Table of Contents

Volume 1, Issue 2

  April/May/June 2013

RARE DISEASE FOUNDATION SPOTLIGHT

Open Access Article

The ALS Association: Fighting Lou Gehrig disease on multiple fronts

The ALS Association Media Relations
eLocation ID: e24910
http://dx.doi.org/10.4161/rdis.24910
Full Text | PDF




ADDENDA

Open Access Article

IGSF1 deficiency syndrome: A newly uncovered endocrinopathy

Sjoerd D. Joustra, A. S. Paul van Trotsenburg, Yu Sun, Monique Losekoot, Daniel J. Bernard, Nienke R. Biermasz, Wilma Oostdijk and Jan M. Wit
eLocation ID: e24883
http://dx.doi.org/10.4161/rdis.24883
Abstract | Full Text | PDF

A recently uncovered X-linked syndrome, caused by loss-of-function of IGSF1, is characterized by congenital central hypothyroidism and macroorchidism, variable prolactin deficiency, occasional growth hormone deficiency, delayed pubertal testosterone secretion and obesity. We propose to call this endocrinopathy “IGSF1 deficiency syndrome.” Based on an estimated incidence of isolated congenital central hypothyroidism of 1:65,000, we predict that the incidence of IGSF1 deficiency related hypothyroidism is approximately 1:100,000. IGSF1 encodes a plasma membrane immunoglobulin superfamily glycoprotein that is highly expressed in pituitary and testis, but is of unknown function. The variable profile of pituitary dysfunction suggests that IGSF1 may play a role in pituitary paracrine regulation. The clinical significance of the syndrome, particularly the clinical consequences of untreated hypothyroidism, justifies screening family members of patients with IGSF1 mutations for carriership and to study potential carriers of IGSF1 mutations, including patients with idiopathic central hypothyroidism, combined GH and TSH deficiency, macroorchidism or delayed puberty.

Drosophila as a starting point for developing therapeutics for the rare disease Duchenne Muscular Dystrophy

Mario Pantoja and Hannele Ruohola-Baker
eLocation ID: e24995
Abstract | Full Text

Progress into developing therapeutics for rare diseases can be accelerated for those diseases that can be modeled in genetically tractable organisms. Here we comment on one disease, Duchenne Muscular Dystrophy (DMD), modeled in Drosophila that brought together disparate lines of research toward the goal of developing a therapeutic. Though the bioactive lipid sphingosine 1-phosphate (S1P) has been implicated in many anabolic processes in many cell types and tissues, including muscle, this work confirmed the therapeutic potential of assessing this pathway for DMD. Genetic dissection of sphingolipid metabolism showed the suppression of muscle structural and functional defects in flies. Moreover, improvement of muscle defects using known pharmacological agents that raise S1P levels in vivo highlight the potential of Drosophila as a drug-screening tool for DMD. We and others have extended S1P studies into the mouse model of DMD and have shown a partial amelioration of symptoms associated with DMD. Translation of this work to mammals makes the sphingolipid metabolism pathway a promising target for further drug development that may benefit the human condition.

Open Access Article

Specialized tools are needed when searching the web for rare disease diagnoses

Radu Dragusin, Paula Petcu, Christina Lioma, Birger Larsen, Henrik L. Jørgensen, Ingemar J. Cox, Lars Kai Hansen, Peter Ingwersen and Ole Winther
eLocation ID: e25001
Abstract | Full Text

In our recent paper Dragusin, Petcu, Lioma, Larsen, Jørgensen, Cox, Hansen, Ingwersen and Winther, FindZebra: A search engine for rare diseases, International Journal of Medical Informatics, February 2013 (10.1016/j.ijmedinf.2013.01.005) we study web search as an aid in the process of diagnosing rare diseases. To answer the question of how well Google Search and PubMed perform, we created an evaluation framework with 56 diagnostic cases and made our own specialized search engine FindZebra (findzebra.com). FindZebra uses a set of publicly available curated sources on rare diseases and an open-source information retrieval system Indri. Our evaluation and the feedback received after the publication of our paper both show that FindZebra outperforms Google Search and PubMed. In this paper we summarize the original findings and the response to FindZebra, discuss why Google Search is not designed for specialized tasks and outline some of the current trends in using web resources and social media for medical diagnosis.




SHORT COMMUNICATION

Open Access Article

Xeroderma Pigmentosum-Trichothiodystrophy overlap patient with novel XPD/ERCC2 mutation

Henrik H. Kralund, Lilian Ousager, Nicolaas G. Jaspers, Anja Raams, Erling B. Pedersen, Else Gade and Anette Bygum
eLocation ID: e24932
http://dx.doi.org/10.4161/rdis.24932
Abstract | Full Text | PDF

Xeroderma Pigmentosum (XP), Trichothiodystrophy (TTD) and Cockayne Syndrome (CS) are rare, recessive disorders caused by mutational defects in the Nucleotide Excision Repair (NER) pathway and/or disruption of basic cellular DNA transcription. To date, a multitude of mutations in the XPD/ERCC2 gene have been described, many of which give rise to NER- and DNA transcription related diseases, which share certain diagnostic features and few overlap patients have been described. Despite increasing understanding of the roles of XPD/ERCC2 in mammalian cells, there is still weak predictability of somatic outcome from many of these mutations. We demonstrate a patient, believed to represent an overlap between XP and TTD/CS. In addition to other organ dysfunctions, the young man presented with Photosensitivity, Ichthyosis, Brittle hair, Impaired physical and mental development, Decreased fertility and Short stature (PIBIDS) suggestive of TTD, but lacking the almost patognomonic “tiger tail” banding of the hair under polarized light. Additionally, he developed basal cell carcinoma aged 28, as well as adult onset kidney failure, features normally not associated with TTD but rather XP/CS. His freckled appearance also suggested XP, but fibroblast cultures only demonstrated x2 UV-sensitivity with expected NER and TFIIH-activity decrease. Genetic sequencing of the XPD/ERCC2 gene established the patient as heterozygote compound with a novel, N-terminal Y18H mutation and a known C-terminal (TTD) mutation, A725P. The possible interplay between gene products and the patient phenotype is discussed.