Intractable & Rare Diseases Research
Online ISSN : 2186-361X
Print ISSN : 2186-3644
ISSN-L : 2186-3644
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Showing 1-11 articles out of 11 articles from the selected issue
Policy Forum
  • Zhiye Ying, Li Gong, Chunyang Li
    2021 Volume 10 Issue 3 Pages 148-153
    Published: August 31, 2021
    Released: September 05, 2021
    [Advance publication] Released: June 01, 2021
    JOURNAL FREE ACCESS

    Over the past few years, China has paid greater attention to the topic of rare diseases. The Chinese Government has made considerable efforts to gradually improve the situation of patients with rare diseases in terms of diagnosis and treatment, access to medication, and affordability of care. The National Health Commission implemented a raft of measures, including the first Catalog of Rare Diseases, establishment of a rare diseases alliance, establishment of the Network for Collaboration in Rare Disease Diagnosis and Treatment, formulation of the Guidelines for the Diagnosis and Treatment of Rare Diseases, sharing of diagnostic and treatment information, and creation of expert committees, to ensure the standardization of rare disease diagnosis and treatment and to promote the improvement of rare disease diagnosis and treatment capabilities nationwide. In order to encourage the research, development, and production of drugs to treat rare diseases, the National Medical Products Administration has drafted a series of policies to accelerate the review and approval of drug registration and to support the research and development of drugs to treat rare diseases. The Ministry of Finance has also helped to implement tax incentives for drugs to treat rare diseases, to encourage the marketing and importation of drugs to treat rare diseases, and to reduce the cost of drugs for patients with rare diseases. Through adjustment of the List of Drugs Covered by National Medical Insurance, the National Healthcare Security Administration has covered an increasing number of drugs to treat rare diseases under basic medical insurance. It has also negotiated to reduce the price of some drugs to treat rare diseases, further reducing the economic burden on patients with rare diseases.

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Review
  • Ling Zhang, Yihang Zhang, Jihong Pan
    Type: review-article
    2021 Volume 10 Issue 3 Pages 154-164
    Published: August 31, 2021
    Released: September 05, 2021
    [Advance publication] Released: April 08, 2021
    JOURNAL FREE ACCESS

    Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease characterized by synovitis and symmetrical joint destruction. RA has become one of the key diseases endangering human health, but its etiology is not clear. Therefore, identifying the immunopathogenic mechanisms of RA and developing therapeutic drugs to treat autoimmune diseases have always been difficult. This article mainly reviews the immunopathogenic mechanism of RA and advances in the study of anti-inflammatory drugs in order to provide a reference for the treatment of RA and drug development in the future.

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Original Article
  • Pengchao Liu, Yongtao Zhang, Shanshan Zhang, Chuanming Peng, Wei Yang, ...
    Type: research-article
    2021 Volume 10 Issue 3 Pages 165-172
    Published: August 31, 2021
    Released: September 05, 2021
    [Advance publication] Released: May 27, 2021
    JOURNAL FREE ACCESS

    Human interferon-induced transmembrane proteins (IFITMs) family is a multi-functional biomacromolecule family playing a critical role in various physiological processes, such as, antiviral immunity, tumor suppression, and bone formation. Although there are many studies proving that a subset of tumors strongly links to the changes of IFITMs, the link between different IFITMs mutant types and diverse tumors has not been studied thoroughly. To investigate the law of expression among IFITMs internal members and the linking of IFITMs mutant types and cancers, online databases were used to pool together relevant data for bioinformatics analysis. Here, we summarize mutations, expression, and functions of human IFITMs, analyze diverse expression levels of IFITMs in physiological and pathological tissues, predict protein-protein interaction (PPI) networks, and target miRNAs and relevant signaling pathways of IFITMs. The results show that IFITM1, IFITM2, and IFITM3 have similar motif pattern constructions and physiological functions, while IFITM5 and IFITM10 show far diversity from them. Particularly, IFITM1-3, in conjunction with interacting proteins, is strongly related to development and overall survival rates of a portion of cancers, including renal cancer and uveal melanoma (UVM). This trait may make IFITM1-3 become a prognostic marker of cancers. Meanwhile, hsa_circ_0116375 has been found as the common circRNA for IFITM2, IFITM3, IFITM5, and IFITM10.

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  • Xianxian Li, Shanshan Zhang, Yongtao Zhang, Pengchao Liu, Mian Li, Yan ...
    Type: research-article
    2021 Volume 10 Issue 3 Pages 173-178
    Published: August 31, 2021
    Released: September 05, 2021
    [Advance publication] Released: June 01, 2021
    JOURNAL FREE ACCESS

    Muscle is a contractile tissue responsible for maintaining posture and the movement of all parts of the body. Prolonged oxidizative stress can lead to the damage of cells, tissues, and organs. In this study, we investigated the possibility of oxidative stress in the process of myoblast differentiation of C2C12 cells. First, the myoblast differentiation model of C2C12 cells was constructed and verified by Giemsa staining. The expression of hypoxia inducible factor1-alpha (HIF1-α), hypoxia inducible factor1-beta (HIF1-β), Von Hippel-Lindau (VHL), lysyl oxidase (Lox), EGL-9 family hypoxia-inducible factor 1 (EGLN1), proline 4-hydroxylase alpha 1 (P4HA1) and heme oxygenase-1 (HOMX1) in the process of myoblast differentiation was verified by in vitro experiments and Gene Expression Omnibus (GEO) bioinformatic analysis. We found that with the increased expression of myogenic factor 5 (MYF5), myogenic differentiation 1 (MYOD1), and Desmin, myotube fusion became more obvious during the process of C2C12 cell differentiation. Both experimental and GEO analysis indicated that the expression of HIF1-α, HIF1-β, VHL, LOX, EGLN1 and P4HA1 increased, and the expression of HOMX1 decreased during myogenic differentiation. Therefore, we suggest that the myoblast differentiation of C2C12 cells may be related to oxidative stress. Their possible relationship was proposed, though further studies are needed.

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  • Deborah Ribeiro Nascimento, Suzana Lopes Bomfim Balaniuc, Durval Batis ...
    Type: research-article
    2021 Volume 10 Issue 3 Pages 179-189
    Published: August 31, 2021
    Released: September 05, 2021
    [Advance publication] Released: May 22, 2021
    JOURNAL FREE ACCESS

    Fibrodysplasia Ossificans Progressiva (FOP) is a rare congenital intractable disease associated with a mutation in ACVR1 gene, characterized by skeleton malformations. Ascorbic acid (AA) and propranolol (PP) in combination is reported to minimize flare-ups in patients. FOP leukocyte phenotype may possibly be modulated by AA and PP treatment. In this study, expression of 22 potential target genes was analyzed by RT-PCR in peripheral blood mononuclear cells culture (PBMC) from FOP patients and controls to determine effectiveness of the combination therapy. PBMC were treated with AA, PP and AA+PP combination. Basal expression of 12 of the 22 genes in FOP PBMC was statistically different from controls. ACVR1, ADCY2, ADCY9 and COL3 were downregulated while COL1 was upregulated. ADRB1, ADRB2, RUNX2, TNF-α and ACTB, were all overexpressed in FOP PBMC. In control, AA upregulated COL1, SVCT1, ACTB, AGTR2 and downregulated ADCY2. In FOP cells, AA upregulated ACVR1, BMP4, COL1, COL3, TNF-α, ADCY2, ADCY9, AGTR2 and MAS, while downregulated ADBR2, RUNX2, ADCY1, SVCT1 and ACTB. PP increased ADBR1 and decreased RUNX2, TNF-α, AGTR1, ACTB and CHRNA7 genes in treated control PBMC compared to untreated. PP upregulated ADBR1, ADBR2 and MAS, and downregulated TNF-α and ACTB in treated FOP PBMC versus untreated. AA+PP augmented ADRB1 and ADRB2 expressions in control PBMC. In FOP PBMC, AA+PP augmented ACVR1, COL1, COL3, ADBR1, AGTR2 and MAS expression and downregulated ADBR2, RUNX2, ACTB and MRGD. These data show distinct gene expression modulation in leukocytes from FOP patients when treated with AA and or PP.

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  • Jiahao Hu, Lin Zhu, Jiangjiang He, Dingguo Li, Qi Kang, Chunlin Jin
    Type: research-article
    2021 Volume 10 Issue 3 Pages 190-197
    Published: August 31, 2021
    Released: September 05, 2021
    [Advance publication] Released: July 30, 2021
    JOURNAL FREE ACCESS

    Lysosomal storage diseases (LSDs) are a group of rare diseases that cause progressive physical dysfunction and organ failure, which significantly affected patients' quality of life. The objective of this study was to explore the characteristics and usage of Enzyme Replacement Treatments (ERTs), which is the only specific therapy for LSDs, of patients with the four different LSDs (Gaucher, Fabry, Pompe disease and Mucopolysaccharidosis) in Shanghai, and then evaluate the economic burden and quality of life of these patients. A total of 31patients, involving 5, 14, 4 and 8 patients with Gaucher, Fabry, Pompe disease and Mucopolysaccharidosis, respectively, were included in analysis. The result showed that only five Gaucher disease (GD) patients in Shanghai used Imiglucerase in 2019, while the other 26 patients with the other three LSDs did not receive ERTs. The total health expenditure of GD patients was 2,273,000CNY on average mainly resulted by the high cost of Imiglucerase. The total health expenditure of the other 26 patients was 37,765CNY on average. Though the cost-sharing mechanism between basic medical insurance, charity fund and patients had been explored for Gaucher disease in Shanghai, the out-of-pocket part, which was 164,301 CNY, still laid a heavy economic burden on the patients and their families. The mean EQ-VAS score of GD patients was 76.4 ± 15.5, which was higher than that of the other three LSDs. It is recommended that the scope of drug reimbursement list and the reimbursement level should be further expanded and raised to help improve the living conditions of patients with LSDs.

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Brief Report
  • Min Yang, Jun Ye, Lianshu Han, Wenjuan Qiu, Yongguo Yu, Xuefan Gu, Hui ...
    Type: brief-report
    2021 Volume 10 Issue 3 Pages 198-201
    Published: August 31, 2021
    Released: September 05, 2021
    [Advance publication] Released: August 25, 2021
    JOURNAL FREE ACCESS

    Endocrine disorders are common in patients with Prader-Willi syndrome (PWS). Whether hypothyroidism is present in patients with PWS, and especially infants and young children, remains unclear. The aims of this study were to evaluate thyroid function in patients with PWS, to assess the prevalence of thyroid dysfunction, and to evaluate the effect of growth hormone on thyroid function. Subjects were 23 patients with PWS ages 3 months to 3 years who were followed for up to one year. Four patients were lost to follow-up after the first visit. The remaining 19 patients were treated with recombinant human growth hormone (rhGH). PWS was diagnosed based on a genetic analysis. Free thyroxine (FT4), free triiodothyronine (FT3), and thyroid-stimulating hormone (TSH) levels were evaluated before and after growth hormone treatment. A total of 9 patients (9/23 = 39.1%) developed abnormal thyroid function. Five out of 23 patients (21.7%) had abnormal thyroid function before growth hormone treatment. Four patients developed thyroid dysfunction during the 3- to 9-month period of rhGH treatment. Of the 9 patients with abnormal thyroid function, 7 (5 boys, 2 girls) had central hypothyroidism, and the other 2 patients had subclinical hypothyroidism. TSH levels were higher in patients with PWS due to maternal uniparental disomy (UPD) than in patients with PWS due to a 15q11-q13 deletion. The prevalence of hypothyroidism was high in infants and young children with PWS. Thyroid function should be regularly monitored in patients with PWS at both diagnosis and follow-up.

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  • Anna Skorczyk-Werner, Dorota Raczynska, Anna Wawrocka, Dinara Zholdyba ...
    Type: brief-report
    2021 Volume 10 Issue 3 Pages 202-206
    Published: August 31, 2021
    Released: September 05, 2021
    [Advance publication] Released: May 22, 2021
    JOURNAL FREE ACCESS

    Genetically determined ophthalmic diseases form a numerous and heterogenic group of disorders. Making the accurate clinical diagnosis of genetic eye disease is often a challenge for an ophthalmologist. In many cases, only genetic testing enables the establishment of the proper clinical diagnosis. Here we describe two ultra-rare diseases: gyrate atrophy of the choroid and retina (GACR) and Kjer-type optic atrophy coexisting in a 39-year-old Polish patient with severe visual impairment including a significant reduction of visual acuity and night blindness. Atrophic pigmented changes with large pigment deposits and chorioretinal atrophy with the retina's disturbed structure (with atrophic scarring changes and the epiretinal membrane) of both eyes were observed. Electroretinography (ERG) revealed extinguished responses. A Next-Generation Sequencing (NGS) panel comprising 275 retinal genes revealed a presence of potentially pathogenic variants in two genes: a homozygous variant c.1058G>A (p.Gly353Asp) in the OAT gene and a heterozygous variant c.1886C>G (p.Ser629Ter) in the OPA1 gene. The diagnosis established based on NGS is surprising because initially, several different diagnoses have been made, including high degenerative myopia, choroideremia, Leber congenital amaurosis, and severe, atypical retinitis pigmentosa. This report provides the unquestioned diagnostic value of the combination of chorioretinal imaging and the NGS technique. To our knowledge, this is the first and the only description of the coincidence of gyrate atrophy and Kjer-type optic atrophy.

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  • Izabela Łoń, Jolanta Kunikowska, Piotr Jędrusik, Jarosław Góra, Sadegh ...
    Type: brief-report
    2021 Volume 10 Issue 3 Pages 207-213
    Published: August 31, 2021
    Released: September 05, 2021
    [Advance publication] Released: June 04, 2021
    JOURNAL FREE ACCESS

    Familial paraganglioma may be related to mutations in succinate dehydrogenase (SDH) enzyme complex genes. Among patients with hereditary paraganglioma, SDH subunit B (SDHB) gene mutations are associated with the highest morbidity and mortality related to a higher malignancy rate. We report a family with the c.689G>A (p.Arg230His) mutation in the SDHB gene identified in two family members, a father and his daughter. While the 14-year-old daughter had no evidence of clinical disease, recurrent and later disseminated [131I]metaiodobenzylguanidine uptake-negative head and neck paraganglioma with multiple bone metastases developed in the father who underwent peptide receptor radionuclide therapy with [90Y]Y/[177Lu]Lu-dodecane tetraacetic acid octreotate (DOTATATE) at the time of the genetic diagnosis. This treatment was repeated 6 years later due to disease progression and the patient, who is currently 49 years old, remains alive and in good overall clinical condition at 8 years of follow-up after the original presentation at our unit. The growing armamentarium of imaging methods available for such patients may inform decision making regarding choice of the optimal treatment approach, potentially contributing to improved outcomes.

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Case Report
  • Filippo Tommaso Gallina, Virginia Ferraresi, Alessio Annovazzi, Sabrin ...
    Type: case-report
    2021 Volume 10 Issue 3 Pages 214-219
    Published: August 31, 2021
    Released: September 05, 2021
    [Advance publication] Released: August 05, 2021
    JOURNAL FREE ACCESS

    Ewing's sarcoma of the bone is a rare, highly aggressive tumor that typically affects children and young adults. Progress in the treatment of Ewing's sarcoma has improved survival from about 10%, before the introduction of chemotherapy, to about 75% today for patients with localized tumors. On the contrary, metastatic disease still has a poor prognosis, and a multidisciplinary approach is essential to improve the outcome. Molecular techniques and new imaging modalities are affecting the diagnosis and classification of patients with Ewing's sarcoma. The most frequent sites of metastases in Ewing's sarcoma include lungs, bones and bone marrow. Lymph nodes are a rare site of metastatic spread, particularly in the mediastinum. In this report, we present two consecutive cases of patients with Ewing's Sarcoma, diagnosed, and treated at our institute. We focused particularly on the rarity of the atypical presentation of the disease and on the synergistic strategy to adopt as a model of networking in treating patients with rare diseases.

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Letter
  • Mirac Yildirim, Ozgur Balasar, Engin Kose, Melih Timucin Dogan
    Type: letter
    2021 Volume 10 Issue 3 Pages 220-222
    Published: August 31, 2021
    Released: September 05, 2021
    [Advance publication] Released: May 22, 2021
    JOURNAL FREE ACCESS

    Centronuclear myopathies (CNMs) are a subgroup of congenital myopathies (CMs) characterized by muscle weakness, genetic heterogeneity, and predominant type 1 fibers and increased central nuclei in muscle biopsy. Mutations in CNM-causing genes such as MTM1, DNM2, BIN1, RYR1, CACNA1S, TTN, and extraordinary rarely SPEG (striated muscle preferentially expressed protein kinase) have been identified for about 60-80% of patients. Herein, we report a case of CM due to a novel variation in the SPEG gene, manifested by mild neonatal hypotonia, muscle weakness, delayed motor milestones, and ophthalmoplegia, without dilated cardiomyopathy. We identified a novel variation [c.153C>T (p.Asn51=) in exon 1] in the SPEG gene with whole-exome sequencing and confirmed by Sanger sequencing. Mild intellectual disability has not been associated with SPEG-related CM in the previous reports. We suggest that this report expands the phenotypic spectrum of SPEG-related CM, and further case reports are required to expand the genotype-phenotype correlations.

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