Intractable & Rare Diseases Research
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Volume 5 , Issue 4
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Policy Forum
  • Qi Tang, Peipei Song, Lingzhong Xu
    Volume 5 (2016) Issue 4 Pages 238-243
    Released: November 28, 2016
    [Advance publication] Released: October 24, 2016
    JOURNALS FREE ACCESS

    The World Health Organization (WHO) has emphasized that aging of the population is inextricably linked to many other global public health issues, such as universal health coverage, non-communicable diseases, and disability. However, Alzheimer's Disease International (ADI) estimates that 46.8 million elderly people worldwide were living with dementia in 2015. Alzheimer's disease (AD), the most common form of dementia, is one of the most common neurodegenerative diseases and is the main cause of cognitive impairment. AD will affect 5-7 out of every 100 older adults who are age 60 years or over. In response to the serious challenge posed by AD, governments are expected to play an important role in the prevention, diagnosis, and treatment of AD. As specific examples, i) the Japanese Government has instituted and supported regulations to encourage the development of AD drugs in order to accelerate research and development of innovative drugs; ii) the United States Government has cooperated with multiple partners such as non-governmental organizations in the response to AD; iii) Chinese governmental measures have standardized clinical diagnosis and treatment as part of the response to AD, including eligible patients, diagnostic criteria, therapeutic schedules, drug selection, and required inspections; iv) with political support from member governments, the European Union has issued guidelines and conducted clinical studies on medicines for the treatment of AD in order to ascertain the various stages of the disease and the relevance of biomarkers. AD is an intractable disease, so different countries need to share clinic trial information and cooperate in the conduct of those trials. International cooperation will play a key role in the response to other intractable and rare diseases.

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Reviews
  • Gayathri Balasubramanian, Suman Morampudi, Pankdeep Chhabra, Arun Gowd ...
    Volume 5 (2016) Issue 4 Pages 244-254
    Released: November 28, 2016
    [Advance publication] Released: October 04, 2016
    JOURNALS FREE ACCESS

    The past decade witnessed rapid development of novel drugs and therapeutic biological agents. The marketing authorization for novel therapies is often time consuming and distressing for patients. Earlier clinical trials were the only way to access new drugs under development. However, not every patient meets the enrolment criteria, and participation is difficult for patients with life-threatening, long-lasting or seriously debilitating diseases like rare diseases. Early access programs like "Compassionate Use Program (CUP)" have generated alternative channels for such patients. The European Medical Agency provides regulations and recommendations for compassionate use, upon which every European Union (EU) member state has developed its own rules and regulations. Despite previous reviews and studies, the available information is limited and gaps exist. This literature review explores CUP in 28 EU member states. Data was collected through literature review and use of country-specific search terms from the healthcare domain. Data sources were not limited to databases and articles published in journals, but also included grey literature. The results implied that CUP was present in 20 EU member states (71%). Of 28 EU states, 18 (~64%) had nationalized regulations and processes were well-defined. Overall, this review identified CUP and its current status and legislation in 28 EU member states. The established legislation for CUP in the EU member states suggest their willingness to adopt processes that facilitate earlier and better access to new medicines. Further research and periodic reviews are warranted to understand the contemporary and future regulatory trends in early access programs.

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  • Zukhrofi Muzar, Reymundo Lozano, Alexander Kolevzon, Randi J. Hagerman
    Volume 5 (2016) Issue 4 Pages 255-261
    Released: November 28, 2016
    [Advance publication] Released: November 14, 2016
    JOURNALS FREE ACCESS

    Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism, caused by a CGG expansion to greater than 200 repeats in the promoter region of FMR1 on the bottom of the X chromosome. A subgroup of individuals with FXS experience hyperphagia, lack of satiation after meals and severe obesity, this subgroup is referred to have the Prader-Willi phenotype of FXS. Prader-Willi syndrome is one of the most common genetic severe obesity disorders known and it is caused by the lack of the paternal 15q11-13 region. Affected individuals suffer from hyperphagia, lack of satiation, intellectual disability, and behavioral problems. Children with fragile X syndrome Prader-Willi phenotye and those with Prader Willi syndrome have clinical and molecular similarities reviewed here which will impact new treatment options for both disorders.

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Original Article
  • Sreeraj Konadath, Puttabasappa Manjula
    Volume 5 (2016) Issue 4 Pages 262-268
    Released: November 28, 2016
    [Advance publication] Released: September 05, 2016
    JOURNALS FREE ACCESS

    Tinnitus is a commonly encountered complaint in routine audiology practice. The pathophysiology and exact generation site of tinnitus is not precisely established. Auditory brainstem response (ABR) and late latency response (LLR) findings in individuals with tinnitus show mixed results in the literature. Majority of studies have focused on individuals having tinnitus with peripheral hearing loss. The present study explores ABR and LLR characteristics among tinnitus patients with normal audiometric presentation; with no direct indication of any cochlear lesion. This study aims at characterizing the ABR and LLR findings in individuals with tinnitus having normal audiometric presentation. ABR and LLR waveform characteristics were recorded and compared between participants with tinnitus (Group 1) and those without tinnitus (Group 2). The ABR analysis indicated no significant differences in latency and amplitude between Groups 1 and 2. However, patients with tinnitus showed abnormally reduced absolute amplitudes of peaks I and V. LLR analysis indicated no significant differences in latency and amplitude between Groups 1 and 2 except enhanced amplitude of P1. The reduced amplitude of peaks I and V along with normal absolute latencies of peaks I, III and V indicate that the origin of tinnitus is possibly due to reduced excitation of auditory nerve fibres arising from a peripheral hearing loss beyond 8 kHz. The P1 amplitude enhancement could be attributed to mechanism explaining central gain model; which suggests that central auditory structures recalibrates the mean firing rate, considering the reduced output from sensory structures, generating neural noise perceived as tinnitus.

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Brief Reports
  • Jun-ichi Satoh, Motoaki Yanaizu, Youhei Tosaki, Kenji Sakai, Yoshihiro ...
    Volume 5 (2016) Issue 4 Pages 269-274
    Released: November 28, 2016
    [Advance publication] Released: October 04, 2016
    JOURNALS FREE ACCESS

    Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder characterized by sclerosing leukoencephalopathy and multifocal bone cysts, caused by a loss-of-function mutation of either TYROBP (DAP12) or TREM2. TREM2 and DAP12 constitute a receptor/adaptor signaling complex expressed exclusively on osteoclasts, dendritic cells, macrophages, and microglia. Premortem molecular diagnosis of NHD requires genetic analysis of both TYROBP and TREM2, in which 20 distinct NHD-causing mutations have been reported. Due to genetic heterogeneity, it is often difficult to identify the exact mutation responsible for NHD. Recently, the revolution of the next-generation sequencing (NGS) technology has greatly advanced the field of genome research. A targeted sequencing approach allows us to investigate a selected set of disease-causing genes and mutations in a number of samples within several days. By targeted sequencing using the TruSight One Sequencing Panel, we resequenced genetic mutations of seven NHD cases with known molecular diagnosis and two control subjects. We identified homozygous variants of TYROBP or TREM2 in all NHD cases, composed of a frameshift mutation of c.141delG in exon 3 of TYROBP in four cases, a missense mutation of c.2T>C in exon 1 of TYROBP in two cases, or a splicing mutation of c.482+2T>C in intron 3 of TREM2 in one case. The results of targeted resequencing corresponded to those of Sanger sequencing. In contrast, causative variants were not detected in control subjects. These results indicate that targeted sequencing is a useful approach to precisely identify genetic mutations responsible for NHD in a comprehensive manner.

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  • Jun-ichi Satoh, Yoshihiro Kino, Motoaki Yanaizu, Youhei Tosaki, Kenji ...
    Volume 5 (2016) Issue 4 Pages 275-279
    Released: November 28, 2016
    [Advance publication] Released: November 07, 2016
    JOURNALS FREE ACCESS

    The superoxide-producing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex of phagocytes (phox) plays a key role in production of reactive oxygen species (ROS) by microglia. The catalytic subunits of the NADPH oxidase are composed of p22phox and gp91phox. Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder caused by a loss-of-function mutation of either TYROBP (DAP12) or TREM2. Pathologically, the brains of NHD patients exhibit extensive demyelination designated leukoencephalopathy, astrogliosis, accumulation of axonal spheroids, and remarkable activation of microglia predominantly in the white matter of frontal and temporal lobes. However, a pathological role of the gp91phox-p22phox complex in generation of leukoencephalopathy in NHD remains unknown. We clarified the expression of gp91phox and p22phox in the white matter of the frontal cortex derived from five NHD and eight control subjects. We identified the expression of p22phox and gp91phox immunoreactivity almost exclusively on microglia. Microglia overexpressed gp91phox in NHD brains and p22phox in myotonic dystrophy (MD) brains, when compared with non-neurological control (NC) brains. These results suggest that the enhanced expression of gp91phox by microglia might contribute to overproduction of ROS highly toxic to myelinating oligodendrocytes, resulting in oligodendrocyte cell death that induces leukoencephalopathy in NHD brains.

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  • Adem Özkan, Hatice Asuman Özkara
    Volume 5 (2016) Issue 4 Pages 280-283
    Released: November 28, 2016
    [Advance publication] Released: November 07, 2016
    JOURNALS FREE ACCESS

    Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by Arylsulfatase A (ASA) deficiency. The hallmark of the disease is central and peripheral neurodegeneration. More than 200 mutations have been identified in ARSA gene so far. Some of these mutations were characterized. The aim of this study is to reinforce genotype-phenotype correlation and to understand the effect of mutations on the enzyme by biochemical characterization. Two missense mutations (c.919G→A, p.307Glu→Lys and c.954G→T, p.318Trp→Cys in exon 5) were constructed on WT-ASA cDNA and were confirmed by DNA sequence analysis. Plasmid DNA carrying mutant or normal ASA cDNA was transferred to Chinese Hamster Ovary (CHO) cells through transient transfection. ASA protein was produced by CHO cells. Hexosaminidase beta-subunit gene was cotransfected into the CHO cells as a control gene of transfection efficiency. 48 hours after transfection, cells were collected and homogenized. ASA and hexosaminidase activities were measured in supernatant. ASA enzyme activity is decreased 100% according to the control by the effect of both mutations. The mutations are located in the higly conserved region of the protein. In this study, we showed that both mutations result in null ASA activity in CHO cells making the protein nonfunctional. We confirmed that p.307Glu→Lys and p.318Trp→Cys mutations cause late infantile form of MLD disease.

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Case Reports
  • Juan David González-Rodríguez, María Isabel Luis-Yanes, Esther Inglés- ...
    Volume 5 (2016) Issue 4 Pages 284-289
    Released: November 28, 2016
    [Advance publication] Released: November 05, 2016
    JOURNALS FREE ACCESS

    Sclerosing bone dysplasias are a series of clinically and genetically heterogeneous diseases characterized by functional failure of the osteoclasts in bone resorption, leading to an excessive amount of bone mineral density (BMD) which could have serious clinical consequences. We treated three children affected with seriously high levels of BMD with acetazolamide, with the intention of inducing metabolic acidosis, thus increasing bone resorption and reducing BMD. All our patients tolerated and followed the treatment well and the clinical response was satisfactory in all cases.

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  • Abhinav Agrawal, Rutuja R Sikachi
    Volume 5 (2016) Issue 4 Pages 290-293
    Released: November 28, 2016
    [Advance publication] Released: October 24, 2016
    JOURNALS FREE ACCESS

    Infectious aortitis (IA) is a rare but life-threatening condition, and most commonly affects the abdominal aorta or thoracic aorta. Various microorganisms have been associated with infectious thoracic aortitis, most commonly Staphylococcus, Enterococcus, Streptococcus, and Salmonella species. Campylobacter fetus (C. fetus) has been seen as a cause of infective aortitis only in a few case reports. We report a rare case of infective aortitis of the abdominal aorta caused due to C. fetus bacteremia. While C. fetus infections usually occur in patients with immunosuppression, such as malignancy, or those with diabetes mellitus, but our patient was not immunocompromised. Furthermore, the IA occurred in the absence of an aortic aneurysm, unlike its usual presentation. Thus, it is extremely important to establish an early diagnosis of IA and find out the causative organism for appropriate medical treatment,

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  • Priyanka Minocha, Ankur Setia
    Volume 5 (2016) Issue 4 Pages 294-296
    Released: November 28, 2016
    [Advance publication] Released: October 24, 2016
    JOURNALS FREE ACCESS

    Abdominal pain is a very common symptom in all age groups but retroperitoneal fibrosis is a rare differential diagnosis suspected in young patients presenting with nonspecific abdominal pain and symptoms of obstructive uropathy. Presented here is a case of a 16-year-old boy who presented with symptoms of persistent abdominal pain and a previous history of swelling in the left leg. A computed tomography (CT) scan suggested retroperitoneal fibrosis and an exploratory laparotomy and histopathological examination were performed for definitive diagnosis. This case report is intended to promote awareness of retroperitoneal fibrosis in young patients among health care providers.

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  • Guohua He, Hongwen Zhang, Shanshan Cao, Huijie Xiao, Yong Yao
    Volume 5 (2016) Issue 4 Pages 297-300
    Released: November 28, 2016
    [Advance publication] Released: September 12, 2016
    JOURNALS FREE ACCESS

    Dent's disease is an X-linked recessive proximal tubular disorder that mostly affects male patients in childhood or early adult life. The condition is caused by mutations in the CLCN5 (Dent disease 1) or OCRL (Dent disease 2) genes located on chromosome Xp11.22 and Xq25, respectively. In most male patients, proteinuria is subnephrotic but may reach nephrotic levels. Here, we report the first case of Dent's disease complicated by nephrotic syndrome. Dent's disease should be considered in the differential diagnosis of nephrotic syndrome, and especially in male patients with early onset of nephrotic syndrome. A urinary α1-microglobulin/albumin ratio > 1 may provide the first clue to a tubulopathy.

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  • Aram Behdadnia, Seyyed Farshad Allameh, Mehrnaz Asadi Gharabaghi, Seye ...
    Volume 5 (2016) Issue 4 Pages 301-305
    Released: November 28, 2016
    [Advance publication] Released: October 24, 2016
    JOURNALS FREE ACCESS

    A 31-year old woman with persistent fever for 6 weeks and unresponsive to antibiotic therapy came for rheumatologic investigation. After computed tomography (CT) studies of her neck, thorax and abdomen revealed bilateral cervical, axillary and retroperitoneal lymph node enlargements, histopathologic evaluation of the resected nodes showed features of histiocytic necrotizing lymphadenopathy suggestive of Kikuchi-Fujimoto's lymphadenopathy. Kikuchi-Fujimoto Disease (KFD) involving the retroperitoneal nodes is extremely unusual and even more challenging to diagnose when there are no early signs of extranodal involvement or abdominopelvic pain. We present a case of systemic KFD involving the cervical, axillary and retroperitoneal lymph nodes and emphasize the clinical interest to properly differentiate between the benign condition of KFD that requires no more than minimal to low dosage steroid therapy and the potentially life-threatening lupus lymphadenitis that mandates intensive immunosuppressive treatment.

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  • Yan Zhang, Yafei Zhang, Shiyang Ma, Haitao Shi, Xiaolan Lu
    Volume 5 (2016) Issue 4 Pages 306-307
    Released: November 28, 2016
    [Advance publication] Released: September 12, 2016
    JOURNALS FREE ACCESS

    We present a rare case of a 32-year-old female with gastric ulcers caused by pressure from trauma. The patient was diagnosed with stress-related acute gastritis by a local hospital and she was discharged 1 week later after her symptoms improved. She was given oral proton pump inhibitors (PPI). However, epigastric pain intensified, so the woman was seen at this Hospital 3 days later. Gastric endoscopy revealed kissing ulcers in the lower body of the stomach. A point worth mentioning is that the kissing gastric ulcers were caused by trauma due to impact with the steering wheel.

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Commentary
  • Xiaowei Jin, Li Chen
    Volume 5 (2016) Issue 4 Pages 308-313
    Released: November 28, 2016
    [Advance publication] Released: October 05, 2016
    JOURNALS FREE ACCESS

    Of over 7,000 known rare diseases, only 5% currently have an available treatment option worldwide. Moreover, the vast majority of rare disease patients in China have no access to treatment due to limited availability and the lack of appropriate infrastructure in China's healthcare system. Despite increased interest in orphan drug development, drug companies in China with active programs on drugs to treat rare diseases are still limited. Hence, there is a huge unmet need in China, with over 10 million patients suffering from rare diseases. Nonetheless, this has created unprecedented opportunities for the Chinese drug development market. Life science innovation in China has recently received a healthy boost from the 13th National Five-Year Plan and from on-going reform of the China Food and Drug Administration (CFDA). Rare diseases are now recognized as a national priority with increasing governmental support, creating tremendous opportunities for both domestic and multinational drug companies. China is anticipated to play an increasingly important role in the global fight against rare diseases. To ensure future success, Chinese drug companies should leverage the valuable knowledge assembled over the past three decades by Western countries in the area of orphan drug development.

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Letter
  • Raymond Fertig, Antonella Tosti
    Volume 5 (2016) Issue 4 Pages 314-315
    Released: November 28, 2016
    [Advance publication] Released: September 05, 2016
    JOURNALS FREE ACCESS

    Frontal fibrosing alopecia (FFA) is a rare dermatologic disease that causes scarring and hair loss and is increasing in prevalence worldwide. FFA patients typically present with hair loss in the frontal scalp region and eyebrows which may be associated with sensations of itching or burning. FFA is a clinically distinct variant of lichen planopilaris (LPP) that affects predominantly postmenopausal women, although men and premenopausal women may also be affected. Early diagnosis and prompt treatment are necessary to prevent definitive scarring and permanent hair loss. Data from retrospective studies indicate that 5-alpha-reductase inhibitors (5aRIs) are effective in stabilizing the disease. In our clinical experience, we have seen optimal results treating FFA patients with oral finasteride in conjunction with hydroxychloroquine, topical calcineurin inhibitors (tacrolimus) and excimer laser in patients with signs of active inflammation.

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