The association of neurodevelopmental abnormalities, congenital heart and renal defects in a tuberous sclerosis complex patient cohort

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

Neurite density of white matter significantly correlates with tuberous sclerosis complex disease severity

“…Also, the small group did not allow a comparison between TSC1 and TSC2 patients, in terms of the affected regions or clinical manifestations. Quantitative MR-derived indices like total brain volume and tuber volume were shown to be different between patients with TSC1 and TSC2 mutations in previous studies ( Ogórek et al, 2020 , Robinson et al, 2022 ), therefore, it would be interesting to observe these groups with advanced diffusion-derived indices. Another limitation is the wide age range of the study group.…”

An X-linked PLXNB3 mutation identified in patients with congenital heart disease with neurodevelopmental disabilities

“…C H D i s o f t e n a s s o c i a t e d w i t h o t h e r neurodevelopmental disabilities (NDD) and genetic or syndromic conditions (4,5): 10% of children with CHD and 50% of those with severe CHD also have NDD (6). Epidemiological studies suggest that environmental or genetic factors are involved in the causation of approximately 20-30% of CHD cases, while other unexplained CHD with NDD cases are believed to have a multifactorial causation (7). In recent years, an increasing number of studies have identified single-gene variants that are closely related to CHD.…”