Introduction
Tuberous sclerosis (TSC) is rare, genetic disease with autosomal-dominant model of inheritance which is presented with various clinical manifestations. Some epidemiological studies in USA shown that the incidence of tuberous sclerosis is 0.28–0.56 per 100 000 newborns.1
The main genetic mechanism includes mutations in tuberous sclerosis 1 and 2 genes (TSC1 and TSC2) gene locus responsible for encoding hamartin and tuberin protein, what leads to overactivation of mTOR pathway and finally leads to the growth of hamartomas in multiple organs, what is main pathological base of clinical presentations.2
The main clinical presentations include different neurological symptoms usually presented with cognitive and behavioural disorders. Epilepsy is the most prevalent and clinically important manifestation of tuberous sclerosis, with wide range of clinical presentation from infantile spasms to refractory epilepsy. On the other side the first symptoms of tuberous sclerosis can be disorders form autism spectrum.3
The first clinical manifestations can also be cutaneous manifestations and newborns can be presented with hypomelanotic lesions and „confetti"-skin lesions in aproximately 90% of patients. Neurological symptoms are usually accompanied with opthamological and pulmonary lessions.4
Renal failure is one of the leading cause of mortality and morbidity in adult patients then 30 years. Angiomyolipomas (AMLs) are the main renal lessions, but renal lessions can be presented with renal cysts and renal cell carcinoma. For a long period of time frequent embolisations and hemoorrhage in AMLs were main cause of renal failure.5 Revolution in treatmant and better control of progression to end stage of renal disease corelate with usage of mTOR inhibitors. As a results of two clinical studies EXIST-1 and EXIST-2 mTOR inhibitors found crucial place in treatmant of those patients. Main mechanism of those drugs include inhbition of angiogenesis. It can be used for the successful treatment not only for renal angymolipomas, but also for different types of brain tumors.6
There is a small number of studies where corellation between CKD and neurological manifestation of tuberous sclerosis is found. Particullary, there is no reasarchs where corellation between different stages of CKD and ESRD where made with neurological manifestations of TSC event the common pathways of mTOR inhibitors signaling.
The aim of this study was to correlate neurological manifestations with different stages of chronic kidney disease (CKD). Our hypothesis was that neurological manifestations are more common in end-stage renal disease (ESRD) patients than to CKD patients in earlier stages of CKD
Methods
This multicentric retrospective study included 51 patients from clinical centres from seven South-Eastern Europe countries (Albania, Bosnia and Herzegovina, Croatia, Greece, Montenegro, Serbia and Slovenia), in the period from February to April 2020.
We included patients older then 18 years with possible or definitive diagnosis of TSC. Data were collected from nephrological and neurological registries form clinical centres form mentioned countries in accordance to national and local Ethical committees’ guidelines. Research was performed in accordance of Helsinki Declaration. All patients accepted voluntary to participate and signed informed consent.
For the classifications of patients with possible and definite diagnosis of TSC, we used current TSC updated guidelines 2021.7
Chronic kidney disease was defined regarding to KDIGO guidelines regarding the eGFR (less then 60ml/min/1.73m2), level of albuminuria (greater then 30mg) and ESRD was defined when eGFR was less then 15 ml/min/1.73m2.8
Categorical data were presented by absolute and relative frequencies. The normality of the distribution of continuous variables was tested by the Shapiro-Wilk test. Continuous data were described by the median and the limits of the interquartile range (IQR) and categorical variables were shown as relative or absolute frequencies. The level of significance was set at P<0.05. The statistical analysis was performed using IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp.
Results
This study enrolled 51 patients with a median age of 32.3 years (range, 18-46 years), and predominant female gender (60.45%).
The most prevalent renal lesions leading to CKD were AMLs in 76.6%. Nephrectomy was performed in 43% of patients, while the mTOR inhibitors were used in 18 patients (37.5%). Patients’ characteristics are presented in Table 1.
Neurological manifestations of TSC were frequent, represented with epileptic seizures (68.80%) and cognitive disorders (43.80%).
The majority of patients had cutaneous manifestations of TSC - 83.30% had hypomelanotic cutaneous lesions, and 68.80% had angiofibromas.
Those clinical presentation were followed by multiple renal nodal hamartomas (27.70%), lymphangioleiomyomatosis (12.50%), and cardiac rhabdomyoma (10.60%).
The percentage of patients with CKD diagnosis of the total number of patients was 66.90%, with ESRD development in 39.6%.
Neurological symptoms represented with epiletic sizures were more common in patients in earlier stages of CKD (nonESRD patients) then to patients in end-stage renal disease (ESRD) what is presented in table 2.
Discussion
The main finding of this study is that epileptic seizures and cognitive disabilities are more frequent in earlier stages of CKD.
In our cohort the middle age of patients was 32.3 what is older than mean age of patients in other studies. Vobret and al. reported mean age at the diagnosis of TSC 25, while Zöllner et al. have shown that the mean age at the diagnosis was 29.2 years.9,10
Early detection and better screening for this disease gave opportunity for better control of disease and better long-term outcome related to surveillance and quality of life.11
In analysed group of patients, neurological symptoms represented with epileptic seizures and cognitive disorders where more common in the group of patients in earlier stages of CKD then to patients in end-stage renal disease.
The most common clinical manifestation in out cohort were neurological manifestations (54%). Epilepsy was diagnosed in 68.80% and cognitive disorders in 43.80% of patients.
Those results correlate with the results of the the largest TOSCA registry which included data of 2093 patients, epilepsy was diagnosed in 1748 (83.5%), 451 (54.9%) had a cognitive disability and 1199 (57.3%).
Usage of m-tor inhibitors as a first line of therapy, reduced the size of hamarotma. It has been used to reduce not only renal AMLs but also to reduce subependimal astrocytoma and retinal hamartoma.12
Some studies have shown beneficial efects of usage of mTOR inhibitor not only in regression of volume of angyomilipoma in those group of patients but also in decrease of epileptic seizures
mTOR signaling pathway could also be involved in mechanisms of epileptogenesis. Abnormal cell growth and proliferation as a consequence of mTOR hyperactivation in TSC could indirectly promote excitability of neuronal circuits and promote seizures.13
In our cohort 37.50% of patients received a mTORi.
Possible correlation between renal angiomyolipoma, but especially of patients with polycistic renal damages and neurological manifestation represented with epileptic seizures can be the deletions of the TSC2-PKD1 gene, because of close position of those two genes.14
This study has proven possible correlation between neurological and nephrological symptoms in TSC patients, what can be beneficial also from therapeutic approach.
The main limitiation of this study is small number of patients so further multicentric studies with large number of patients shuld be needed.
Conclusion
This study has shown that neurological manifestations in this cohort of patients represented with epileptic seizure and cognitive disabilities correlates with renal lessions in earlier stages of chronic kidney disease what is novel finding in the light of renal and neurological impairaments in TSC patients.