Rare diseases (Austin, Tex.)最新文献

In our recent paper, 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.

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.

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.

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.

Prader-Willi syndrome (PWS) is a rare (~1 in 12,000) genetic disorder that involves at least six genes on chromosome 15q11-q13. Children with PWS not only rapidly gain weight and become severely obese because of reduced voluntary activity and increased food intake, but also exhibit growth hormone deficiency, excessive daytime sleepiness, endocrine dysregulation and infertility. These phenotypes suggest dysfunction of the hypothalamus, the brain region that regulates short- and long-term energy balance and other body functions. The physiological basis for obesity in children with PWS has eluded researchers for decades. Mercer et al. now demonstrate that Magel2, the murine ortholog of one of the PWS genes, is a component of the hypothalamic leptin-melanocortin pathway that is critical for energy balance. Most interestingly, disruptions of other components of this pathway cause obesity in both mice and humans, suggesting a mechanistic link between PWS and other rare genetic forms of severe childhood-onset obesity.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by a selective loss of motor neurons. There is no cure and few effective treatments. The RNA-binding protein TDP-43 contributes to the pathogenesis of ALS. TDP-43 is depleted from the nucleus and accumulates in cytoplasmic aggregates in the degenerating neurons and glia of most ALS patients. Furthermore, mutations in the TDP-43 gene cause rare familial and sporadic forms of the disease. Thus, therapeutic strategies targeting TDP-43 may be efficacious. We have used the yeast model system to identify the mechanisms by which TDP-43 aggregation contributes to ALS and to identify approaches to protect cells from the toxic effects of TDP-43 aggregation. Using an unbiased yeast genetic screen we discovered Dbr1 as a potent suppressor of TDP-43 toxicity. Yeast cells in which Dbr1 is deleted are resistant to TDP-43 toxicity. Dbr1 inhibition in mammalian cells is also sufficient to protect against TDP-43 cytotoxicity. Here, we review this recent discovery, highlighting future approaches aimed at extending these studies and pursuing Dbr1 as a novel therapeutic target for ALS.

Small molecules with low molecular weight are of interest for drug development, as they are more likely to be absorbed. In cancer research, p53 is often mutated in many tumors, and many small molecules targeting mutant p53 have been tested. One of such low molecular weight compounds is APR246/PRIMA-1(MET) that was identified as a compound targeting and reactivating p53 mutants based on a cell-based screening for rescuing the apoptotic activity of p53. Recently, we have reported two different model systems, (1) corneal epithelial cells differentiated from induced pluripotent stem cells (iPSCs) derived from reprogramming of patient fibroblasts and (2) skin organotypic reconstitution of patient-derived keratinocytes. We have shown that APR246/PRIMA-1(MET) can rescue epithelial differentiation defects caused by mutations in p63 that is a family member of p53 and shares high sequence and structural similarity with the p53 protein.(1) (,) (2) The rationale of the two cellular models for drug screening and the potential of APR246/PRIMA-1(MET) to restore visual impairment of patients are discussed (Fig. 1).

CMT1B is the second most frequent autosomal dominant inherited neuropathy and is caused by assorted mutations of the myelin protein zero (MPZ) gene. MPZ mutations cause neuropathy gain of function mechanisms that are largely independent MPZs normal role of mediating myelin compaction. Whether there are only a few or multiple pathogenic mechanisms that cause CMT1B is unknown. Arg98Cys and Ser63Del MPZ are two CMT1B causing mutations that have been shown to cause neuropathy in mice at least in part by activating the unfolded protein response (UPR). We have recently treated Arg98Cys mice with derivatives of curcumin that improved the neuropathy and reduced UPR activation.(1) Future studies will address whether manipulating the UPR will be a common or rare strategy for treating CMT1B or other forms of inherited neuropathies.