For rare diseases, how to mimic the pathological progression is of importance for better understanding the molecular mechanism and identifying potential targets. Induced pluripotent stem cells (iPSCs) technology provides an ideal model to in vitro obtain the diseases-associated cells. In this issue of Intractable & Rare Diseases Research, two birth detect diseases iPS models on phenylketonuria and trisomy 18 were established, and have demonstrated great potential in the research on these rare diseases.

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).

Spinocerebellar ataxia (SCA) is a heterogeneous genetic disorder with overlapping clinical phenotypes arising from the degeneration of purkinje cells and other regions of the brain. There are approximately 36 different subtypes of SCA, but SCA 1, 2, 3, 6 and 7 are most prevalent in the Indian population. Many findings suggested that cerebellar Purkinje cells region may be a uniquely vulnerable neuronal cell type, and more susceptible to a wider variety of genetic or cellular problems than other neuron types. In this review we emphasized mainly five common subtypes of SCA (1, 2, 3, 6 and 7) their pathophysiology, therapeutics, drugs studies and the technical challenges in the field of molecular genetic diagnosis.

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.

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.

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.

The aim of this study was to examine the expression and clinicopathological role of caudal homeobox 2 (CDX2) in intrahepatic cholangiocarcinoma (ICC). CDX2 expression was determined immunohistochemically in 93 patients with ICC. The association between CDX2 expression and clinicopathological features of ICC was also examined in patients with ICC. Immunohistochemical staining for CDX2 was noted in 27 patients (29.03%); patients with CDX2-positive tumors had significant survival advantages over those with CDX2-negative tumors (median survival was 40 months for patients with CDX2-positive tumors and 13 months for patients with CDX2-negative tumors; the hazard ratio was 0.36, the 95% confidence interval was 0.22-0.59, and p < 0.001). The rate of CDX2 expression was 13.46% in patients with lymphatic invasion and 48.78% in patients without lymphatic invasion (χ² = 13.88, p < 0.01); positivity for CDX2 expression was significantly higher in patients with well-differentiated or moderately differentiated tumors than that in patients with poorly differentiated tumors (41.7% in patients with well-differentiated tumors, 47.6% in patients with moderately differentiated tumors, and 20.0% in patients with poorly differentiated tumors; Mann-Whitney U test, p = 0.01). In addition, CDX2 expression differed significantly in patients with ICC due to hepatolithiasis and patients with ICC not due to hepatolithiasis (36.51% and 13.33%, respectively, χ² = 5.30, p = 0.02). Positivity for CDX2 expression resulted in significant survival advantages for patients with ICC. CDX2 might be used as a prognostic marker in patients with ICC.

Primary and secondary intrahepatic malignant mesothelioma (PIHMM & SIHMM) caused by Peritoneal mesothelioma (PM) are extremely rare tumors and their clinicopathological characteristics remain unclear. The current study presented a case of a 63-year-old female with PIHMM and a literature review of Chinese case reports of SIHMM and PIHMM was performed. The patient received curative left hemihepatectomy because of a 5.5 × 5.0 × 4.0 cm mass occupying the II, III and the lateral portion of the IV segments and meanwhile tightly infiltrating the diaphragm (yellow arrow) was also observed. The pathological diagnosis was epithelial type PIHMM. Immunohistochemistry revealed that the tumor was positive for Calretinin, CK5/6, WT-1 and D2-40(N). The literature review included 11 studies and 6 case reports with a total of 293 PM patients accompanied with 31 SIHMM cases and then 3 case reports of PIHMM. SIHMM and PIHMM are extremely rare, easy to misdiagnose malignant tumors. Immunohistochemistry should be performed strictly in accordance with guidelines, which is crucial for pathological diagnosis. Comprehensive treatment of surgery combined with chemotherapy are mainstream methods for SIHMM and PIHMM. Also, exact survival data should be carefully explored so that objective evaluation of the efficacy of the treatment could be achieved.

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.

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.

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.

A 61-year-old male was admitted from the outpatient setting for treatment of severe hyperglycemia. Five months earlier, his hemoglobin A1c had been 5 mmol/mol. At presentation, hemoglobin A1c was 11.3 mmol/mol and he required insulin therapy at discharge. Later magnetic resonance imaging (MRI) identified bilateral renal masses, previously seen on ultrasound during workup for chronic kidney disease, as being suspicious for renal cell carcinoma (RCC). He underwent partial nephrectomy and cryoablation with pathology showing papillary type RCC. Hyperglycemia resolved after resection and insulin therapy was discontinued, requiring only an oral hypoglycemic. Hyperglycemia as a paraneoplastic syndrome related to RCC is rare. The cause of this acute hyperglycemia is not understood, though previously suggested mechanisms include ectopic glucagon production, autoimmune causes and interleukin-6 (IL-6) mediated pathways. Severe, new-onset hyperglycemia in the absence of common causes and with a renal mass on imaging may represent an uncommon paraneoplastic syndrome secondary to RCC.

Although tumor necrosis factor (TNF)-α inhibitors are effective in patients with rheumatoid arthritis (RA), an increased risk of infections often becomes a serious problem. It is well known that TNF-α inhibitors increase the risk of tuberculosis, but extrapulmonary tuberculosis often induced by them is difficult to diagnose using routine imaging examinations. We described a case of delayed diagnosis of a tuberculous lymphadenitis in a patient with RA treated with TNF-α inhibitor because of the complications of severe bacterial sepsis. In this case, rescreening with the interferon-γ release assay and excisional biopsy were useful in confirming the diagnosis of extrapulmonary tuberculosis. In the case we presented, she had other risk factors, that is, advanced age at the start of anti-TNF-α treatment or concomitant use of corticosteroid, might contribute to the development of complex infections. We should keep in mind that careful follow-up and appropriate examinations are necessary in caring for patients administering immunosuppressive treatments including anti- TNF-α drugs.

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.

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.