Neuroscience and Mental Health Research Institute, Hadyn Ellis Building, Cardiff, CF24 4HQ, UK.
School of Bioscience, The Sir Martin Evans Building, Museum Ave, Cardiff, CF10 3AX, UK.
BMC Med. 2022 Apr 20;20(1):123. doi: 10.1186/s12916-022-02325-0.
Tuberous sclerosis complex (TSC) is a rare multi-system genetic disorder characterised by the presence of benign tumours throughout multiple organs including the brain, kidneys, heart, liver, eyes, lungs and skin, in addition to neurological and neuropsychiatric complications. Intracardiac tumour (rhabdomyoma), neurodevelopmental disorders (NDDs) and kidney disorders (KD) are common manifestations of TSC and have been linked with TSC1 and TSC2 loss-of-function mutations independently, but the dynamic relationship between these organ manifestations remains unexplored. Therefore, this study aims to characterise the nature of the relationship specifically between these three organs' manifestations in TSC1 and TSC2 mutation patients.
Clinical data gathered from TSC patients across South Wales registered with Cardiff and Vale University Health Board (CAV UHB) between 1990 and 2020 were analysed retrospectively to evaluate abnormalities in the heart, brain and kidney development. TSC-related abnormalities such as tumour prevalence, location and size were analysed for each organ in addition to neuropsychiatric involvement and were compared between TSC1 and TSC2 mutant genotypes. Lastly, statistical co-occurrence between organ manifestations co-morbidity was quantified, and trajectories of disease progression throughout organs were modelled.
This study found a significantly greater mutational frequency at the TSC2 locus in the cohort in comparison to TSC1. An equal proportion of male and female patients were observed in this group and by meta-analysis of previous studies. No significant difference in characterisation of heart involvement was observed between TSC1 and TSC2 patients. Brain involvement was seen with increased severity in TSC2 patients, characterised by a greater prevalence of cortical tubers and communication disorders. Renal pathology was further enhanced in TSC2 patients, marked by increased bilateral angiomyolipoma prevalence. Furthermore, co-occurrence of NDDs and KDs was the most positively correlated out of investigated manifestations, regardless of genotype. Analysis of disease trajectories revealed a more diverse clinical outcome for TSC2 patients: however, a chronological association of rhabdomyoma, NDD and KD was most frequently observed for TSC1 patients.
This study marks the first empirical investigation of the co-morbidity between congenital heart defects (CHD), NDDs, and KDs in TSC1 and TSC2 patients. This remains a unique first step towards the characterisation of the dynamic role between genetics, heart function, brain function and kidney function during the early development in the context of TSC.
结节性硬化症（TSC）是一种罕见的多系统遗传性疾病，其特征是在多个器官中存在良性肿瘤，包括脑、肾、心、肝、眼、肺和皮肤，此外还有神经和神经精神并发症。心脏肿瘤（横纹肌瘤）、神经发育障碍（NDD）和肾脏疾病（KD）是 TSC 的常见表现，并已分别与 TSC1 和 TSC2 功能丧失突变有关，但这些器官表现之间的动态关系尚未得到探索。因此，本研究旨在专门描述 TSC1 和 TSC2 突变患者这三种器官表现之间的关系性质。
回顾性分析了 1990 年至 2020 年期间在南威尔士注册的加的夫和瓦尔大学健康委员会（CAV UHB）的 TSC 患者的临床数据，以评估心脏、大脑和肾脏发育的异常情况。分析了每个器官的 TSC 相关异常，如肿瘤患病率、位置和大小，以及神经精神受累情况，并比较了 TSC1 和 TSC2 突变基因型之间的差异。最后，对器官表现合并症的统计共现进行了量化，并对整个器官的疾病进展轨迹进行了建模。
本研究发现，与 TSC1 相比，该队列中 TSC2 基因座的突变频率显著更高。该组中观察到男性和女性患者的比例相等，通过对以前研究的荟萃分析也是如此。TSC1 和 TSC2 患者的心脏受累特征无显著差异。TSC2 患者的大脑受累程度更严重，表现为皮质结节和交流障碍的患病率更高。TSC2 患者的肾脏病理进一步加重，表现为双侧血管平滑肌脂肪瘤的患病率增加。此外，在所研究的表现中，无论基因型如何，NDD 和 KD 的共现与其他表现的相关性最强。疾病轨迹分析显示，TSC2 患者的临床结果更为多样化：然而，对于 TSC1 患者，最常观察到横纹肌瘤、NDD 和 KD 的时间顺序关联。
本研究标志着首次对 TSC1 和 TSC2 患者的先天性心脏缺陷（CHD）、NDD 和 KD 之间的合并症进行实证研究。这是朝着在 TSC 背景下描述遗传、心脏功能、大脑功能和肾功能在早期发育过程中动态关系的独特的第一步。
