workshop, September 3 and 4, 2015.

Ann Am Thorac Soc. 2016 Dec;13(12):385-393

Authors: Young LR, Trapnell BC, Mandl KD, Swarr DT, Wambach JA, Blaisdell CJ

Abstract
Pediatric rare lung disease (PRLD) is a term that refers to a heterogeneous group of rare disorders in children. In recent years, this field has experienced significant progress marked by scientific discoveries, multicenter and interdisciplinary collaborations, and efforts of patient advocates. Although genetic mechanisms underlie many PRLDs, pathogenesis remains uncertain for many of these disorders. Furthermore, epidemiology and natural history are insufficiently defined, and therapies are limited. To develop strategies to accelerate scientific advancement for PRLD research, the NHLBI of the National Institutes of Health convened a strategic planning workshop on September 3 and 4, 2015. The workshop brought together a group of scientific experts, intramural and extramural investigators, and advocacy groups with the following objectives: (1) to discuss the current state of PRLD research; (2) to identify scientific gaps and barriers to increasing research and improving outcomes for PRLDs; (3) to identify technologies, tools, and reagents that could be leveraged to accelerate advancement of research in this field; and (4) to develop priorities for research aimed at improving patient outcomes and quality of life. This report summarizes the workshop discussion and provides specific recommendations to guide future research in PRLD.

PMID: 27925785 [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 2018/01/18

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.

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 2018/01/18

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.

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 2018/01/17

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.

Cover Image, Volume 176A, Number 2, February 2018.

Am J Med Genet A. 2018 Feb;176(2):i

Authors: Chen MH, Choudhury S, Hirata M, Khalsa S, Chang B, Walsh CA

Abstract
The cover image, by Ming Hui Chen et al., is based on the Original Article Thoracic Aortic Aneurysm in Patients with Loss of Function Filamin A Mutations: Clinical Characterization, Genetics, and Recommendations, DOI: 10.1002/ajmg.a.38580.

PMID: 29334595 [PubMed - in process]

Thoracic aortic aneurysm in patients with loss of function Filamin A mutations: Clinical characterization, genetics, and recommendations.

Am J Med Genet A. 2018 Feb;176(2):337-350

Authors: Chen MH, Choudhury S, Hirata M, Khalsa S, Chang B, Walsh CA

Abstract
The frequency and gender distribution of thoracic aortic aneurysm as a cardiovascular manifestation of loss-of-function (LOF) X-linked FilaminA (FLNA) mutations are not known. Furthermore, there is very limited cardiovascular morbidity or mortality data in children and adults. We analyzed cardiac data on the largest series of 114 patients with LOF FLNA mutations, both children and adults, with periventricular nodular heterotopia (PVNH), including 48 study patients and 66 literature patients, median age of 22.0 years (88 F, 26 M, range: 0-71 years), with 75 FLNA mutations observed in 80 families. Most (64.9%) subjects had a cardiac anomaly or vascular abnormality (80.8% of males and 60.2% of females). Thoracic aortic aneurysms or dilatation (TAA) were found in 18.4% (n = 21), and were associated with other structural cardiac malformations in 57.1% of patients, most commonly patent ductus arteriosus (PDA) and valvular abnormalities. TAA most frequently involved the aortic root and ascending aorta, and sinus of Valsalva aneurysms were present in one third of TAA patients. Six TAA patients (28.5%) required surgery (median age 37 yrs, range 13-41 yrs). TAA with its associated complications was also the only recorded cause of premature, non-accidental mortality in adults (2 M, 2 F). Two adult patients (1 F, 1 M, median 38.5 yrs), died of spontaneous aortic rupture at aortic dimensions smaller than current recommendations for surgery for other aortopathies. Data from this largest series of LOF FLNA mutation patients underscore the importance of serial follow-up to identify and manage these potentially devastating cardiovascular complications.

PMID: 29334594 [PubMed - in process]

Finding patients using similarity measures in a rare diseases-oriented clinical data warehouse: Dr. Warehouse and the needle in the needle stack.

J Biomed Inform. 2017 Sep;73:51-61

Authors: Garcelon N, Neuraz A, Benoit V, Salomon R, Kracker S, Suarez F, Bahi-Buisson N, Hadj-Rabia S, Fischer A, Munnich A, Burgun A

Abstract
OBJECTIVE: In the context of rare diseases, it may be helpful to detect patients with similar medical histories, diagnoses and outcomes from a large number of cases with automated methods. To reduce the time to find new cases, we developed a method to find similar patients given an index case leveraging data from the electronic health records.
MATERIALS AND METHODS: We used the clinical data warehouse of a children academic hospital in Paris, France (Necker-Enfants Malades), containing about 400,000 patients. Our model was based on a vector space model (VSM) to compute the similarity distance between an index patient and all the patients of the data warehouse. The dimensions of the VSM were built upon Unified Medical Language System concepts extracted from clinical narratives stored in the clinical data warehouse. The VSM was enhanced using three parameters: a pertinence score (TF-IDF of the concepts), the polarity of the concept (negated/not negated) and the minimum number of concepts in common. We evaluated this model by displaying the most similar patients for five different rare diseases: Lowe Syndrome (LOWE), Dystrophic Epidermolysis Bullosa (DEB), Activated PI3K delta Syndrome (APDS), Rett Syndrome (RETT) and Dowling Meara (EBS-DM), from the clinical data warehouse representing 18, 103, 21, 84 and 7 patients respectively.
RESULTS: The percentages of index patients returning at least one true positive similar patient in the Top30 similar patients were 94% for LOWE, 97% for DEB, 86% for APDS, 71% for EBS-DM and 99% for RETT. The mean number of patients with the exact same genetic diseases among the 30 returned patients was 51%.
CONCLUSION: This tool offers new perspectives in a translational context to identify patients for genetic research. Moreover, when new molecular bases are discovered, our strategy will help to identify additional eligible patients for genetic screening.

PMID: 28754522 [PubMed - indexed for MEDLINE]

The TGF-β System As a Potential Pathogenic Player in Disease Modulation of Amyotrophic Lateral Sclerosis.

Front Neurol. 2017;8:669

Authors: Peters S, Zitzelsperger E, Kuespert S, Iberl S, Heydn R, Johannesen S, Petri S, Aigner L, Thal DR, Hermann A, Weishaupt JH, Bruun TH, Bogdahn U

Abstract
Amyotrophic lateral sclerosis (ALS) represents a fatal orphan disease with high unmet medical need, and a life time risk of approx. 1/400 persons per population. Based on increasing knowledge on pathophysiology including genetic and molecular changes, epigenetics, and immune dysfunction, inflammatory as well as fibrotic processes may contribute to the heterogeneity and dynamics of ALS. Animal and human studies indicate dysregulations of the TGF-β system as a common feature of neurodegenerative disorders in general and ALS in particular. The TGF-β system is involved in different essential developmental and physiological processes and regulates immunity and fibrosis, both affecting neurogenesis and neurodegeneration. Therefore, it has emerged as a potential therapeutic target for ALS: a persistent altered TGF-β system might promote disease progression by inducing an imbalance of neurogenesis and neurodegeneration. The current study assessed the activation state of the TGF-β system within the periphery/in life disease stage (serum samples) and a late stage of disease (central nervous system tissue samples), and a potential influence upon neuronal stem cell (NSC) activity, immune activation, and fibrosis. An upregulated TGF-β system was suggested with significantly increased TGF-β1 protein serum levels, enhanced TGF-β2 mRNA and protein levels, and a strong trend toward an increased TGF-β1 protein expression within the spinal cord (SC). Stem cell activity appeared diminished, reflected by reduced mRNA expression of NSC markers Musashi-1 and Nestin within SC-paralleled by enhanced protein contents of Musashi-1. Doublecortin mRNA and protein expression was reduced, suggesting an arrested neurogenesis at late stage ALS. Chemokine/cytokine analyses suggest a shift from a neuroprotective toward a more neurotoxic immune response: anti-inflammatory chemokines/cytokines were unchanged or reduced, expression of proinflammatory chemokines/cytokines were enhanced in ALS sera and SC postmortem tissue. Finally, we observed upregulated mRNA and protein expression for fibronectin in motor cortex of ALS patients which might suggest increased fibrotic changes. These data suggest that there is an upregulated TGF-β system in specific tissues in ALS that might lead to a "neurotoxic" immune response, promoting disease progression and neurodegeneration. The TGF-β system therefore may represent a promising target in treatment of ALS patients.

PMID: 29326641 [PubMed]