Department of Neurology, Xiangya Hospital of Central South University, Changsha, Hunan, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
Neurol Sci. 2023 Sep;44(9):3363-3368. doi: 10.1007/s10072-023-06767-z. Epub 2023 Mar 29.
POLR3-related leukodystrophy is a group of rare neurodegenerative disorders characterized by degeneration of the white matter with different combinations of major clinical features.
An 18-year-old lady was admitted for no menstruation since childhood. She gradually developed slight symptoms, such as choking after drinking water and unsteady walking in the last 2 years. Furthermore, her test scores and response capability were far lower than that of her peers. Physical examination revealed her to be of a slightly short stature, with stiff expressions and bilateral breast enlargement. She revealed clumsy movements when examined for ataxia, with an SARA score of 9.
The laboratory data revealed a decreased level of estradiol, FSH, and LH, with a MoCA score of 7. Conventional karyotype analysis revealed a 46 XX 9qh + karyotype. Ultrasound indicated primordial uterus (19 × 11 × 10 mm). Brain MRI showed bilateral cerebral hemisphere myelin dysplasia, brain atrophy, thin corpus callosum, and small pituitary gland with uneven reinforcement and enlarged ventricles. Exome sequencing exhibited two missense mutations in the POLR3A gene (c.3013C > T and c.1757C > T), which were inherited from her mother and father, respectively.
Collectively, we identified novel compound heterozygous mutations of the POLR3A gene that caused POLR3A-related hypomyelinating leukodystrophy with hypogonadism in the patient combined with the clinical presentation, MRI brain pattern, and medical exome sequencing.
The complexity of clinical phenotypes and heterogeneity of genotypes raise new challenges in genetic diagnoses. This study will further aid our understanding of POLR3A-related leukodystrophy and promote further analysis of phenotype-genotype correlations of related diseases.
POLR3 相关脑白质营养不良是一组罕见的神经退行性疾病，其特征是白质退化，伴有不同组合的主要临床特征。
一名 18 岁女性自幼无月经，近 2 年来逐渐出现轻度饮水呛咳和行走不稳等症状，且其测试成绩和反应能力均远低于同龄人。体格检查发现患者身材略矮小，表情僵硬，双侧乳房增大。共济失调检查时，患者动作笨拙，SARA 评分为 9 分。
实验室数据显示雌二醇、FSH 和 LH 水平降低，MoCA 评分为 7 分。常规核型分析显示 46，XX，9qh+核型。超声提示始基子宫（19×11×10mm）。脑 MRI 显示双侧大脑半球髓鞘发育不良、脑萎缩、胼胝体变薄、垂体不均匀强化且增大。外显子组测序显示 POLR3A 基因存在 2 个错义突变（c.3013C>T 和 c.1757C>T），分别来自于其母亲和父亲的遗传。
综上，我们发现了该患者 POLR3A 基因复合杂合突变，导致 POLR3A 相关脑白质营养不良伴性腺功能减退，结合临床表现、脑 MRI 模式和医学外显子组测序结果，我们明确了诊断。
临床表型的复杂性和基因型的异质性给基因诊断带来了新的挑战。本研究将进一步加深我们对 POLR3A 相关脑白质营养不良的认识，并促进对相关疾病表型-基因型相关性的进一步分析。
