RESUMO
Objective: Clinical manifestations, imaging findings, pathologic features, and genetic mutations of Chinese adult patients with cerebrotendinous xanthomatosis (CTX) were analyzed in order to achieve a greater understanding of CTX that can improve early detection, diagnosis, and treatment. Methods: Clinical data including medical history, neurologic and auxiliary examinations, imaging findings, and genetic profile were collected for an adult patient with CTX admitted to the Sixth Medical Center of Chinese People's Liberation Army General Hospital in August 2020. Additionally, a systematic review of genetically diagnosed Chinese adult CTX cases reported in major databases in China and other countries was performed and age of onset, first symptoms, common signs and symptoms, pathologic findings, imaging changes, and gene mutations were analyzed. Results: The proband was a 39-year-old female with extensive, early-onset nervous system manifestations including cognitive dysfunction and ataxia. Systemic lesions included juvenile cataract and a tendon mass. Cranial magnetic resonance imaging revealed cerebral atrophy, symmetric white matter changes predominantly in the pyramidal tract, and lesions in the cerebellar dentate nucleus. A novel homozygous mutation in the sterol-27-hydroxylase (CYP27A1) gene (c.1477-2A>C) was identified. There were no family members with similar clinical presentation although some were carriers of the c.1477-2A>C mutation. The patient showed a good response to deoxycholic acid treatment. Totally there were 56 cases of adult CTX patients in China, mostly in East China (31/56, 55.4%), at a male-to-female ratio of 1.8 to 1. Multiple organs and tissues including nervous system, tendon, lens, lung, and skeletal muscle were affected in these cases. The most common neurologic manifestations were cognitive dysfunction (44/52, 84.6%) and ataxia (44/51, 86.3%). The cases were characterized by early onset, chronic progressive damage of multiple systems, long disease course, and delayed diagnosis, making the disease difficult to manage clinically and resulting in poor prognosis. The 2 most common genetic mutations in Chinese adult CTX patients were c.1263+1G>A and c.379C>T. Exon 2 of the CYP27A1 gene was identified as a mutation hot spot. Conclusions: Chinese adult patients with CTX have complex clinical characteristics, a long diagnostic cycle, and various CYP27A1 gene mutations. Early diagnosis and intervention can improve the prognosis of these patients.
Assuntos
Humanos , Masculino , Adulto , Feminino , Xantomatose Cerebrotendinosa/patologia , Linhagem , Colestanotriol 26-Mono-Oxigenase/genética , Mutação , AtaxiaRESUMO
@#【Objective】To investigate the effects of up-regulating RA signal and inhibiting AP-1 transcriptional activity on TGF-β2 secretion by RPEs and its possible pathways.【Methods】① To investigate the effects of ATRA treat⁃ ment，human retinal pigment epithelial cell line ARPE-19 cells were divided into 5 groups：control group and 4 interven⁃ tion groups（6 h，12 h，24 h and 48 h after RA treatment）. Western blot，RT-qPCR and immunofluorescence staining were carried out to analyze RARβ and c-Fos expression. ②To investigate the effects of RARβ inhibitor LE540 treatment on expression of RARβ and c-Fos that were induced by ATRA，ARPE-19 cells were divided into 4 groups：control group，ATRA group，LE540 group and ATRA+LE540 group. RARβ and c-Fos expression was assessed by western blot and RT-qPCR. ③ To investigate the effects of AP-1 inhibitor T-5224 treatment，ARPE-19 cells were divided into 4 groups：control group and treatment groups（12 h，24 h and 48 h after T-5224 treatment）. EMSA was carried out to ana⁃ lyze the AP-1 DNA binding activity. ④To investigate the effects of LE540 and T-5224 administration on ATRA- induced TGF-β2 secretion，ARPE-19 cells were divided into 4 groups：control group，ATRA group，ATRA+LE540 group and ATRA+LE540 group. Western blot and ELISA were carried out to analyze TGF-β2 secretion in ARPE-19 cells.【Results】 RARβ level in ARPE-19 cells was significantly higher in treatment group than in control group after being treated with ATRA for 24 and 48 hours（P＜0.05）. C-Fos level was first up-regulated and then decreased. After treatment with ATRA for 6 and 12 hours，c-Fos expression were significantly upregulated（P＜0.01），but at 48 h after treatment，their expression were significantly decreased to the level which had no statistical difference compared with the control group （P＞0.05）. The AP-1 DNA binding activity was significantly decreased in ARPE-19 cells after being treated with T-5224 for 24 and 48 hours（P＜0.01）. Compared with ATRA group，TGF-β2 secretion was statistically down-regulated after being treated with LE540 and T-5224 for 48 hours（P＜0.05）.【Conclusion】ATRA can induce TGF-β2 secretion in RPE cells through affecting RARβ expression and AP-1 transcriptional activity.