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.

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 patient’s height. This article describes the incidence, complications, diagnosis, and treatment of TS.

A series of our "inflammageing" study examining serum samples from a maximum of 217 healthy Japanese individuals aged between 1 and 100 years and mutation-proven 40 patients with Werner syndrome (WS) indicated normal aging-associated elevations of highly sensitive CRP (hsCRP) and matrix metalloproteinase-9 (MMP-9). To further study the contribution of environmental factors such as persistent herpes viral infection to inflammageing, IgG antibodies against varicella/zoster virus (VZV) and cytomegalovirus (CMV) were examined in the same serum samples as has been done for hsCRP and MMP-9 analyses. The mean levels of serum IgG viral antibodies were comparable between normal (mean ± SE: 31.0 ± 4.3 unit) and WS (38.6 ± 7.6) for CMV, and between normal (42.0 ± 12.2) and WS (29.8 ± 3.8) for VZV, respectively. Significant associations of aging with IgG anti-CMV antibody were in normal aging (p = 0.023) and WS (p = 0.037), but not with IgG VZV in both conditions. Aging-associated change of IgG anti-CMV antibody titer in WS increased significantly (1.32 times higher) compared with normal aging (p = 0.037). IgG anti-CMV level was significantly elevated in the male gender than female in both conditions (p = 0.006). Elevated hsCRP level was significantly associated with IgG anti-CMV (p = 0.016) and IgG anti-VZV (p = 0.008) antibodies in normal aging, but not in WS. Serum MMP-9 was significantly associated with IgG anti-CMV level (p = 0.0002) in normal aging, but not in WS. Persistent herpes viral infection may constitute a part of "inflammageing" in normal aging and WS.

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.

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.

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.

Thalassemia and other hemoglobinopathies together with red cell enzymopathies are a common cause of anemia, which can be prevented by population screening and genetic counseling. This study was designed to screen the anemic patients for thalassemia, structural hemoglobin variants and red cell enzymopathies. A total of 17047 cases were evaluated from 2009 to 2018 for thalassemia, hemoglobin variants, glucose 6 phosphate dehydrogenase deficiency, pyruvate kinase deficiency and hereditary spherocytosis. Patients' records were entered in a Microsoft excel sheet and a spectrum of disorders was evaluated. Year wise spectrum was also analyzed to see the difference in incidence at different time periods. Incidence of beta thalassemia trait and thalassemia major was found in 11.0% and 3.4% respectively, whereas other hemoglobinopathies were observed in 3.2% of the cases. G6PD deficient cases were 0.2 % and 0.4% had hereditary spherocytosis. No significant difference was observed in incidence of thalassemia and other hemoglobinopathies at different time points. This study provided a health burden and detailed spectrum and prevalence of hemoglobinopathies in North Indians high risk population which contribute toward the development of prevention strategies for better management of hemoglobinopathies. In view of high incidence of thalassemia a routine hematological screening at a primary health center may be introduced as a prospective premarital screening under a thalassemia control program. Moreover rapid and easy quantification of hemoglobin variants (Hb variants) make Cation exchange – High Performance Liquid Chromatography (CE-HPLC) a suitable diagnostic test for the routine investigation of genetic causes of anemia.

Bronchial asthma (BA), atopic dermatitis (AD), and allergic rhinitis (AR) are well known atopic disorders with complex etiologies. This study was undertaken to investigate the role of filaggrin, eosinophil major basic protein (MBP) and leukotriene B4 (LTB4) in patients with BA, AD, and AR. Sera from 1,246 patients with different atopic disorders and 410 normal healthy controls were collected and were evaluated for filaggrin, MBP and LTB4 by specific sandwich ELISAs, whereas immunoglobulin E (IgE) was used as a positive control for atopic patients. Serum analysis showed that filaggrin levels were remarkably high in patients with AD and in patients with multiple (mixed) atopic disorders (p < 0.001), whereas its levels in BA and AR patients were low but much higher than in normal human sera (p < 0.01). MBP levels were also high in AR, BA and mixed atopic patients, whereas AD patients showed no increase of MBP (p > 0.05). In contrast, LTB4 level was found to be significantly low in all tested atopic patients groups as compared to the levels of LTB4 present in normal human sera (p < 0.001). In conclusion, these findings support an association between filaggrin, MBP or LTB4 and atopic disorders. Our data strongly suggest that filaggrin, MBP or LTB4 might be useful in elucidating the mechanisms involved in the pathogenesis of these atopic disorders.

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.

Ataxia with ocular apraxia type 2 is an autosomal recessive disorder caused by a mutation in the senataxin (SETX) gene. The disease is characterized by early onset cerebellar ataxia, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia, and increased levels of α-fetoprotein. Reported here is a rare homozygous frameshift deletion c.5308_5311del, p.(Glu1770Ilefs*15) in the SETX gene in a Saudi family. Ataxia with ocular apraxia type 2 was diagnosed based on the patient's history, an examination, and genetic testing. Genetic testing remains the only definitive method with which to identify the gene responsible. This is the third case report of this rare mutation in the literature. Ataxia with ocular apraxia type 2 continues to be a challenging disease to manage with no therapeutic options available to date. In the current case, the medication 4-aminopyridine was inefficacious in improving walking or balance. Further research is needed to identify potential treatments for this challenging condition.

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.

A 58-year-old man with a history of diabetes mellitus and end-stage renal disease acquired pneumonia with acute respiratory failure during his stay in an intensive care unit (ICU). Empirical antimicrobial therapy with ceftazidime and vancomycin was initiated, and imipenem replaced ceftazidime 2 days later due to the patient’s pulmonary condition failed to improve. However, within 5 days, pulmonary consolidation rapidly progressed to necrotizing pneumonia complicated by lung abscess, empyema, pyopneumothorax, and tension pneumothorax, leading to the patient's death. After the patient had died, all bacterial isolates from cultures of pleural effusion, blood, and tracheal aspirate were identified as Enterobacter cloacae (E. cloacae), which was susceptible to imipenem but resistant to ceftazidime. E. cloacae should be considered in the differential diagnosis of complicated necrotizing pneumonia with lung abscess, empyema, pyopneumothorax, and tension pneumothorax. Carbapenem therapy should be immediately initiated until the pathogen in such rapidly progressive ICU-acquired pneumonia is confirmed. Increased awareness among physicians regarding E. cloacae-induced complicated necrotizing pneumonia acquired in ICUs could enable earlier detection and appropriate antimicrobial therapy for this invasive disease.

The left internal mammary artery (LIMA) is widely used in coronary artery bypass grafting surgery due to its long term perfect patency rates. However, coronary steal syndrome can occur because of unligated LIMA side branches and it causes blood flow from coronary artery to LIMA. Even though the optimal therapy of coronary steal syndrome is still controversial, some percutaneous and surgical treatment modalities can be used in the treatment of steal phenomenon for relieving angina and resolving ischemia. It was demonstrated that percutaneous treatments such as the use of gelatin sponge particles or drug-eluting stents with covered stent, and coil and vascular plug embolization were used to treat this phenomenon successfully. Several studies revealed that these percutaneous treatments can reduce the ischemic area and results in prevention of blood flow from coronary artery to LIMA side branches. Supporting these findings, we herein present a 48-year-old male patient with objective ischemia with coronary steal syndrome treated successfully with the Amplatzer vascular plug (AVP) 4 and coil embolization in the same procedure. To the best of our knowledge, the combined therapy has not been described in the literature yet. Supporting the literature findings, successful treatment of LIMA side branches in our case with two different percutaneous modalities results in improvement of coronary flow and a reduced ischemic area and angina.

Shanghai has always attached importance to the prevention and treatment of rare diseases and has been at the forefront in China. The Shanghai Rare Diseases Diagnosis and Treatment Center, Shanghai Children's Rare Diseases Diagnosis and Treatment Center, and Shanghai Rare Diseases Specialist Clinic were established in February 2018. Moreover, with the development of clinical pathways for rare diseases and the provision of related services such as diagnosis, treatment, screening, information and training, the service system for diagnosis and treatment of rare diseases in Shanghai has formed, which greatly improves the accessibility of medical services for patients with rare diseases in Shanghai and surrounding areas, and is of great significance in reducing the burden on patients with rare diseases. Meanwhile, it also gives an important reference for other regions of China for providing rare disease diagnosis and treatment services.

Duchenne muscular dystrophy (DMD) is a result of a X-linked recessive inherited mutation of the DMD gene which contains 79 exons. This rare disease is passed on by the mother who is called a carrier. Primarily it affects boys, but in rare cases it can affect girls. Dystrophin protein is mostly located in skeletal and cardiac muscles, which explains muscular and cardiac manifestations in symptomatic female DMD-carriers. Dystrophin is also present in extramuscular tissues. Some dystrophin isoforms are exclusively or predominantly expressed in the brain or the retina. It has been reported that DMD patients and DMD-carriers present normal visual acuity, but abnormal electroretinographic findings. As symptomatic female DMD are very rare, ophthalmic screening of the female patient with deletions of exons 12-29 is valuable. Studying the functional relationship between ocular symptoms and related different deletions of exons dystrophin gene may further elucidate the pathophysiology in