Showing papers in "Intractable & Rare Diseases Research in 2018"
TL;DR: Publisher reports on national plans, polices and legislation related to all rare diseases in different countries are examined and strategies or programs that countries may have for these diseases are examined.
Abstract: Previous studies have focused on the comparison of specific laws among multiple countries and regions; for example, laws related to facilitating treatments with orphan drugs or laws seeking to address the multiple needs of patients with rare diseases. The purpose of this scoping review is to examine and compare published reports on national plans, polices and legislation related to all rare diseases in different countries. We also examine strategies or programs that countries may have for these diseases. Articles were obtained from journals and books published between January 1, 2000, through December 15, 2017. Reports from the grey literature (documents issued by government and private organizations) were included if they were available on the internet. The databases used were Google and Google Scholar, PubMed, and the websites of Orphanet and the National Organization for Rare Disorders (NORD). We obtained information on 23 countries. Among these countries, the way in which rare diseases were defined varied from having similar definitions to no definition. Multinational programs supported by common or similar laws are likely to have a greater impact on rare diseases than single country programs.
51 citations
TL;DR: 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.
Abstract: 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.
47 citations
TL;DR: The improvement of pathogenesis, diagnosis and treatment in MMA is reviewed, and the reported epidemiological data of MMA patients in China and the hot mutation sites in Chinese patients are listed, which will aid in improving healthcare of Chinese patients in the future.
Abstract: Methylmalonic acidemia (MMA) is a lethal, severe heterogeneous disorder of methylmalonate and cobalamin (cbl; vitamin B12) metabolism with poor prognosis. Two main forms of the disease have been identified, isolated methylmalonic acidurias and combined methylmalonic aciduria and homocystinuria, which is respectively caused by different gene mutations. Here, we review the improvement of pathogenesis, diagnosis and treatment in MMA. Importantly, the reported epidemiological data of MMA patients in China and the hot mutation sites in Chinese patients are listed, which will aid in improving healthcare of Chinese patients in the future. c.729_730insTT was the most common mutation in Chinese isolated MMA patients, while c.609G>A and c.658_660delAAG were in Chinese cblC type patients according to unrelated studies. The estimated newborn screening incidence was reported to be 1:26,000, 1:3,920, 1:11,160, 1:6,032 respectively in Beijing and Shanghai, Shandong province, Taian district, and Henan province of China. Alternatively, when patients with suspected inherited metabolic diseases were used as the screened sample, the relatively high incidence 0.3% and 1.32% were respectively obtained in southern China and throughout all the provinces of mainland China and Macao with the exception of five provinces (Hainan, Neimenggu, Tibet, Ningxia, and Hong Kong).
44 citations
TL;DR: The incidence, complications, diagnosis, and treatment of Turner syndrome mainly involves administration of growth hormone combined with very low doses of estrogen to increase the patients height.
Abstract: Turner syndrome (TS), also known as Congenital ovarian hypoplasia syndrome, occurs when the X chromosome is partially or completely missing in females. Its main clinical manifestations include growth disorders, reproductive system abnormalities, cardiovascular abnormalities, and autoimmune diseases. TS is highly prevalent in China. Timely diagnosis is crucial, and non-invasive prenatal DNA testing can identify TS and other diseases. Treatment of TS mainly involves administration of growth hormone combined with very low doses of estrogen to increase the patients height. This article describes the incidence, complications, diagnosis, and treatment of TS.
39 citations
TL;DR: This effort will enhance the management of rare diseases in China, raise the level of diagnosis and treatment for rare diseases, and safeguard the health-related rights and interests of patients with rare diseases.
Abstract: Over the past few years, the Chinese Government has paid greater attention to rare diseases and it has incorporated rare diseases in national health strategy and planning. On May 22, 2018, the Chinese Government officially released its first list of rare diseases, which included 121 rare diseases. The list was published to facilitate greater societal awareness of rare diseases, to improve the ability of front-line medical staff to treat rare diseases, to introduce incentives for research and development of orphan drugs, and to increase the availability of medicines for rare diseases. This effort will enhance the management of rare diseases in China, raise the level of diagnosis and treatment for rare diseases, and safeguard the health-related rights and interests of patients with rare diseases. The classification of rare diseases is based on a common international standards, which will promote international cooperation in drug research and policymaking with regard to rare diseases.
35 citations
TL;DR: Therapeutic inhibition of Aurora kinase showed great promise as a probable anticancer regime because of its important role during cell division.
Abstract: A critical step for maintenance of genetic stability is chromosome segregation, which requires a high coordination of cellular processes. Loss of mitotic regulation is a possible cause of aneuploidy in human epithelial malignancy and it is thought to create an abnormal nuclear morphology in cancer cells. Serine/threonine protein kinase Aurora B gene plays a regulatory role from G2 to cytokinesis, encompassing key cell cycle events such as centrosome duplication, chromosome bi-orientation, and segregation. The overexpression of Aurora B has been observed in several tumour types, and has been linked with a poor prognosis for cancer patients. Therapeutic inhibition of Aurora kinase showed great promise as a probable anticancer regime because of its important role during cell division.
30 citations
TL;DR: Recent advances in the study of the relationship between intestinal microflora and bone disease are reviewed to provide a basis for preventing and treating bone diseases.
Abstract: Intestinal microbial flora, known as the second gene pool of the human body, play an important role in immune function, nutrient uptake, and various activities of host cells, as well as in human disease. Intestinal microorganisms are involved in a variety of mechanisms that affect bone health. Gut microbes are closely related to genetic variation, and gene regulation plays an important part in the development of bone-related diseases such as osteoporosis. Intestinal microorganisms can disrupt the balance between bone formation and resorption by indirectly stimulating or inhibiting osteoblasts and osteoclasts. In addition, intestinal microorganisms affect bone metabolism by regulating growth factors or altering bone immune status and can also alter the metabolism of serotonin, cortisol, and sex hormones, thereby affecting bone mass in mice. Moreover, probiotics, antibiotics, and diet can change the composition of the intestinal microbial flora, thus affecting bone health and also potentially helping to treat bone disease. Studying the relationship between intestinal flora and osteoblasts, osteoclasts, and bone marrow mesenchymal stem cells may provide a basis for preventing and treating bone diseases. This paper reviews recent advances in the study of the relationship between intestinal microflora and bone disease.
30 citations
TL;DR: In this paper, the impact of early exposure of electronic screen on language development and autistic-like behavior was revealed, where the authors found that children who spent viewing ≤ 3 hours per day had language delay and short attention span, while children that spent viewing ≥ 3 hours of daily had language delays, short attention spans, and hyperactivity.
Abstract: 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.
28 citations
TL;DR: The expression of Aβ and phosphorylated tau (p-tau) in the frontal cortex and the hippocampus of five NHD cases were studied and several small Aβ-immunoreactive spheroids, almost undetectable in NHD brains were identified.
Abstract: 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.
23 citations
TL;DR: The findings included clinical characteristics, diagnostics, therapy, and clinical outcomes, which included congenital aplasia of the abdominal wall and a variety of urogenital malformations in patients with Prune Belly syndrome.
Abstract: Prune Belly syndrome (PBS) or Eagle-Barrett syndrome is an anatomo-radiological syndrome consisting of a complex and rare malformation characterized by the following triad of symptoms: deficiency of the abdominal muscles, malformations of the urinary tract, and bilateral cryptorchidism. The exact etiology is unknown, though PBS predominantly occurs in males. The clinical manifestations can vary widely, from stillbirth to renal and major respiratory dysplasia to almost normal children. The current study included a total of 3 patients. The findings included clinical characteristics, diagnostics, therapy, and clinical outcomes. All patients were diagnosed with congenital aplasia of the abdominal wall and a variety of urogenital malformations. Cryptorchidism and a mega-bladder were observed in 2 patients and distinctive renal malformations, such as renal dysplasia, were observed in 1 patient. Treatment varies but usually includes surgical management of symptoms. One patient required urgent urinary surgery; a vesicotomy was urgently performed due to anuria. These aspects explain the great diversity of opinions on the approach to this syndrome, but the severity of renal dysplasia is the main prognostic factor. Two newborns died a few days later due to severe renal failure. Despite these concerns, many patients with PBS report being in physical and mental health and having a good quality of life.
18 citations
TL;DR: E. meningoseptica infection should be considered as a possible etiological agent of sepsis in patients who do not respond to empirical therapy, as this results in an inappropriate choice of antimicrobial therapy, leading to increased morbidity and mortality of patients.
Abstract: Elizabethkingia meningoseptica (E. meningoseptica) is a non-fermenting gram negative organism that is commonly detected in the soil and water but is rarely reported to cause human infection. However it is emerging as a nosocomial pathogen in patients admitted in intensive care units (ICUs). Infections caused by this organism have a high mortality rate due to lack of effective therapeutic regimens and its intrinsic resistance to multiple antibiotics. We report our experience in managing Elizabethkingia meningoseptica (E. meningoseptica) septicemia in our ICU patients with septic shock during prolonged intensive care management. Over a two year period four cases were admitted into the polytrauma ICU developed sepsis due to E. meningoseptica. All these patients were on mechanical ventilation, had central venous catheter (CVC) and were exposed to various broad spectrum antibiotics. Of the four patients, three died and one recovered. E. meningoseptica infection should be considered as a possible etiological agent of sepsis in patients who do not respond to empirical therapy, as this results in an inappropriate choice of antimicrobial therapy, leading to increased morbidity and mortality of patients. Its unusual resistance pattern along with inherent resistance to colistin makes this organism difficult to treat unless susceptibility patterns are available.
TL;DR: The ratio of urinary α1-microglobulin to microalbumin, greater than 1, can be used as a diagnostic criterion for tubuloproteinuria in patients with renal tubular and interstitial diseases.
Abstract: 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.
TL;DR: Female carriers of mutations in the dystrophin gene (DMD-carriers) may manifest clinically in the skeletal muscle, the heart, or both before, after, or together with the muscle manifestations; muscle manifestations in DMD- carriers with deletions of exons 12-29 may start years before cardiac involvement becomes clinically apparent.
Abstract: Female carriers of mutations in the dystrophin gene (DMD-carriers) may manifest clinically in the skeletal muscle, the heart, or both. Cardiac involvement may manifest before, after, or together with the muscle manifestations. A 46y female developed slowly progressive weakness of the lower and upper limbs with left-sided predominance since age 26y. Muscle enzymes were repeatedly elevated and muscle biopsy showed absence of dystrophin. MLPA analysis revealed a deletion of exons 12-29. After starting steroids at age 39y, she developed palpitations and exertional dyspnoea. Cardiac MRI at age 41y revealed mildly reduced systolic function, a slightly enlarged left ventricle, mild hypokinesia of the entire myocardium, and focal, transmural late gadolinium enhancement (LGE) of the midventricular lateral wall. She did not tolerate beta-blockers but profited from ivabradine and lisinopril. In conclusion, muscle manifestations in DMD-carriers with deletions of exons 12-29 may start years before cardiac involvement becomes clinically apparent. Progressive worsening of systolic function in DMD-carriers is attributable to progressive myocardial fibrosis, as demonstrated by LGE. Steroids may trigger the development of cardiac disease in DMD-carriers.
TL;DR: The characteristics of circRNAs and recent research on their role in rare hereditary bone diseases are reviewed.
Abstract: 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.
TL;DR: This is the first case of cellulitis caused by S. pseudoporcinus isolated from the genitourinary tract of women and it could become an important pathogen in elderly people and in those who have underlying medical conditions, as with other β-hemolytic Streptococci.
Abstract: A 94-year-old woman was admitted to our hospital with a 5-day history of painful redness in the left lower leg. She was diagnosed with cellulitis and initiated antibiotic therapy with cefazolin. After two days, she presented with an extremely high fever (39.9°C), high C-reactive protein level (256 mg/L; normal, < 3), and signs of disseminated intravascular coagulation. In bacteriological examination, Streptococcus pseudoporcinus was detected from her lower leg wound purulence. An antibiogram revealed multidrug resistance except for cefepime, carbapenems, and vancomycin. We changed the antibiotics to cefepime and vancomycin according to the antibiogram and administered immunoglobulin concurrently. As the result of these therapies, her conditions gradually resolved over two weeks. S. pseudoporcinus, one of the β-hemolytic Streptococcus species recently described, has been isolated from the genitourinary tract of women. To our knowledge, this is the first case of cellulitis caused by S. pseudoporcinus. Typically, most antibiotics indicate adequate drug susceptibilities of S. pseudoporcinus, but in our case, multidrug resistance contributed to the prolonged duration of treatment. Because the colonization of S. pseudoporcinus in healthy individuals is not rare, it could become an important pathogen in elderly people and in those who have underlying medical conditions, as with other β-hemolytic Streptococci.
TL;DR: The PKU-UiPSCs created here had typical characteristics and are suitable for further differentiation, and had increased expression of stem cell biomarkers, it efficiently formed EBs, and it stained positive for alkaline phosphatase (ALP).
Abstract: The aim of the study was to establish an induced pluripotent stem cell line from urine-derived cells (UiPSCs) from a patient with phenylketonuria (PKU) in order to provide a useful research tool with which to examine the pathology of this rare genetic metabolic disease. Urine-derived epithelial cells (UCs) from a 15-year-old male patient with PKU were isolated and reprogrammed with integration-free episomal vectors carrying an OCT4, SOX2, KLF4, and miR-302-367 cluster. PKU-UiPSCs were verified as correct using alkaline phosphatase staining. Pluripotency markers were detected with real-time PCR and flow cytometry. Promoter methylation in two pluripotent genes, NANOG and OCT4, was analyzed using bisulphite sequencing. An embryoid body (EB) formation assay was also performed. An induced pluripotent stem cell line (iPSC) was generated from epithelial cells in urine from a patient with PKU. This cell line had increased expression of stem cell biomarkers, it efficiently formed EBs, it stained positive for alkaline phosphatase (ALP), and it had a marked decrease in promoter methylation in the NANOG and OCT4 genes. The PKU-UiPSCs created here had typical characteristics and are suitable for further differentiation.
TL;DR: The importance of a training program for ARSACS patients in order to improve their quality of life is supported and through these types of interventions, it may be possible to slow down the progression of the disease and help maintain functional capacity.
Abstract: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neuromuscular disorder caused by the mutation of the SACS gene. Clinical symptoms of this disease include progressive ataxia, spasticity, and peripheral neuropathy. Similar to other neuromuscular disorders, these patients are prone to physical deconditioning which may lead to a loss of functional capacity. This paper aims to evaluate the impact of a training program on the physical fitness and the functional capacity of ARSACS patients. Twelve patients (age: 28.1 ± 8.2 years) participated in this study. They followed an eight-week training program including physical activities, strength-power and aerobic training. Compared to the initial evaluation, measures of physical fitness and functional capacity were significantly improved (p ≤ 0.05) for 11 of the 12 tests. Positive gains were also observed for fall frequency and for upper-limb incoordination. This paper supports the importance of a training program for ARSACS patients in order to improve their quality of life. Through these types of interventions, it may be possible to slow down the progression of the disease and help maintain functional capacity.
TL;DR: Design and development of an integrated information system for rare diseases considering data architecture principles in practice could help eliminating issues with management of rare diseases through facilitating sharing information and experiences.
Abstract: The study aims to systematically review literature on the rare diseases information system to identify architecture of this system from a data perspective. The search for relevant English language articles, based on keywords in title, abstract, Mesh and Emtree terms, was done in Pubmed and Embase (from 1980 to June 2017), Scopus, Science Direct and Cochran (from 1980 to July 2017). Articles were selected if they addressed data architecture of information systems with a focus on rare disease, and if at least one of their objectives dealt with design, implementation, and development of rare diseases information systems. Thirty-five studies met the inclusion criteria. The findings were categorized into six groups. This first group addressed organizations acting as data generators, data users, and data governors. The second group was related to data sources and databases. Datasets and data elements formed the third group of findings, including common datasets, specific datasets, and complementary datasets. The fourth group of findings was in relation to data standards. Data sharing and interactions among relevant bodies included the fifth group of the findings. The last group of findings was pertinent to procedures and criteria used for checking the quality of data, as cross review checking was a main procedure assessing the accuracy, consistency, and completeness of data. Design and development of an integrated information system for rare diseases considering data architecture principles in practice could help eliminating issues with management of rare diseases through facilitating sharing information and experiences.
TL;DR: For cerebral screening programmes in HHT, the findings support informed patient choice incorporating understanding that cerebral AVMs are rare in non-symptomatic HHT patients, but that screening scans commonly detect silent cerebral infarction due to pulmonary AVMs.
Abstract: Hereditary haemorrhagic telangiectasia (HHT) results in arteriovenous malformations (AVMs), most commonly in the lungs, liver and brain. Discussion of cerebral vascular malformations is an important element of patient management. The current study objectives were to examine uptake and results of screening cerebral magnetic resonance (MR) scans, excluding symptomatic patients requiring neurological investigations. The remaining non-symptomatic individuals received formal pretest counselling that differed according to family history. For the 603 patients with no neurological symptoms of concern, screening scan uptake was higher after publication of the ARUBA trial. Patients with a family history of cerebral haemorrhage were 4 to 14-fold more likely to have a screening scan than patients with no such family history. For patients without neurological symptoms suggesting cerebral AVMs, none of the 59 screening scans performed at our institution demonstrated a cerebral AVM. Four scans (6.8%) demonstrated small aneurysms. The most common abnormality was cerebral infarction (20/59, 33.9%), predominantly identified in patients with pulmonary AVMs. Of 29 pulmonary AVM patients with no previous history of clinical stroke, 16 (55.2%) had between one and five silent infarcts. For HHT patients with pulmonary AVMs, the most frequently affected sites were the cerebellum (40%) and thalamus (14.3%), and the age-adjusted odds ratio for an infarct was 21.6 (95% confidence intervals 3.7, 126), p = 0.001. We concluded that for cerebral screening programmes in HHT, the findings support informed patient choice incorporating understanding that cerebral AVMs are rare in non-symptomatic HHT patients, but that screening scans commonly detect silent cerebral infarction due to pulmonary AVMs.
TL;DR: Appropriate sampling, surgery supplemented by a comprehensive microbiological work up aided in pathogen identification and appropriate antibiotic administration for a successful outcome of these patients.
Abstract: Salmonella paratyphi A causes paratyphoid fever which is characterized by acute onset of fever, abdominal pain, diarrhoea, nausea and vomiting. Localized disease can occur following both overt and silent bacteremia followed by seeding of bacteria at distant sites. Salmonella species though associated with abscess formation in various organs,are rarely associated with breast abscess. We report 2 cases of breast abscess due to Salmonella enterica serotype paratyphi A. Appropriate sampling, surgery supplemented by a comprehensive microbiological work up aided in pathogen identification and appropriate antibiotic administration for a successful outcome of these patients.
TL;DR: A 30-year-old Chinese male with OI type III and EDS is described, finding a heterozygous COL1A1 mutation that affected the N-anchor domain of the alpha 1 chain of collagen type I has expanded the genotypic spectrum of the OI/EDS overlap syndrome.
Abstract: 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.
TL;DR: This case report emphasizes that disseminated histoplasmosis should be considered one differential diagnosis in case of long duration of fever, even in an immunocompetent patient, and gives due significance to a trivial symptom and thorough evaluation of the same.
Abstract: Histoplasmosis is a systemic fungal infection caused by Histoplasma capsulatum which occurs endemically in some parts of the world like North and Central America particularly in Mississippi and Ohio River valleys, but is uncommon in India. Progressive disseminated form of histoplasmosis (PDH) usually occurs in the immune-compromised hosts especially in HIV positive population. In PDH any organ can be involved like lung, liver, spleen, brain, adrenals etc. Involvement of oral cavity and buccal mucosa in PDH is common but pharyngeal involvement is rare. We here report a case of progressive disseminated histoplasmsosis with pharyngeal involvement in an immunocompetent male from non-endemic area. This case presented to us with history of long duration fever and we found the etiology by giving due significance to a trivial symptom and thorough evaluation of the same. Etiology was found as disseminated histoplasmosis, which is not a common disease. We treated him initially with amphotericin-B then subsequently with itraconazole for one year. He recovered fully over the period of one year with the given treatment. This case report emphasizes that disseminated histoplasmosis should be considered one differential diagnosis in case of long duration of fever, even in an immunocompetent patient. It also emphasizes that in evaluation of a case of long duration of fever, even a trivial symptom is very crucial, which may direct towards the diagnosis.
TL;DR: This is the first case of BOR syndrome in mainland China to be diagnosed based on clinical manifestations and mutations in the EYA1 gene, and a novel single base-pair deletion resulting in a truncated protein is detected.
Abstract: 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.
TL;DR: The generated induced pluripotent stem cells line has typical pluripotency characteristics and can provide a useful tool with which to understand the development of 18T.
Abstract: Trisomy 18 (18T) is the second most common autosomal trisomy syndrome in humans, but the detailed mechanism of its pathology remains unclear due to the lack of appropriate models of this disease. To resolve this problem, the current study reprogrammed human 18T amniotic fluid cells (AFCs) into an induced pluripotent stem cell (iPSC) line by introducing integration-free episomal vectors carrying pCXLE-hOCT3/4-shp53-F, pCXLE-hSK, pCXLE-hUL, and pCXWB-EBNA1. The pluripotency of 18T-iPSCs was subsequently validated by alkaline phosphatase staining, detection of iPSC biomarkers using real-time PCR and flow cytometry, detection of embryoid body (EB) formation, and detection of in vivo teratoma formation. Moreover, this study also investigated the transcriptomic profiles of 18T-iPSCs using RNA sequencing, and several gene clusters associated with the clinical manifestations of 18T were identified. In summary, the generated induced pluripotent stem cells line has typical pluripotency characteristics and can provide a useful tool with which to understand the development of 18T.
TL;DR: Gamma-interferon-inducible lysosomal thiol reductase expression in NHD and AD brains is studied to indicate that microglia, expressing constitutively high levels of GILT, act as a principal cell type of APCs in AD brains, in contrast to baseline levels of the enzyme.
Abstract: Gamma-interferon-inducible lysosomal thiol reductase (GILT), expressed in antigen-presenting cells (APCs), facilitates the reduction of disulfide bonds of endocytosed proteins in the endocytic pathway and they are further processed for presentation of immunogenic peptides loaded on major histocompatibility complex (MHC) class II. Although the constitutive and IFNγ-inducible expression of GILT was observed in various APCs, such as dendritic cells, monocytes/macrophages, and B cells, GILT-expressing cell types remain unknown in the human central nervous system (CNS). 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, both of which are expressed on microglia. A rare heterozygous variant of the TREM2 gene encoding p.Arg47His causes a 3-fold increase in the risk for late-onset Alzheimer's disease (LOAD), suggesting that both NHD and AD are induced by dysfunction of the microglial TREM2 signaling pathway in the brains. We studied by immunohistochemistry GILT expression in NHD and AD brains. GILT was expressed on amoeboid microglia with the highest levels of expression in AD brains, compared with those in non-neurological control (NC) brains and in NHD brains. In AD brains, the clusters of amoeboid microglia surrounding amyloid-beta (Aꞵ) deposition strongly expressed GILT. Furthermore, a human microglial cell line expressed GILT in response to IFNγ. These results indicate that microglia, expressing constitutively high levels of GILT, act as a principal cell type of APCs in AD brains, in contrast to baseline levels of GILT expression in NHD brains.
TL;DR: In this paper, the authors found that younger age, generalized anxiety disorder and presence of a triggering event were associated with early recovery of left ventricular systolic function in Takotsubo cardiomyopathy.
Abstract: Takotsubo cardiomyopathy (TTC) is a transient systolic dysfunction of the left ventricle which is usually seen in elderly women, often following a physical or emotional stressful event. Little is known about the prognostic factors affecting the recovery of systolic function. Thirty-six patients diagnosed with TTC from January 2006 to January 2017 at our hospital were included. Median time to recovery of ejection fraction (EF) was calculated to be 25 days. Early recovery of ejection fraction was defined as less than or equal to 25 days (group 1) and late recovery was defined as more than 25 days (group 2). Demographic and clinical factors were compared between the groups. Fifty percent patients had early recovery of EF with a mean time to recovery of 7.11 days and 50% had late recovery of ejection fraction with a mean time to recovery of 58.38 days. Younger age at presentation was associated with early recovery of systolic function (58.83 ± 2.7 years vs. 67.33 ± 2.7 years, p = 0 .032). Presence of an identifiable triggering event was associated with early recovery (83% in group 1 vs. 50% in group 2, p = 0.034). Generalized anxiety disorder was seen more commonly in the group with early recovery (78% in group 1 vs. 45% in group 2, p = 0.040). In conclusion, younger age, generalized anxiety disorder and presence of triggering event were seen more commonly in patients with early recovery of left ventricular systolic function in Takotsubo cardiomyopathy.
TL;DR: This study identified a paternal uniparental disomy of chromosome 1 in a patient with a neurodevelopmental disorder associated with severe intellectual disability, intractable epilepsy, autistic features, distinctive features, and transient macrocephaly, and reported the first report of a homozygous missense SZT2 variant.
Abstract: Because biallelic SZT2 variants have been reported in patients with neurodevelopmental disorders associated with various degrees of developmental delay, intractable seizures, and distinctive features; this condition is recognized as an autosomal recessive disorder. Previously, eleven patients have been reported and most of them have compound heterozygous SZT2 variants, leading to premature termination. In these patients, all reported variants were unique and there were no common pathogenic variants identified. In this study, we identified a paternal uniparental disomy of chromosome 1 in a patient with a neurodevelopmental disorder associated with severe intellectual disability, intractable epilepsy, autistic features, distinctive features, and transient macrocephaly. This resulted in homozygous patterns through chromosome 1. Among the variants in chromosome 1, a rare SZT2 variant, NM_015284.3:c.6553C>T (p.Arg2185Trp), was selected as a powerful candidate variant in this patient. Although the clinical features of this patient are relatively milder than that reported previously, it may be derived from genetic heterogeneity. This is the first report of a homozygous missense SZT2 variant.
TL;DR: Patients with CML can present with symptoms mimicking CNS involvement of the disease such as headaches and blurry vision, but that could be attributed to the poor CSF resorption given the leukocytosis rather than spread of the Disease itself.
Abstract: 28-year-old African American female with chronic myeloid leukemia (CML) presented with blurry vision for 4-5 days prior to presentation associated with right-sided headaches. Patient was on treatment for the CML but never had hematological remission. Patient saw an ophthalmologist who told her that she has bilateral optic disc swelling and advised her to get an MRI of the brain. She came to the ER due to worsening headache and blurry vision. The funduscopic examination showed significant bilateral papilledema. Laboratory evaluation revealed a leukocytosis of 240 × 103/uL with platelet count of 1,202 × 103. The white cell differential count showed 17% blasts along with myelocytes and meta-myelocytes. MRI of brain revealed non-specific CSF flair signal. Lumbar puncture (LP) showed significantly elevated opening pressures. The CSF composition was however normal. The patient felt much relief of her symptoms following the LP. The papilledema was thought to be due to benign intracranial hypertension (ICH), which was attributed to poor CSF absorption due to resistance to flow of CSF caused by the high WBC count. She received 2 cycles of leukopheresis which dropped her WBC count. She was also started on acetazolamide for the benign ICH and her symptoms improved considerably. Patients with CML can thus present with symptoms mimicking CNS involvement of the disease such as headaches and blurry vision, but that could be attributed to the poor CSF resorption given the leukocytosis rather than spread of the disease itself.
TL;DR: 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, and this disease might make it a good model for neurodegenerative disorders.
Abstract: 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.
TL;DR: Vascular BD has to be suspected in cases of thrombosis recurrence despite correct anticoagulation, and intense immunosuppressive treatment should be considered.
Abstract: Behcet'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.