In May 2019, China National Medical Products Administration approved the marketing of an elosulfase alfa injection (brand name: Vimizim) from BioMarin Pharmaceutical for the treatment of patients with mucopolysaccharidosis (MPS) type IVA. This is the first drug to treat MPS in China, and it has ended the "dearth of medicines" to treat MPS in China, a situation that has persisted for many years. One can reasonably say that the drug has benefited from the continuous reform of the drug review and approval system in China and the increasing attention paid to rare diseases. At present, China has implemented a series of preferential policies for the review and approval of drugs for rare diseases, mainly including priority review and approval, accelerated review and approval, special review and approval (mainly simplified review and approval), data protection, and communication. Moreover, China now has a specific reference for the review and approval of drugs for rare diseases with the creation of China's First List of Rare Diseases and the publication of two batches of the List of Overseas New Drugs Urgently Needed in Clinical Settings. Drug review and approval has been significantly accelerated, as has marketing. The two batches of lists of new drugs, issued in November 2018 and May 2019, include 43 drugs for rare diseases (58.1% of all drugs in the lists), 37 of which were included in China's First List of Rare Diseases. The lists also include three other drugs for MPS. As of July 1, 2019, four drugs for rare diseases from the first batch of new drugs have been approved for marketing. In order to further improve the review and approval of drugs for rare diseases in China, a special department should be established for the evaluation of drugs for rare diseases, research on and management of drugs in the post-approval phase should be enhanced, international cooperation in research on use of drugs to treat rare diseases should be enhanced, and the incentive policy for marketing drugs for rare diseases should be improved.
Mutations in the GJB2 gene are the most common cause of pre-lingual hearing loss (HL) worldwide. Previous studies have shown the frequency of GJB2 mutations to be 16% in Iran, but varies among different ethnic groups. Here, we have reviewed results from previous published mutation reports to provide a comprehensive collection of data for GJB2 mutations and HL in eastern Iran. We conducted a systematic literature review of PubMed, Google Scholar, Web of Science, and Science Direct databases for articles published before March, 2019. The literature search was performed by 2 independent researchers. The primary data of these studies including the number of samples, allelic frequency, and so on were extracted. Six studies involving 812 unrelated families from four different eastern provinces were included and analyzed for the type and prevalence of GJB2 mutations. A total of 19 different genetic variants were detected. GJB2 mutations were 8.8% in the studied eastern provinces, which was lower than that reported in northern populations of Iran. Moreover, a gradient in the frequency of GJB2 mutations from north to south Iran was observed. c.35delG was the most frequent mutation, accounting for 48.5% % of the populations studied. However, this mutation was absent in the Baluchi population. This review shows that particular rare mutations are frequent in some Iranian ethnic groups, and should be considered for genetic counselling.
This study aims at characterizing and comparing the findings of auditory brainstem response (ABR) using narrow-band chirp (NB-chirp) and tone burst (TB) for both latency and amplitude parameters among those exposed to occupational noise and to determine which among the two serves as a better indicator of noise-induced cochlear neuropathy. Forty adult males in the age range of 20-35 years were considered, wherein 20 of them were exposed to noise > 80 dB (A) for 8 hours per day constituting Noise-exposed group; and Control group consisted of 20 individuals without occupational noise exposure. ABR was recorded using NB-chirp and TB for four frequencies at 80 dB nHL through Etymotic Research – 3A (ER-3A) Insert phones using Interacoustics Eclipse EP-25 in individuals with and without noise exposure. MANOVA was performed to compare between TB ABR and NB-chirp ABR between the two groups. Statistical analysis revealed a notable difference for NB-chirp comparisons between the two groups at three frequencies: 500 Hz, F(1, 38) = 10.6; 1000 Hz, F(1, 38) = 7.91; and 2000 Hz, F(1, 38) = 6.64. Whereas, the difference was evident at only 500 Hz: F(1, 38) = 4.98 in case of TB ABR. However, there was no significant difference seen at any of the frequencies for amplitude parameters in both TB and NB-chirp ABR. Latency of wave V using NB-chirp was considered to be a better indicator compared to TB, acting as a better clinical tool in early identification, diagnosis, and monitoring of noise induced hearing loss (NIHL).
3-Hydroxyisobutyryl-coenzyme A (CoA) hydrolase deficiency (HIBCHD; MIM: #250620) is a rare autosomal recessive inborn error of metabolism caused by a defect in the HIBCH enzyme, resulting in a deficiency of the conversion of 3-hydroxy-isobutyryl-CoA to 3-hydroxy-isobutyric acid, a critical step in valine catabolism. This neurodegenerative disease of infancy is associated with hypotonia, developmental delay, cerebral atrophy and lesions in the basal ganglia on magnetic resonance imaging (MRI). In this study, we describe two unrelated patients with infantile-onset progressive neurodegenerative disease and mutations in HIBCH identified using whole exome sequencing (WES). In Case 1, WES revealed a novel homozygous variant in the HIBCH gene: c.808A>G (p.Ser270Gly). In Case 2, a novel compound heterozygous mutation in the HIBCH gene is described: c.808A>G (p.Ser270Gly) and c.173A>G (p. Asn58Ser). Parent analysis revealed that c.808A>G (p.Ser270Gly) was inherited from the father and c.173A>G (p. Asn58Ser) from the mother. These novel mutations were predicted as a disease-causing mutation. Plasma acylcarnitine analysis was normal in both patients. Physical examination showed similar features, such as axial hypotonia and spastic hypertonia in the legs. The first patient presented with difficult-to-treat seizures, while the second patient has not yet experienced documented seizures. In conclusion, our findings would widen the mutation spectrum of HIBCH deficiency and the phenotypic spectrum of the disease. The potential genotype–phenotype correlation would be profitable for the correct diagnosis, treatment and integral management of patients with HIBCH deficiency.
Spinocerebellar ataxia (SCA) is a rare, heterogeneous genetic group of disorders with overlapping clinical features that arises as a result of the degeneration of Purkinje cells. The most prominent clinical feature of SCA is difficulty with whole body movements. The aim of the current study was to analyze the allelic frequency of normal repeat sizes in different SCA subtypes in the north Indian population. Blood samples were collected from 200 subjects, DNA was extracted, and then multiplex PCR and fragment analysis were performed using the ABI-310 genetic analyzer. The prevalent cytosine-adenine-guanine (CAG) repeat size or allelic frequency for SCA1, 2, 3 , 6, and 7 were 29 repeats (59%), 21 repeats (72.5%), 23 repeats (13.1%), 9 repeats (30%), and 3 repeats (75%), respectively. Results indicated that the normal repeats are shifting to lower or upper ranges in the Indian scenario, and similar findings have been reported in other previous studies. Thus, this and other studies have suggested that the normal range of repeats for various SCA in the Indian scenario needs to be redefined and should be confirmed by studies with larger samples and by functional studies.
Pelizaeus–Merzbacher disease (PMD) is an X-linked, recessively inherited disorder associated with hypomyelination in the brain white matter. Mutations involving the proteolipid protein 1 gene (PLP1) located on Xq22.2 are responsible for PMD. PLP1 duplication is the major genetic abnormality in PMD patients. In this study, we utilized droplet-digital polymerase chain reaction (ddPCR) as a potential method to detect PLP1 duplications. Samples from four PMD patients and one of their mothers were used as positive controls. They had been previously diagnosed as having an additional PLP1 copy by chromosomal microarray testing. Genomic copy number of PLP1 was analyzed in triplicate experiments and compared with reference genes XIST and AR on the X-chromosome, and RPP30 and RPPH1 on the autosomes. As a result, precise results were obtained for each triplicate procedure. Thus, we concluded that triplicate experiments are no longer necessary. Compared to other methods, including fluorescence in-situ hybridization, multiplex ligation-dependent probe amplification, chromosomal microarray testing, and quantitative PCR, we were able to establish ddPCR results rapidly with very small amounts of DNA. In conclusion, we showed that ddPCR can be a potential diagnostic tool to confirm genomic copy number as a routine clinical application, including in prenatal diagnostic settings.
Extramammary Paget's disease (EMPD) is a carcinoma of the genital, perianal, and, rarely, axillary skin. The malignant Paget cells migrate extensively in the epidermis before invading the underlying dermis. Toker cells and keratinocytes have both been suggested as the cells of origin of EMPD. Paraffin sections of eight cases of EMPD were immunohistochemically stained for carcinoembryonic antigen, a known marker for Paget cells. The presence of carcinoembryonic antigen in some keratinocytes in all of the observed cases of EMPD suggests that EMPD originates from keratinocytes. Thus, keratinocytes containing carcinoembryonic antigen are pre-Paget cells.
Lemièrre's syndrome (LS) is an uncommon disease characterized by septic thrombophlebitis of the jugular vein in the context of otorhinolaryngologic infections. These patients are often young and the pharyngotonsillar infection is the most frequent primary focus, but other foci like acute otitis media or otomastoiditis have been described. Although the internal jugular vein is the most commonly affected site, a few case reports have been published with thrombosis of other veins, such as the facial vein or transverse sinus. We report the case of a 93-year-old woman with an atypical presentation of LS presenting with thrombophlebitis of the internal jugular vein, transverse sinuses and Herophili torcula after an acute otitis media complicated with acute otomastoiditis. Infectious cerebral venous thrombosis (CVT) is rare and accounts for 6-12% of the total in large adult series and is usually associated to otorhinolaryngologic infections. CVT is an atypical presentation of LS that can be potentially lethal, especially during the acute phase. For this reason, clinical suspicion and early treatment are vital to improve the prognosis of these patients. Although surgical treatment is recommended in cases of LS complicated with CVT, conservative management with antibiotics and anticoagulation lead to ad integrum restitutio without neurological sequelae in our case, suggesting that surgical treatment may not be necessary in all cases of LS complicated with CVT.
Pituitary incidentaloma (PI) is a generic term for pituitary tumors that are identified on images acquired for non-malignant conditions. Acromegaly is an extremely rare form of PI. Occasionally, a functional pituitary adenoma (PA) may be misdiagnosed as PI, which may result in a poor clinical outcome. Here we report the first case, to the best of our knowledge, of PI diagnosed as trauma-triggered acromegaly. A 42-year-old man with a chief complaint of head trauma was referred to our hospital after computed tomography (CT) revealed a pituitary tumor. His appearance was suggestive of acromegaly. Mild hypertrophy of the extremities was also observed. Preoperative blood tests, magnetic resonance imaging (MRI), and endocrine tolerance test findings indicated acromegaly. Accordingly, we suspected a growth hormone (GH)-producing PA, and we performed endoscopic transsphenoidal surgery (eTSS). Histopathology showed a densely granulated GH-producing PA, which was also confirmed via immunohistochemistry. Two months after surgery, blood tests showed decreased levels of GH and insulin-like growth factor-1. In addition, a postoperative endocrine tolerance test revealed no abnormalities. There was no recurrence at 24 months after surgery. The findings from this case suggest that PIs can also present as functional adenomas, which can be diagnosed using initial hormone examinations and endocrine tolerance tests. Therefore, thorough endocrine examination is necessary for early diagnosis and treatment and improved patient outcomes.
Biliary leakage at the site of the hepaticojejunostomy after liver transplantation is a life- threatening complication. We herein present the case of a 7-year-old girl who underwent complete external biliary drainage during difficult living donor liver retransplantation as a bailout procedure. The patient had undergone duct-to-duct biliary reconstruction in the initial living donor liver transplantation. In the retransplantation, Roux-en-Y (RY) reconstruction was planned but abandoned due to the critical condition in the operation. As an alternative procedure, the patient underwent complete external drainage using a 6Fr drainage tube with cuff. Five months after retransplantation when the nutrition status and physical strength of a patient recovered fully, RY hepaticojejunostomy was successfully performed. This is a case report of two-staged biliary reconstruction with temporary complete external biliary drainage used in pediatric liver retransplantation, which was performed after some months not a few days. It is a safe and feasible alternative when primary anastomosis is deemed to carry a high risk of bile leakage in cases of difficult liver transplantation in critically ill patients.
There are few reports of pituitary adenomas (PA) mimicking dementia. Delay in disease diagnosis and treatment may result in poor clinical outcome. We experienced a rare case where endoscopic transsphenoidal surgery (eTSS) effectively treated a gonadotroph adenoma mimicking dementia and report on literature considerations. We report the case of a 72-year-old man with chief complaints of cognitive decline, bradykinesia, anorexia, dressing apraxia, and vigor decline over several months. He was admitted to our hospital for scrutiny in a disoriented state. Blood tests showed hyponatremia and thyroid hormone depression. Magnetic resonance imaging showed a pituitary tumor, and preoperative endocrine stress tests showed reduced reactivities of growth hormone, adrenocorticotropic hormone/cortisol, and luteinizing hormone/follicle-stimulating hormone. Symptomatic pituitary adenoma was suspected, and eTSS was performed. The permanent pathological diagnosis was of gonadotroph adenoma. Postoperatively, the hyponatremia, cognitive decline, movement retardation, loss of appetite, dressing apraxia, and limb edema markedly improved. The patient was discharged under hydrocortisone 15 mg/day administration without complications. The endocrine stress test performed 2 months postoperatively showed secondary hypoadrenocorticism, while the other endocrine functions had normalized. No recurrence had occurred by 30 months postoperatively; the medication of hydrocortisone was gradually discontinued and the patient at the time was still being followed as an outpatient with modified Rankin Scale score 0. Secondary hypothyroidism and secondary hypoadrenocorticism due to the pituitary tumor primarily caused the condition. It is important to consider PA in the differential diagnosis of dementia, and early diagnosis and treatment can contribute to a patient's good clinical outcome.
Esophageal perforation with subsequent development of a mediastinal abscess is a well-known clinical entity. Etiologies including idiopathic and iatrogenic with invasive procedures have been reported in medical literatures. This condition is seriously associated with high co-morbidity and in some cases especially if intervention has not been applied associated with high mortality. For long time, open surgical intervention was the only available treatment modality for esophageal perforation with subsequent development of a mediastinal abscess. However, recently there are some other less invasive modalities that have been used with comparable if not preferable success including; self-expandable metallic or plastic stents and imaging guided percutaneous drainage of the mediastinal abscess combined with stenting. We report a patient who presented with esophageal perforation complicated with a mediastinal abscess that was treated successfully with an imaging guided percutaneous drainage of the mediastinal abscess. This case is to emphasize on the fact that endoscopic stent placement is safe and effective for esophageal perforations. Percutaneous CT-guided drainage of associated mediastinal abscesses is an uncommon procedure, but the results suggest that it is associated with high technical and clinical success rates. There should be increased involvement of interventional radiology in the management of those cases.
On August 10, 2019, the Multidisciplinary Expert Seminar on Healthcare Security for Rare Diseases in China was held in Beijing. The seminar was organized by the Shanghai Foundation for Rare Disease and Shanghai Health Development Research Center and advised by the China Alliance of Rare Diseases. Participants in this seminar included government officials, experts in clinical medicine, pharmacy, epidemiology, health economics, and law as well as representatives from rare disease patient organizations. The participating experts cited three key elements of healthcare security, including its concept, data, and mechanism, to solve the problem of health care security for patients with rare diseases at the national level. Collection of basic data and creation of a model of healthcare security for rare diseases were discussed. Data collection should be actively promoted. Creation of a special zone to ensure medical care for patients with rare diseases should be considered. Healthcare security should be classified, which means that basic medical insurance provides better care for rare diseases that respond to treatment, and channels should be established for rare diseases that respond poorly to treatment.