Intractable & Rare Diseases Research
Online ISSN : 2186-361X
Print ISSN : 2186-3644
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Review
  • Naixiang Zhai, Yanqin Lu, Yanzhou Wang, Xiuzhi Ren, Jinxiang Han
    Volume 7 (2018) Issue 1 Pages 1-6
    Released: March 15, 2018
    JOURNALS FREE ACCESS

    Circular RNA (circRNA) is a non-linear form of RNA derived from exonic, intronic, and exon-intron gene regions. circRNAs are characterized by covalent closed loops, highly stable nuclease resistance, and specific expression in species and developmental stages. CircRNA molecules have been identified as playing roles in the regulation of cell transcription, transcriptional expression after translation, interactions with microRNAs, and protein coding. A high stability and tissue- and disease-specific expression allow circRNAs to serve as potential biomarkers both for diseases and prognosis. CircRNAs function in bone remodeling by directly participating in bone-related signaling pathways and by forming the circRNA-miRNA-mRNA axis. Studies have seldom reported on the low incidence of circRNAs in genetic bone disorders. The current study reviews the characteristics of circRNAs and recent research on their role in rare hereditary bone diseases.

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Original Articles
  • Natsumi Fujisaki, Shugo Suwazono, Masahito Suehara, Ryo Nakachi, Miwak ...
    Volume 7 (2018) Issue 1 Pages 7-12
    Released: March 15, 2018
    [Advance publication] Released: February 26, 2018
    JOURNALS FREE ACCESS

    Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is a motor and sensory neuronopathy with autosomal dominant inheritance, adult onset, slowly progressive course, and is associated with TRK-fused gene (TFG) mutation. At advanced stages, respiratory failure and dysphagia becomes life-threatoning, and patients typically die by their 70s. Although there is currently no evidence for effective treatment, a therapy may be found by elucidation of the function of TFG. Recently its pathomechanism has been proposed to be associated with abnormalities in protein transfer from the endoplasmic reticulum. Such pathomechanisms might involve a similar process in amyotrophic lateral sclerosis; thus, its pathomechanisms and treatment strategy might make it a good model for neurodegenerative disorders. It is of great value to clarify the natural history of HMSN-P, in oder to judge the treatment effect. By evaluating 97 patients (79 out of 97 were examined and all confirmed with p.Pro 285 Leu mutation) in this study, it was confirmed that this disease follows a uniform course in the earlier stages, and there are individual differences in the onset between 20 and 30 years. Such uniformity might be due to the proposed single gene abnormality. At advanced stages, there are larger individual differences in the progression, but the reasons for these are unknown. Longer survival might be achieved with a better care for respiratory failure and dysphagia if such cares were undertaken at appropriate times.

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  • Qian Xu, Yuying Zhao, Xiaoyan Zhou, Jing Luan, Yazhou Cui, Jinxiang Ha ...
    Volume 7 (2018) Issue 1 Pages 13-18
    Released: March 15, 2018
    JOURNALS FREE ACCESS

    Amyotrophic Lateral Sclerosis (ALS) is a muscle-bone degenerative disease, which lacks a specific index for diagnosis. In our previous studies, we found that exosomes mediated the interaction mechanism between muscle and bone at the cellular level, and myoblast exosomes can transfer miR-27a-3p to promote osteoblast mineralization. Therefore, we suppose that the expression of miR-27a-3p in the serum exosomes of ALS patients also changes. In this study, we used healthy human serum as a sample to find out the conditions and methods for extraction and detection. Then through comparison of the expression of miR-27a-3p in the serum exosomes of 10 ALS patients and healthy subjects, we found that in the ALS patients miR-27a-3p was down-regulated, and may be involved in the development of ALS, and therefore has potential as a reference for the diagnosis of ALS in the clinic.

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  • Yanqin Lu, Yunzhang Dai, Yanzhou Wang, Naixiang Zhai, Jian Zhang, Junl ...
    Volume 7 (2018) Issue 1 Pages 19-24
    Released: March 15, 2018
    JOURNALS FREE ACCESS

    Osteogenesis imperfecta (OI) is a heritable connective tissue disorder with a predominately autosomal-dominant inheritance pattern. Recessive forms of OI are rare and involve many different causative genes. WNT1 mutations were found to cause either autosomal-recessive OI or dominantly inherited early-onset osteoporosis. Here we describe a 32-year-old boy with severe osteopenia and deformity of the extremities. The relative long thumb and ring finger are obvious. We identified a novel combination of complex heterozygous WNT1 mutation of c.397 A>T (p.Ala133Thr) and c.506dupG (p.Cys170Leufs*) in the proband, both parents and young brother were shown to be heterozygous asymptomatic carriers of the mutation. This is the eleventh family and the thirteenth patient we have ever found in China. Mutation of c.397 A>T (p.Ala133Thr) was found for the third time following our previous findings in two individual families with four patients in total, and may be a hotspot mutation in Chinese WNT1-related OI patients. In silico programs supported the damaging effects for both mutations. The three-D structure demonstrated the severely destroyed stability of WNT1. Serum levels of WNT1, LRP5, and β-catenin were decreased, while higher levels of GSK-3β were detected. The molecular mechanisms of the complex heterozygous mutations need further study.

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  • Sebastian Gorgonius Passon, Viviane Küllmar, Anna Katharina Blatzheim, ...
    Volume 7 (2018) Issue 1 Pages 25-31
    Released: March 15, 2018
    [Advance publication] Released: February 26, 2018
    JOURNALS FREE ACCESS

    Pseudoxanthoma Elasticum (PXE), caused by autosomal-recessive mutations in the ATP-binding cassette transporter (ABCC6) gene, is known for high prevalence of atherosclerosis. A novel method investigating elastic properties of arteries in atherosclerotic patients is vascular strain analysis. We compared 44 PXE patients with peripheral artery disease (PXE+PAD group) with 50 control patients, each 25 without (control group) and with PAD (PAD group). All participants underwent an angiological examination including ankle-brachial index (ABI) and were examined with speckle-tracking based vascular strain analysis of common carotid arteries, measuring radial displacement (r.Dis), radial velocity (r.Vel), radial strain (r.Str), circumferential strain (c.Str), radial strainrate (r.SR) and circumferential strainrate (c.SR). We found significant lower ABI in patients with PXE compared to all other groups (each p < 0.01). The vascular strain analysis resulted in significantly decreased values in the PAD group compared to PXE with PAD (each p ≤ 0.01) and controls without PAD (each p ≤ 0.05), whereas no significant difference could be found between PXE+PAD and controls without PAD. We found significant negative correlations between low strain values and a higher prevalence of PAD in non-PXE patients (r.Str r = -0.34; c.Str r = -0.35; r.SR: r = -0.51; c.SR: r = -0.53). In conclusion, PXE patients had similar values for arterial stiffness compared to controls without PAD in vascular strain analysis. In this group, arterial stiffness parameters were significantly higher compared to non-PXE PAD patients. It is worth to discuss whether PAD-like manifestations in PXE are a different kind of disease and might need another strategy in diagnostics and therapy.

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Brief Reports
  • Jun-ichi Satoh, Yoshihiro Kino, Motoaki Yanaizu, Yuko Saito
    Volume 7 (2018) Issue 1 Pages 32-36
    Released: March 15, 2018
    [Advance publication] Released: February 26, 2018
    JOURNALS FREE ACCESS

    Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder, characterized by progressive presenile dementia and formation of multifocal bone cysts, caused by genetic mutations of either triggering receptor expressed on myeloid cells 2 (TREM2) or TYRO protein tyrosine kinase binding protein (TYROBP), alternatively named DNAX-activation protein 12 (DAP12), both of which are expressed on microglia in the brain and form the receptor-adaptor complex that chiefly recognizes anionic lipids. TREM2 transmits the signals involved in microglial survival, proliferation, chemotaxis, and phagocytosis. A recent study indicated that a loss of TREM2 function causes greater amounts of amyloid-β(Aβ) deposition in the hippocampus of a mouse model of Alzheimer's disease (AD) owing to a dysfunctional response of microglia to amyloid plaques, suggesting that TREM2 facilitates Aβ clearance by microglia. TREM2/DAP12-mediated microglial response limits diffusion and toxicity of amyloid plaques by forming a protective barrier. However, the levels of Aβ deposition in postmortem brains of NHD, where the biological function of the TREM2/DAP12 signaling pathway is completely lost, remain to be investigated. By immunohistochemistry, we studied the expression of Aβ and phosphorylated tau (p-tau) in the frontal cortex and the hippocampus of five NHD cases. Although we identified several small Aβ-immunoreactive spheroids, amyloid plaques were almost undetectable in NHD brains. We found a small number of p-tau-immunoreactive neurofibrillary tangle (NFT)-bearing neurons in NHD brains. Because AD pathology is less evident in NHD than the full-brown AD, it does not play an active role in the development of NHD.

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  • Yanqin Lu, Yanzhou Wang, Frank Rauch, Hu Li, Yao Zhang, Naixiang Zhai, ...
    Volume 7 (2018) Issue 1 Pages 37-41
    Released: March 15, 2018
    JOURNALS FREE ACCESS

    Osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS) are rare genetic disorders that are typically inherited in an autosomal dominant manner. Few cases of OI/EDS overlap syndrome have been documented. Described here is a 30-year-old Chinese male with OI type III and EDS. Sequencing of genomic DNA revealed a heterozygous COL1A1 mutation (c.671G>A, p.Gly224Asp) that affected the N-anchor domain of the alpha 1 chain of collagen type I. Ultrastructural analysis of a skin biopsy specimen revealed thin collagen fibers with irregular alignment of collagen fibers. These findings have expanded the genotypic spectrum of the OI/EDS overlap syndrome.

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  • Guomin Li, Qian Shen, Li Sun, Haimei Liu, Yu An, Hong Xu
    Volume 7 (2018) Issue 1 Pages 42-45
    Released: March 15, 2018
    [Advance publication] Released: February 26, 2018
    JOURNALS FREE ACCESS

    Branchio-oto-renal (BOR) syndrome is a rare autosomal dominant disorder characterized by branchial cleft fistulae or cysts, preauricular pits, ear malformations, hearing loss, and renal anomalies. Mutations in the human homologue of the Drosophila eyes absent gene (EYA1) are the most common cause of BOR syndrome. PCR and direct sequencing were used to investigate all of the exons and exon-intron boundaries in the EYA1 gene in a patient with BOR syndrome from China. The patient was a child who displayed clinical features of BOR syndrome. Analysis of mutations in the EYA1 gene revealed a novel single base-pair deletion resulting in a truncated protein (c.1381delA; p.R461fs467X), and an analysis of mutations in the family revealed that this mutation was a de novo mutation. This is the first case of BOR syndrome in mainland China to be diagnosed based on clinical manifestations and mutations in the EYA1 gene. The novel c.1381delA mutation detected here expands the spectrum of known mutations in the EYA1 gene.

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  • Hongwen Zhang, Fang Wang, Huijie Xiao, Yong Yao
    Volume 7 (2018) Issue 1 Pages 46-50
    Released: March 15, 2018
    [Advance publication] Released: February 26, 2018
    JOURNALS FREE ACCESS

    Low-molecular-weight proteinuria is one of the characteristic clinical manifestations of renal tubular and interstitial diseases. Low-molecular-weight proteinuria is defined as excessive urinary loss of α1-microglobulin, β2-microglobulin, or other low-molecular-weight plasma proteins. The current study examined the ratio of urinary α1-microglobulin to microalbumin in 24 Chinese pediatric patients with renal tubular and interstitial diseases, including 10 patients with Dent disease, 2 patients with Lowe syndrome, 6 patients with acute tubulointerstitial nephritis (ATIN), 4 patients with acute tubulointerstitial nephritis with uveitis syndrome (TINU), and 2 patients with nephronophthisis (NPHP). Patients with steroid-sensitive nephrotic syndrome, IgA nephropathy, Henoch-Schonlein purpura nephritis, or lupus nephritis served as control groups. In all of the patients with tubular and interstitial disease, urinary α1-microglobin increased 10-300-fold above the upper limit of the normal range, the ratio of urinary α1-microglobulin to microalbumin was greater than 1, and the percentage of low-molecular-weight plasma proteins (LMWP) in urine was greater than 50% according to urine protein electrophoresis. There was close correlation between the ratio of urinary α1-microglobulin to microalbumin and the percentage of LMWP in urine according to urine protein electrophoresis (r = 0.797, p = 0.000). We suggested firstly that the ratio of urinary α1-microglobulin to microalbumin, greater than 1, can be used as a diagnostic criterion for tubuloproteinuria.

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Case Reports
  • David Martin, Mirza Muradbegovic, Snezana Andrejevic-Blant, David Pete ...
    Volume 7 (2018) Issue 1 Pages 51-53
    Released: March 15, 2018
    [Advance publication] Released: February 26, 2018
    JOURNALS FREE ACCESS

    The current report presents a case of an omental fibromatosis discovered incidentally in a 46-year-old woman with no particular medical history and few symptoms. A surgical biopsy was performed initially, and microscopic examination revealed myofibroblastic proliferation. After additional immunohistochemical and molecular analyses, omental fibromatosis was diagnosed. Omental fibromatosis, also called intra-abdominal desmoid, is a rare and benign tumour but can be locally aggressive. Majority of cases are asymptomatic, and difficult to diagnose based on clinical presentation and radiological investigation. Final diagnosis is usually made on histopathology and immunohistochemistry studies. Surgical wide excision is currently the treatment of choice.

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  • Francisco Galeano-Valle, Pablo Demelo-Rodriguez, Luís Álvarez-Sala-Wal ...
    Volume 7 (2018) Issue 1 Pages 54-57
    Released: March 15, 2018
    [Advance publication] Released: February 26, 2018
    JOURNALS FREE ACCESS

    Behçet's Disease (BD) is a rare multi-systemic inflammatory disorder classified as a systemic vasculitis of unknown aetiology. Vascular involvement occurs in approximately 5-51.6% cases, affecting venous and arterial vessels. Cardiac involvement is rare in BD (6%). There have been published approximately 93 cases of BD associated with intracardiac thrombosis, with different treatments and courses. We present a case of a 35-year-old spanish male that, after a percutaneous pharmacomechanical thrombectomy with venous stent placement, developed high fever and extensive venous thrombosis despite anticoagulation including intracardiac thrombosis (ICT) in the right ventricle and pulmonary embolism that leaded to the diagnosis of BD. The patient was successfully treated with immunosuppressants, achieving the complete resolution of ICT. We hypotesize that the endovenous procedure could have acted as a trigger for the posterior acute attack of the disease, representing a ‘vascular pathergy phenomenon’. Vascular BD has to be suspected in cases of thrombosis recurrence despite correct anticoagulation, and intense immunosuppressive treatment should be considered.

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  • Emrah Ermis, Serkan Kahraman, Hakan Ucar, Samir Allahverdiyev
    Volume 7 (2018) Issue 1 Pages 58-60
    Released: March 15, 2018
    [Advance publication] Released: February 26, 2018
    JOURNALS FREE ACCESS

    Right coronary artery (RCA) originating from the left coronary system is a subtype of single coronary artery (SCA) anomaly, and the origin of RCA as a branch from the left anterior descending artery (LAD) is a very rare variant. A 55-year-old male who had a percutaneous coronary intervention (PCI) history was hospitalized due to acute coronary syndrome. Coronary angiography revealed an aberrant RCA originating from the mid-LAD as well as stent thrombosis. A successful PCI was performed and he was discharged from the hospital three days after the PCI. It is known that there is an increased incidence of atherosclerosis and stent thrombosis in coronary anomaly patients. Therefore, interventional cardiologists should consider the most suitable PCI strategy before stenting and avoid complex techniques.

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  • Purva V Sharma, Michael Witteman, Swethika Sundaravel, Tulisa Larocca, ...
    Volume 7 (2018) Issue 1 Pages 61-64
    Released: March 15, 2018
    [Advance publication] Released: February 26, 2018
    JOURNALS FREE ACCESS

    Adult T cell lymphoma (ATL), is a peripheral T cell neoplasm associated with infection by human T-lymphotropic virus (HTLV). This is a case of a 28-year-old lady who presented with back pain for the past month and recent onset weakness in her lower extremities bilaterally. She has a history of T-cell lymphoma secondary to HTLV-1 under remission since 2014 and systemic lupus erythematosus complicated by lupus nephritis. On physical examination patient had hyper-reflexia in both knees, ankle clonus bilaterally and spasticity in both her lower extremities. She also had a diffuse, scaly, macular rash in her upper and lower extremities and ulcer-like lesions on the plantar surface of both feet. Her lumbar puncture showed lymphocyte predominance. The Western Blot test was positive for HTLV antibodies in the CSF. The patient was started on IV Methylprednisone which considerably improved her symptoms. The biopsy of her skin lesions showed an immunophenotype of T-cells similar to the cells in the bone marrow at the time of diagnosis of the lymphoma. HTLV infection is an etiologic agent for ATL as well as for tropical spastic paresis. One should have a high degree of suspicion for tropical spastic paresis in patients with HTLV-1 infection as it can easily go undiagnosed. Indolent forms of ATL can also present in the form of skin lesions in later stages. It is also important to distinguish between skin manifestations of ATL and cutaneous T cell lymphomas, and the importance of skin biopsies for the same cannot be undermined.

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  • Vishal Sharma, Sarthak Malik, Harshal S Mandavdhare, Harjeet Singh
    Volume 7 (2018) Issue 1 Pages 65-68
    Released: March 15, 2018
    [Advance publication] Released: February 26, 2018
    JOURNALS FREE ACCESS

    Endoscopic retrograde cholangio-pancreatography (ERCP) is an important tool for treatment of pancreaticobiliary diseases. However, ERCP may be difficult in patients who have altered gastrointestinal anatomy due to congenital or surgical reasons. A 40-year-old male with HIV infection presented with abdominal pain following abdominal trauma. The patient was diagnosed to have traumatic pancreatic injury and underlying situs inversus. The pancreatic fluid collection was drained using radiology guided pigtail placement done for the symptoms of abdominal pain and vomiting. The resulting external pancreatic fistula was successfully managed with ERCP and stenting. The patient improved with disappearance of ascites and resolution of pigtail output which was then removed. We report the technique used for ERCP in this patient. We also review the literature on pancreatic endotherapy in patients with situs inversus. The published literature suggests that with modifications in the standard ERCP technique like mirror image technique, 180 degree turn technique, left lateral technique etc. these patients can be managed successfully.

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Letter
  • Donna Hermawati, Farid Agung Rahmadi, Tanjung Ayu Sumekar, Tri Indah W ...
    Volume 7 (2018) Issue 1 Pages 69-71
    Released: March 15, 2018
    [Advance publication] Released: February 26, 2018
    JOURNALS FREE ACCESS

    Prevalence autism spectrum disorders (ASD) has been on rise, but many studies suggests over-diagnosed. Currently, children have more access to electronic media on the daily basis than those of previous generation. Some studies suggest that increases screen time is associated with melanopsin-expressing neurons and decreasing gamma-aminobutyric acid (GABA) neurotransmitter, and thus results aberrant behavior, decreased cognitive, and language development. Early exposure of electronic media in early life (< 2 years old) gives an impact on language, but it still inconclusive. We made a study aiming at revealing the impact of early exposure of electronic screen on language development and autistic-like behavior. Results showed that children who spent viewing ≤ 3 hours per day had language delay and short attention span, while children who spent viewing ≥ 3 hours per day had language delay, short attention span, and hyperactivity. While, we found that more than a half of children (66.6%) had no parents-child interaction during the exposure, speech delayed and short attention had been reported in all cases, and hyperactivity was found in 66.6% children.

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