Intractable & Rare Diseases Research
Online ISSN : 2186-361X
Print ISSN : 2186-3644
ISSN-L : 2186-3644
Advance online publication
Showing 1-15 articles out of 15 articles from Advance online publication
  • Daisuke Honda, Isao Ohsawa, Satoshi Mano, Hisaki Rinno, Yasuhiko Tomin ...
    Article ID: 2021.01010
    Published: 2021
    [Advance publication] Released: May 09, 2021
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Hereditary angioedema due to C1-inhibitor (C1-INH) deficiency (HAE-C1-INH) induces an acute attack of angioedema. In 2018, icatibant available for self-possession and subcutaneous self-administration was licensed for on-demand treatment in addition to intravenous C1-INH administration in Japan. We retrospectively evaluated the percentage of attacks in critical parts at emergency room (ER) visits and the time until visiting ER for C1-INH administration before and after the initial prescription of icatibant. The percentage of attacks in critical parts at ER visits before the prescription was 69.2%, but that was 80.0% when patients visited ER for additional C1-INH administration after the self-administration of icatibant. The time from the onset of an acute attack to visiting ER for the additional treatment after the self-administration of icatibant significantly increased from 6.2 h to 19.2 h (p < 0.001). Icatibant, therefore, promoted the patients' behavior modification associated with ER visits for C1-INH administration during an acute attack of HAE-C1-INH.

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  • Lama Mohammed El-Attar, Ahmed Abdelrahman Bahashwan, Ameen Deen Bakhsh ...
    Type: research-article
    Article ID: 2021.01016
    Published: 2021
    [Advance publication] Released: May 03, 2021
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Congenital anomalies are a worldwide health problem that places a burden on the family and society. Chromosome abnormalities are one of the leading causes for congenital anomalies in newborns. Despite the remarkable development in cytogenetic services in the past years, still there are limited data from Middle East countries. The current study aimed to evaluate the prevalence and patterns of chromosomal aberrations in newborns admitted to the neonatal intensive care unit (NICU) with major congenital anomalies at Medina province in the western region of Saudi Arabia. Out of 2,541 live births, 150 newborns were selected based on the presence of major birth defects. Demographic and clinical data were collected from hospital medical records and statistically analyzed. The prevalence of major congenital anomalies was 10.7/1,000 live births (95% CI: 9.076-12.583). The most common congenital anomalies in descending order were congenital heart disease, musculoskeletal and chromosome abnormalities. The birth prevalence of chromosome abnormalities was 4.22/1,000 live births (95% CI: 3.211-5.441). The most common chromosome abnormality was Down syndrome-nondisjunction type (66%). Advanced parental age was strongly associated with chromosome aberrations (p < 0.001) while consanguinity was evident in cases with normal karyotype (p < 0.001). High birth prevalence of chromosome abnormalities in newborns with congenital anomalies in Al Madinah was evident and advanced parental age is a potential risk factor. A local registry system for congenital anomalies is highly recommended to provide proper health services to high risk families.

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  • Mohamad Moussa, Mohamad Abou Chakra, Athanasios G. Papatsoris, Baraa D ...
    Type: review-article
    Article ID: 2021.01029
    Published: 2021
    [Advance publication] Released: May 03, 2021
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system. Lower urinary tract dysfunction due to MS includes a dysfunction of the storage phase or dysfunction of the voiding phase or a detrusor-sphincter dyssynergia. Baseline evaluation includes a voiding chart, an ultrasound scan of the urinary tract, urine culture, and an urodynamic study. For storage symptoms, antimuscarinics are the first-line treatment, and clean intermittent catheterization (CIC) is indicated if there is concomitant incomplete bladder emptying. Intradetrusor injections with botulinum toxin A (BTX-A), are recommended for refractory cases. Urinary diversion is rarely indicated. For patients with voiding symptoms, CIC and alpha-blockers are usually offered. Sexual dysfunction in patients with MS is multifactorial. Phosphodiesterase type 5 inhibitors are first-line therapies for MS-associated erectile dysfunction in both male and female patients. This review summarizes the epidemiology, pathogenesis, risk factors, genetic, clinical manifestations, diagnostic tests, and management of MS. Lastly, the urologic outcomes and therapies are reviewed.

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  • Hui Zhang, Jing Luan, Yazhou Cui, Jinxiang Han
    Type: brief-report
    Article ID: 2021.01054
    Published: 2021
    [Advance publication] Released: May 03, 2021
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Muscle-bone interaction might regulate bone remodeling in an endocrine manner, but the exact mediators have not been identified. Previous in vitro studies suggest that exosomal miRNAs are a candidate for this interaction. Here we present an in vivo study to show that targeted knockout of a muscle-specific miR-23a cluster including miR-23a, miR-27, and miR-24-2 in skeletal muscle tissues can suppress bone remodeling in mice. The effect of miR-23a cluster seem to not be related to aging, but can worsen the pathological extent of osteoporosis in mice. Our findings suggest that muscle-derived miRNAs may contribute to bone metabolism regulation through exosomes in muscle-bone interaction.

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  • Vittorio Bolcato, Claudia Carelli, Silvia Damiana Visonà, Marcella Reg ...
    Type: case-report
    Article ID: 2021.01021
    Published: 2021
    [Advance publication] Released: April 22, 2021
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Fibrodysplasia ossificans progressiva (FOP) is a rare genetic condition with soft tissue progressive ossification, leading to severe disability. We describe a 27-years-old female affected by FOP who died after a fall. An autopsy was performed. Upper and lower extremities resulted in fixed flexion, with kyphoscoliosis of the spine and chest wall deformity. Moreover, a cranial fracture was pointed out. At histology, atypical abundance of corpora amylacea in gray matter was observed. In a sample of macroscopically non-affected muscular tissue, small areas with necrosis of myocytes and hyperplasia of fibroblasts were seen in light microscopy, with intracellular inorganic dystrophic inclusions in transmission electron microscopy. Thyroid gland histology showed diffuse lymphocytic infiltration. Postmortem examination of FOP patients provided precious information about involvement of other tissues, suggesting an initial and widespread inflammatory/dystrophic phase, to be further investigated, because it might reveal new insights about a FOP mutation cascade.

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  • Nikolaos S. Salemis
    Type: case-report
    Article ID: 2021.01017
    Published: 2021
    [Advance publication] Released: April 08, 2021
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    The synchronous occurrence of primary breast cancer and lymphoid tissue malignant tumors has been rarely reported in the literature. We present an exceedingly rare case of synchronous breast invasive ductal carcinoma with an abdominal diffuse large B-cell lymphoma (DLBCL). A 78-yearold woman who was diagnosed with a luminal A invasive breast cancer on core biopsy, and complaint of progressively worsening low back pain. An abdominal computed tomography (CT) scan that was performed as part of the preoperative staging showed a large abdominal mass measuring 10.5 × 4.8 × 9.5 cm surrounding the lower part of the abdominal aorta, the right common iliac, right external, right internal iliac, and the left internal iliac arteries. A CT-guided fine-needle aspiration biopsy (FNAB) of the abdominal mass was then performed, to exclude the possibility of being an abdominal tumor metastasis of the known primary breast cancer. Histopathological findings were suggestive of DLBCL. Following a multidisciplinary team discussion, chemotherapy was initiated for DLBCL. The tumor however was refractory to multiple chemotherapy regimens and exhibited a highly aggressive clinical course. The diagnostic evaluation and management of the patient are discussed, along with a review of the relevant literature. This case underscores the fact that the presence of synchronous malignancies may pose both diagnostic and treatment challenges. Accurate staging of both malignancies and multidisciplinary team discussion is of utmost importance to guide an optimal therapeutic approach. Histopathological evaluation is essential for both tumors, for the second malignancy not to be misinterpreted as a secondary deposit of the primary one.

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  • Ling Zhang, Yihang Zhang, Jihong Pan
    Type: review-article
    Article ID: 2021.01022
    Published: 2021
    [Advance publication] Released: April 08, 2021
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    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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  • Sonia Gupta, Amandeep Rakhra, Vinay Thallapally, Joseph Nahas
    Type: case-report
    Article ID: 2020.03144
    Published: 2021
    [Advance publication] Released: March 31, 2021
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Immunosuppression is the cornerstone therapy for anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) myopathy. Typical immunosuppressants such as corticosteroids, methotrexate, and azathioprine have been used in conjunction with removal of the offending agent, yet the use of rituximab is more limited in this type of myopathy. Reported here is a case of a patient who responded well to rituximab (RTX) after the standard immunosuppressants had failed. This case illustrates the importance of further studies to evaluate the role of RTX in anti-HMGCR myopathy.

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  • Ryohei Norioka, Shinsuke Tobisawa, Ryusei Nishigori, Tomiko Kuhara, Ma ...
    Type: case-report
    Article ID: 2021.01003
    Published: 2021
    [Advance publication] Released: March 31, 2021
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    We report a case of saccharopinuria with hyperammonemia and hypercitrullinemia in a Japanese woman who presented with elderly-onset epilepsy, progressive cognitive decline, and gait ataxia. Blood amino acid analysis revealed an increase in citrulline, cystine, and lysine levels, and urine amino acid analysis showed increased citrulline and cystine levels. Urine metabolomics revealed an increased saccharopine level, leading to the definitive diagnosis of saccharopinuria. In western blots of liver biopsy samples, normal citrin levels were observed, suggesting that adult-onset citrullinemia type 2 (CTLN2) was not present. In addition, decreased argininosuccinate synthetase (ASS) levels were observed, and ASS1 gene, a causative gene for citrullinemia type 1 (CTLN1), was analyzed, but no gene mutations were found. Because the causes of hypercitrullinemia were not clear, it might be secondary to saccharopinuria. Muscle biopsy findings of the biceps brachii revealed diminished cytochrome c oxidase (COX) activity, mitochondrial abnormalities on electron microscopy and p62-positive structures in immunohistochemical analyses. Saccharopinuria is generally considered a benign metabolic variant, but our case showed elevated lysine and saccharopine levels causing ornithine circuit damage, mitochondrial dysfunction, and autophagy disorders. This may lead to so far unknown neurological disorders.

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  • Munkhtuya Tumurkhuu, Uranchimeg Batbuyan, Satoru Yuzawa, Yanjinlkham M ...
    Type: brief-report
    Article ID: 2021.01004
    Published: 2021
    [Advance publication] Released: March 31, 2021
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    The bicaudal D homolog 2 (BICD2) gene encodes a protein required for the stable complex of dynein and dynactin, which functions as a motor protein working along the microtubule cytoskeleton. Both inherited and de novo variants of BICD2 are reported with autosomal dominant spinal muscular atrophy with lower extremity predominance (SMALED2). Here, we report a male patient with a novel mutation in the BICD2 gene caused by a heterozygous substitution of arginine with cysteine at residue 162 (Arg162Cys); inherited from his asymptomatic mother. The patient showed typical clinical symptoms of SMALED2, which was genetically confirmed by sequencing. The Arg162Cys mutant clusters with four previously reported variants (c.361C>G, p.Leu121Val; c.581A>G, p.Gln194Arg; c.320C>T, p.Ser107Leu; c.565A>T, p.Ile189Phe) in a region that binds to the dynein-dynactin complex (DDC). The BICD2 domain structures were predicted and the Arg162Cys mutation was localized in the N-terminus coiled-coil segment 1 (CC1) domain. Protein modeling of BICD2's CC1 domain predicted that the Arg162Cys missense variant disrupted interactions with dynein cytoplasmic 1 heavy chain 1 within the DDC. The mutant did this by either changing the electrostatic surface potential or making a broader hydrophobic unit with the neighboring residues. This hereditary case supports the complex and broad genotype-phenotype correlation of BICD2 mutations, which could be explained by incomplete penetrance or variable expressivity in the next generation.

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  • Cesare Faldini, Giovanni Viroli, Michele Fiore, Francesca Barile, Marc ...
    Type: research-article
    Article ID: 2020.03162
    Published: 2021
    [Advance publication] Released: March 26, 2021
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Scoliosis in Ullrich Congenital Muscular Dystrophy (UCMD) is very common, with a reported incidence of more than 50%, and it is rapidly progressive. There are no previous studies which specifically focus on scoliosis surgery in UCMD patients. This article reports three cases of scoliosis surgery in UCMD, focusing on operative course, clinical and radiological results achieved, fusion area and complications, with a 2-year follow-up. The surgical technique adopted for vertebral arthrodesis included: high-density pedicle screw systems, asymmetric rods contouring and direct vertebral rotation. The summary results shown a significative correction of the coronal deformity, with a reduction of the mean Cobb angle from 49° to 25° post-operatively. Mean pelvic tilt remained stable, while L5-tilt showed a decrease from 10° to 6°. Mean screw density was 1.92. None of the patients required extended fixation to S2. No major complications were reported, and patients maintained their pre-operative walking ability. All the patients reported a subjective improvement in quality of life, with a better sitting comfort. In conclusion, posterior spinal fusion with high-density pedicle screw systems and direct vertebral rotation may be safe and effective in surgical correction of scoliosis in UCMD. If pelvic obliquity and L5-tilt are less than 15°, could be possible to achieve an optimal spinal and pelvic balance even without sacral or pelvic fixation.

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  • Haihong Cheng, Di Zhou, Shouhua Wang, Jun Ding, Fei Ma
    Type: letter
    Article ID: 2021.01038
    Published: 2021
    [Advance publication] Released: March 24, 2021
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Biliary tract cancer (BTC), which includes cholangiocarcinoma and gallbladder carcinoma, is a rare malignancy. Due to its low incidence, drugs treating these diseases are scarce, so they can be considered orphan drugs. The main treatment choice for BTC is chemotherapy with gemcitabine or cisplatin or combined use of both, but patients fail to significantly benefit from established chemotherapy. Advancements in immunotherapy and targeted therapy will shed light on ways to improve clinical outcomes for patients with BTC. In conjunction, more new drugs will come onto the market. This article compares the conditions for development of orphan drugs in different countries and it describes several types of new drugs that were recently approved to treat BTC.

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  • Renni Yuniati, Nydia Rena Benita Sihombing, Donny Nauphar, Budi Tiawar ...
    Type: case-report
    Article ID: 2020.03143
    Published: 2021
    [Advance publication] Released: March 18, 2021
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Xeroderma pigmentosum (XP) is a rare autosomal recessive disease characterized by hypersensitivity of the skin to ultraviolet radiation and other carcinogenic agents. This ailment is characterized by increased photosensitivity, skin xerosis, early skin aging, actinic keratosis, erythematous lesions, and hyperpigmentation macules. In this serial case report, we presented four cases with XP from two families in Indonesia. Both families were referred from rural referral health centers, and each family has two affected siblings. They had freckle-like pigmentation on the face, trunk, and extremities, which progressed since childhood. One patient of family 2 died because of an infectious disease. Histopathological examination using cytokeratine (CK), CD10, and Ber-EP4 staining from available tissue biopsy of one affected case of family 1 identified basal cell carcinoma (BCC) on the cheek and melanoma on the right eye. Mutation analysis found ERCC2, c2047C>T and XPC, c1941T>A in the first and second families, respectively. We suppose that this is the first case report of XP in Indonesia that incorporates clinical examination, genetic analysis, and extensive histopathological examination, including immunohistochemistry staining, and a novel pathogenic variant of XPC was found in the second family.

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  • Suci Widhiati, Retno Danarti, Niken Trisnowati, Dewajani Purnomosari, ...
    Type: brief-report
    Article ID: 2020.03150
    Published: 2021
    [Advance publication] Released: March 18, 2021
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Epidermolysis bullosa (EB) is a group of inherited blistering skin diseases known to have heterogenicity of phenotypes and genotypes. There are four main types of EB: simplex, junctional, dystrophic, and Kindler syndrome, which are further classified into 34 distinct subtypes. Twenty different gene mutations are responsible for the loss of function and integrity of the basal membrane zone. In limited-resource settings such as Indonesia, diagnoses of hereditary skin disease often rely on clinical features. This limitation was managed by using the Clinical Diagnostic Matrix EB for clinical diagnosis support and whole-exome sequencing for genetic analysis. This study is the first whole-exome sequencing analysis of Javanese Indonesian patients with EB. The genetic analysis from four patients with EB identified all novel mutations unreported in the dbSNP database. There are Kindler syndrome with FERMT1 frameshift mutation in exon 4, at c.388A (p.I130fs), which causes truncated protein; junctional EB generalized intermediate (JEB-GI) subtype with missense mutation at LAMB3 gene position c.A962C (p.H321P); and recessive dystrophic EB (RDEB) a missense mutation at COL7A1 gene position c.G5000T (p.G1667V). The whole-exome sequencing was further verified by Sanger sequencing. The new mutations' finding is possibly due to the limited genetic database in the Malayo-Polynesian ethnic group. Indonesia has hundreds of ethnic groups, and the Javanese is the largest ethnic group that populates Indonesia. Genetic data of these ethnic groups is important to be established in the international genetic database. This combination of clinical diagnostic and genetic analysis tools with whole-exome sequencing confirmed the challenging diagnosis of epidermolysis bullosa.

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  • Yoko Suzumoto, Valeria Columbano, Luciano Gervasi, Rosa Giunta, Teresa ...
    Type: brief-report
    Article ID: 2020.03158
    Published: 2021
    [Advance publication] Released: March 18, 2021
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    EAST/SeSAME syndrome is a rare disease affecting the Central Nervous System (CNS), inner ear, and kidney. The syndrome is due to loss-of-function mutations in the KCNJ10 gene encoding the inward-rectifying potassium channel Kir4.1. EAST/SeSAME syndrome is mainly diagnosed during childhood with a tonic-clonic seizure being the usual first symptom. Due to a limited number of patients and recent identification of the disease, few data are available on the clinical progress of this disease in adulthood. In particular, neurologic and nephrological outcomes have not been reported. We present a case series of 4 adult patients harbouring homozygous missense mutation p.Ala167Val and homozygous frameshift mutations p.Asn232Glnfs*14 and p.Gly275Valfs*7. Effects of these mutations were predicted by in silico modelling and bioinformatic tools. Patients with truncating mutations were associated with more severe outcomes, both in tubulopathy severity and neurological symptomatology. Conversely, either missense or truncating mutations were correlated with similar severity of epilepsy, with a long free-of-event period up to 20 years old. No eGFR decline was documented. Modelling predicted that truncating mutations lead to complete Kir4.1 dysfunction. Finally, all patients had a mild increase in urinary protein excretion. Our study indicates that the prognosis of patients suffering from EAST/SeSAME syndrome is related to the severity of the mutation causing the disease. As predicted by in silico modelling, truncating mutations of KCNJ10 are associated with more severe disease, with recurrence of symptomatic hypokalemia and more severe neurological phenotype. The type of mutation should be considered for the therapy tailored to patients' phenotype.

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