The contribution of a novel PHEX gene mutation to X-linked hypophosphatemic rickets: a case report and an analysis of the gene mutation dosage effect in a rat model.

A Chinese family was identified to have two patients with rickets, an adult female and a male child (proband), both exhibiting signs related to X-linked hypophosphatemic rickets (XLH). Gene sequencing analysis revealed a deletion of adenine at position 1985 (c.1985delA) in the PHEX-encoding gene. To investigate the relationship between this mutation and the pathogenicity of XLH, as well as analyze the effects of different dosages of PHEX gene mutations on clinical phenotypes, we developed a rat model carrying the PHEX deletion mutation. The CRISPR/Cas9 gene editing technology was employed to construct the rat model with the PHEX gene mutation (c.1985delA). Through reproductive procedures, five genotypes of rats were obtained: female wild type (X/X), female heterozygous (-/X), female homozygous wild type (-/-), male wild type (X/Y), and male hemizygous (-/Y). The rats with different genotypes underwent analysis of growth, serum biochemical parameters, and bone microstructure. The results demonstrated the successful generation of a stable rat model inheriting the PHEX gene mutation. Compared to the wild-type rats, the mutant rats displayed delayed growth, shorter femurs, and significantly reduced bone mass. Among the female rats, the homozygous individuals exhibited the smallest body size, decreased bone mass, shortest femur length, and severe deformities. Moreover, the mutant rats showed significantly lower blood phosphorus concentration, elevated levels of FGF23 and alkaline phosphatase, and increased expression of phosphorus regulators. In conclusion, the XLH rat model with the PHEX gene mutation dosage demonstrated its impact on growth and development, serum biochemical parameters, and femoral morphology.

Hemichorea Associated With Nonketotic Hyperglycemia.

CONTEXT: Hemichorea associated with nonketotic hyperglycemia (HC-NH) is a rare diabetic complication for which the pathogenesis remains unclear. OBJECTIVE: This study reported 16 cases of HC-NH to improve the understanding of the disease and avoid misdiagnosis and missed diagnosis. METHODS: Data of 16 patients with HC-NH in a single center from 2000 to 2021 were analyzed retrospectively, and the relevant literature was reviewed. RESULTS: The participants (8 men and 8 women) had a mean age of 67.6 ± 16.4 years. Bilateral limbs were involved in 2 cases, and the others had hemichorea (6 in the left side and 8 in the right side). The average random blood glucose level was 17.51 ± 7.67 mmol/L, and the glycated hemoglobin A1c level was 11.9%±3.1% at admission. Eleven patients had a history of diabetes, and the other 5 patients were diagnosed with new-onset diabetes mellitus, but no remarkable differences were observed in the presentation or treatment of chorea. Ketonuria was detected in 7 patients. The basal ganglia (putamen, globus pallidus, and caudate nucleus) of 9 cases had typical hyperdensity on computed tomography and/or hyperintensity signals from magnetic resonance imaging. The chorea symptoms of 15 patients improved within 5.0 ± 1.9 days after treatment. CONCLUSION: This study provides additional valuable information about the clinical and neuroimaging features of HC-NH. We hypothesize that chronic ischemia of the basal ganglia due to cerebral atherosclerosis combined with hyperglycemia is associated with HC-NH.

Construction and validation of a metabolic gene-associated prognostic model for cervical carcinoma and the role on tumor microenvironment and immunity.

Metabolic reprogramming is a common feature of tumor cells and is associated with tumorigenesis and progression. In this study, a metabolic gene-associated prognostic model (MGPM) was constructed using multiple bioinformatics analysis methods in cervical carcinoma (CC) tissues from The Cancer Genome Atlas (TCGA) database, which comprised fifteen differentially expressed metabolic genes (DEMGs). Patients were divided into a high-risk group with shorter overall survival (OS) and a low-risk group with better survival. Receiver operating characteristic (ROC) curve analysis showed that the MGPM precisely predicted the 1-, 3- and 5-year survival of CC patients. As expected, MGPM exhibited a favorable prognostic significance in the training and testing datasets of TCGA. And the clinicopathological parameters including stage, tumor (T) and metastasis (M) classifications had significant differences in low- and high-risk groups, which further demonstrated the MGPM had a favorite prognostic prediction ability. Additionally, patients with low-ESTMATEScore had a shorter OS and when those combined with high-risk scores presented a worse prognosis. Through "CIBERSORT" package and Wilcoxon rank-sum test, patients in the high-risk group with a poor prognosis showed lower levels of infiltration of T cell CD8 (P < 0.001), T cells memory activated (P = 0.010) and mast cells resting (P < 0.001), and higher levels of mast cells activated (P < 0.001), and we also found these patients had a worse response for immunosuppressive therapy. These findings demonstrate that MGPM accurately predicts survival outcomes in CC patients, which will be helpful for further optimizing immunotherapies for cancer by reprogramming its cell metabolism.