Intractable & rare diseases research最新文献

Nucleotide variations or deletions in the NK2 homeobox 1 gene (NKX2-1), located at 14q13.3, lead to symptoms associated with the brain, lungs, and thyroid, and the combination of these phenotypes is clinically recognized as the brain-lung-thyroid syndrome. Many types of nucleotide variants of NKX2-1 have been identified, and phenotypic variability has been reported. Chromosomal deletions involving NKX2-1 have also been reported; however, phenotypic differences between patients with nucleotide variants of NKX2-1 and patients with chromosomal deletions involving NKX2-1 have not been well established. Recently, we identified seven patients with 14q13 microdeletions involving the NKX2-1. Most patients exhibited developmental delay. This inquiry arises regarding the potential existence of haploinsufficiency effects beyond those attributed to NKX2-1 within the 14q13 microdeletion. However, a literature review has shown that developmental delay is not rare in patients with nucleotide alterations in NKX2-1. Rather, motor function impairment may have affected the total developmental assessment, and the haploinsufficiency of genes contiguous to NKX2-1 is unlikely to contribute to developmental delay.

Varicella zoster virus (VZV) causes chickenpox at the primary infection and then becomes latent in the spinal dorsal root ganglia; VZV can reactivate with aging, immunosuppression, stress, and other factors, occurring as herpes zoster (HZ) at 1-2 skin segments. HZ peripheral nerve complications caused by VZV reactivation include Hunt syndrome, segmental HZ paresis, post-herpetic neuralgia, and Guillain-Barré syndrome (GBS). We have encountered the rare HZ complications of upper-limb paresis, myeloradiculitis, and polyradiculoneuritis: an adult woman with upper-limb paresis consistent with the nerve root on segments above the thoracic HZ dermatome; another woman exhibiting ascending myeloradiculitis originating at the Th11-12 roots; an elderly woman with ascending VZV polyradiculoneuritis resembling GBS; an adult with VZV quadriplegia with disseminated HZ; and an elderly patient with VZV-associated polyradiculoneuritis. The three polyradiculoneuritis cases may be a new subtype of HZ peripheral neuropathy, but the pathophysiology for these HZ peripheral nerve complications unrelated to HZ dermatomes is unclear. We analyzed host factors, skin lesions, neurological and virological findings, and MRI results including 3D NerveVIEW in 15 Japanese patients treated at our facility for HZ peripheral neuropathy, including six differing from the HZ dermatome. Based on the clinical findings including MRI results of spinal ganglia and roots, we identified four possible routes for the patterns of VZV spread: (i) ascending spinal roots, (ii) ascending spinal cord, (iii) polyradiculopathy, and (iv) intrathecal spread. The incidence of HZ is increasing with the aging of many populations, and clinicians should be aware of these HZ neuropathies.

Dwarfism is a rare condition characterized by small stature. Achondroplasia is predominantly considered the leading cause of dwarfism. Although the condition is not life-threatening, it dramatically impacts the social life of the patient. The United States Food and Drug Administration (US FDA) first approved the drug Voxzogo (vosoritide) for achondroplasia. The drug also received approval from the European Medicines Agency (EMA) via the centralized procedure. The drug is associated with a decrease in blood pressure, a severe adverse event. However, this adverse event/risk has been overcome by benefits, i.e. fulfilling of unmet medical need. In the United States, the drug received accelerated approval as it satisfied the criteria of rare pediatric disease. This review includes a detailed orphan drug approval process with particular reference to vosoritide, which is considered a milestone for the treatment of achondroplasia.

Rett syndrome (RTT) is a rare genetic neurological disorder that primarily affects girls and is caused by mainly mutations in the methyl-CpG-binding protein 2 (MECP2) gene, leading to critical issues in normal brain function. The condition has a global prevalence of 5 to 10 cases per 100,000 females, and there is currently no cure for RTT. However, therapy is available to manage the symptoms and improve quality of life. Trofinetide, an insulin-like growth factor 1, was originally developed as a stroke medication and progressed to Phase II clinical trials, where it exhibited favorable safety and efficacy profiles by improving several core RTT symptoms. Recently, Trofinetide received the US Food and Drug Administration (FDA) approval and orphan drug designation for the treatment of RTT, making it the first approved drug for this rare genetic disorder. It has also shown to be safe, well-tolerated and with no known drug interactions. These findings suggest that Trofinetide is a promising treatment option for individuals with RTT.

Gonadal and extragonadal pediatric germ cell tumors (GCTs) are rare neoplasms with different clinical behavior. Although surgery and cisplatin-based chemotherapy are resolutive in most cases, some patients do not respond to chemotherapy and have a worse outcome. Microsatellite instability (MSI) was correlated to resistance to chemotherapy and sensitivity to immunotherapy in different neoplasms. A series of 21 pediatric GCTs were tested by immuno-histochemistry and PCR to evaluate MSI status. Next generation sequencing was applied to further evaluate cases with discordant results between immunohistochemistry and PCR. Twenty-one cases of pediatric GCT were included in the series. The mean age ranged between 1 and 10 years. Nine cases were gonadal GCTs and the remaining 12 were extra-gonadal GCTs. By immunohistochemistry, one case showed a deficit of Mismatch repair (MMR) proteins. This case was a 1-year-old children affected by gonadal yolk sac tumor. However, all cases resulted microsatellite stable (MSS) by PCR and NGS. MSI was not detected in our series of pediatric GCTs, as well as the data present in literature about adult patients with GCTs. Molecular techniques could have a role to confirm the MSI status in case of dMMR by immunohistochemistry.

Interferon-induced transmembrane proteins (IFITMs 1, 2, and 3) play a critical role in preventing pathogen infection in vertebrates. They are also involved in the occurrence and prognosis of cancer. Myogenesis is a complex process regulated by several factors. This study disclosed that Ifitm1-3 were upregulated in the process of myogenic differentiation of C2C12 myoblasts on days 3, 5, and 7. This positively correlated with the expression of differentiation factors MyoD, myogenin, Mrf5, and desmin. Furthermore, knockdown of Ifitm1-3 by their individual siRNAs inhibited myogenesis of C2C12 myoblasts, with relative downregulation of MyoD, myogenin, Mrf5, and desmin. Subsequently, myotube formation and fusion percentage decreased. Co-immunoprecipitation combined with LC-MS/MS analysis uncovered the interaction proteins of IFITM1 and IFITM3 in C2C12 myoblasts. A total of 84 overlapped interaction proteins of IFITM1 and IFITM3 were identified, and one of the clusters was engaged in cytoskeletal and sarcomere proteins, including desmin, myosin, actin, vimentin, nestin, ankycorbin, and nucleolin. Hence, we hypothesize that these interacting proteins may function as scaffolds for IFITM1-3, possibly through the interaction protein desmin to initiate further interaction with other proteins to participate in myogenesis; however, the molecular mechanisms remain unclear. Our study may contribute to the development of novel therapeutics for myopathic diseases.

Oncogenic PIK3CA mutation activates phosphoinositide 3-kinase (PI3K) enzyme, and PI3K-AKT signaling activation induces several growth-regulatory transcription factors. PIK3CA mutations have attracted attention as biomarker in clinical trials of various inhibitors including PI3K inhibitors. About 80% of PIK3CA mutations in human cancers are observed in 'hot spot' regions: exon 9 (E542K and E545K) and exon 20 (H1047R). There were few reports about clinical significance of PIK3CA mutations in cutaneous cell carcinoma (cSCC). Thus, we investigate the prevalence of three PIK3CA hot spot mutations in 143 cases with cSCC and evaluate the correlation between the presence of these mutations and clinical characteristics by using ddPCR. The frequency of each E542K, E545K and H1047R PIK3CA mutations was 1.4% (2/143), 2.8% (4/143), and 0.7% (1/143) respectively. No significant correlation was found between PIK3CA mutations and clinical characteristics. Although additional basic researches and clinical trials are necessary, various inhibitors may be effective therapeutics for PIK3CA mutation-positive cSCC. Our study revealed the prevalence of PIK3CA mutations in cSCC.

In recent years, China has increased attention on the issue of rare diseases, and the government has promulgated rare disease-related policies to gradually improve rare disease diagnosis, treatment, drug marketing, and patient burden. Orphan drugs were added to the medical insurance directory in 7 batches, of which 22 drugs were first included in the 2004 medical insurance directory and 8, 16, 12, 7, 8, and 7 were included in the 2009, 2017, 2019, 2020, 2021, and 2022 versions, respectively. Currently, 106 orphan drugs are marketed in China, which are suitable for treating 53 rare diseases such as hematologic diseases, congenital metabolism disorders, neuropathies, and digestive system diseases and for other treatment fields. The drugs are mainly manufactured in 15 countries such as China, Switzerland, and the USA, of which 10 drugs can be used to treat different rare diseases. At the same time, there are multiple treatments available for 25 rare diseases. In this paper, we examined the manufacturers, marketing status, indications, and inclusion of orphan drugs in the National Basic Medical Insurance Directory to describe and analyze the current status of 106 orphan drugs that are currently marketed in China to provide a reference for rare disease policy formulation and drug development.

Ortner's syndrome (OS), also called cardiovocal syndrome, is a rare condition hallmarked by left recurrent laryngeal nerve palsy due to underlying cardiopulmonary disease. The purpose of this review is to systemically analyze the existing literature for cases of OS to outline typical presentation, methods of diagnosis, and management of these patients. Case reports, case series, and cohort studies describing OS between 1955 and 2021 were identified. Individual manuscripts were reviewed for clinical features, presentation, and management. A total of 117 patient cases were gathered from 92 published articles. Common symptoms included hoarseness, dyspnea, cough, and dysphagia. The most common associated comorbidity was aortic aneurysm (41%), followed by pulmonary hypertension (35%), mitral stenosis (17%), and hypertension (12%). Among those who were managed via surgical intervention, 85.4% reported improvement in their hoarseness. While historically OS was associated with mitral stenosis, in recent decades, aortic aneurysms and dilation of the pulmonary artery from pulmonary hypertension have emerged as primary etiologies of OS. Therefore, OS should be considered in any patient presenting with hoarseness and history of cardiopulmonary disease. Surgical intervention in appropriate candidates resolves OS in most cases.

VEXAS syndrome, is a hemato-inflammatory chronic disease characterized with predominantly rheumatic and hematologic systemic involvement. It was first described in 2020 by a group of researchers in the United States. VEXAS syndrome is a rare condition that primarily affects adult males and is caused by a mutation in the UBA1 gene located on the X chromosome. Its pathogenesis is related to the somatic mutation affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. Mutant gene lead to decreased ubiquitination and activated innate immune pathways and systemic inflammation occur. The specific mechanism by which the UBA1 mutation leads to the clinical features of VEXAS syndrome is not yet fully understood. VEXAS is a newly define adult-onset inflammatory syndrome manifested with treatment-refractory fevers, arthritis, chondritis, vasculitis, cytopenias, typical vacuoles in hematopetic precursor cells, neutrophilic cutaneous and pulmonary inflammation. Diagnosing VEXAS syndrome can be challenging due to its rarity and the overlap of symptoms with other inflammatory conditions. Genetic testing to identify the UBA1 gene mutation is essential for definitive diagnosis. Currently, there is no known cure for VEXAS syndrome, and treatment mainly focuses on managing the symptoms. This may involve the use of anti-inflammatory medications, immunosuppressive drugs, and supportive therapies tailored to the individual patient's needs. Due to the recent discovery of VEXAS syndrome, ongoing research is being conducted to better understand its pathogenesis, clinical features, and potential treatment options. In this review article, the clinical, diagnostic and treatment approaches of VEXAS syndrome were evaluated in the light of the latest literature data.