Investigation Of Physical Development Status Of Children With Tuberous Sclerosis Before And After The Treatment Of Rapamycin And Its Efficiency And Safety

Aim:Tuberous sclerosis complex is a single gene autosomal dominant genetic disease,which pathogenesis is genetic defects leading to excessive activation of mammalian target of rapamyein (mTOR) signaling pathway, the pathway of mTOR plays an important role in aging process. The Inhibition of the mTOR signaling pathway can improve age-related diseases such as cognitive decline, cancer, Alzheimer’s disease,renal and cardiac disease. Rapamycin can inhibit the mTOR signaling pathway specifically, which is a potential drug for delaying aging and treatment of age-related diseases, as well as the molecular targeted therapy drugs of Tuberous sclerosis complex. Currently almost researches about safety of rapamycin are centered on organ transplantation and patients with cancer. This research which is mainly through the retrospective investigation and observational studies, focus on the physical development status of children with TSC, the physical development of TSC children and healthy children who were treated with long term rapamycin and the comparison of the complete blood test, biochemical indicators and side effects after taking rapamycin. Thereafter, we will evaluate the influence and safety of rapamycin on physical development of children.Part one Investigation on physical development status of children with tuberous sclerosis complexMethod:A retrospective study was collected of the physical development (height and weight)of preschool children were diagnosed as tuberous sclerosis complex, who had not been treated with rapamycin in our hospital in October 2012 -2016. Then, all data of the body growth indicators, including the height, weight, and body mass index were compared with that of standard published by the national health and family planning commission of the people’s republic of china.Result: There were total 295 preschool children with TSC in the study group. The infants and young children accounted for 74.24% of the study population. The incidence of epilepsy in the group was 89.83%, intracranial lesions (cortical calcification + subependymal nodules + SEGA) accounted for 72.88%, mental retardation accounted for 72.54%, the incidence of cardiac rhabdomyoma accounted for 13.9%, and the incidence of renal hamartoma was 7.46%. The height of the enrolled children in the normal range accounted for 91.86%, higher than the same age and sex of normal children X+2SD accounted for 4.75%, lower than the same age and sex of normal children X-2SD accounted for about 3.39%. The body weight in the normal range accounted for 94.24%,higher than the same age and sex of normal children X+2SD accounted for 5.7% (the weight of boys was higher than X+2SD accounted for 5.41%, the weight of girls was higher than X+2SD accounted for 5.04%), there were 10 people older than 3 years old, 7 people less than 3 years old.Therefore no patient’s body weight was lower than the same age and sex normal children . The normal range of BMI accounted for 83.39%; the proportion of obese children accounted for 14.24% (the obesity ratio of boy and girl were 10.9% and 17.99% respectively); malnutrition accounted for 2.37%. The proportion of obesity in children with renal disease was 31.03%. 14.24% higher than X + 2SD (10.9% for boys and 17.99% for girls), accounting for 2.37% less than X-2SD. The proportion of BMI above normal was 31.03% in children with renal lesions.Conclusion: The incidence of epilepsy in children with TSC who were under 7-years old was slightly higher than that reported in the literature. The incidence of intracranial lesions and mental retardation were significantly higher than those report,but the incidence of renal hamartoma was obviously lower than the report. Weight growth was similar to that of children of the same age, and BMI was higher than that of normal children, and the proportion of girls was higher than that of boys. There was no significant difference in body height, body weight, and BMI distribution between TSC patients with epilepsy, heart disease and intracranial lesions, but the proportion of BMI in the children with renal disease was higher than normal.Part two Effects of physical development status of children with tuberous sclerosis after the treatment of rapamycin and its efficiency and safetyMethod: This study was a retrospective open clinical trial. Cases of tuberous sclerosis children in our hospital outpatient clinic from September 2014 to December 2016,which is divided into groups according to the inclusion and exclusion criteria. Then given rapamycin therapy after admission. The height, weight, biochemistry, blood routine and side effects were measured before, first and second year after treatment respectively. Finally, whether rapamycin was affected on their physical growth and its safety were analysed in all the data.Results: There were total 122 cases of TSC patients were enrolled in the group. The incidence of epilepsy in the group was 84.43%, intracranial lesions accounted for 74.59%, cardiac rhabdomyoma accounted for 18.85%, renal hamartoma accounted for 10.67%, and mental disorders accounted for 51.64%, children under the age of 3 accounted for 63.93%. The amount of children who were admitted to the group had normal height was 110 in all 122 cases, accounting for 90.16%. The amount of higher than the same age and sex of normal children x+2SD was 9, accounted for 7.38%, the amount of less than the same age and sex of normal children x-2SD was 3, accounting for 2.46%. In the follow-up patients of 1-year rapamycin therapy, the amount of children with normal height was 116 people, accounted for 95.08%, The amount of higher than that of the x+2SD in the normal children of the same age and gender was 6, accounting for 4.92%. No patients had less height than x-2SD. Weight evaluation:The amount of children who were admitted to the group had normal weight was 114 in all cases, accounting for 93.44%. The amount of higher than the same age and sex of normal children x+2SD was 8, accounted for 6.56%, no patients had less weight than normal. After administration of rapamycin for 1 years, the amount of children had normal weight was 114 in all cases, accounting for 93.44%. The amount of higher than the same age and sex of normal children x+2SD was 8, accounted for 6.56%, no patients had less weight than normal. Body symmetry degree evaluation: Body mass index (BMI): The amount of children who were admitted to the group had normal range was 99 in all cases, accounting for 81.15%. The amount of higher than the same age and sex of normal children x+2SD was 21, accounted for 17.21%, the amount of less than the same age and sex of normal children x-2SD was 2, accounting for 1.64%.After 1-year treatment of rapamycin, the amount of children had normal weight was 99, accounting for 81.15%. The amount of higher than the same age and sex of normal children x+2SD was 20, accounted for16.39%, the amount of less than the same age and sex of normal children x-2SD was 3, accounting for 2.46%. Growth rate evaluation: The amount of children who were admitted to the group had normal rate was 109, accounting for 89.34%. There were 8 patients which the growth rate slowed down ,14 patients growth rate increased, though the comparison of growth rate in 22 children with TSC were treated with drug for 1 or 2 years. In the duration of rapamycin treatment, we observed the main side effects were lipid metabolism: 8 presented increased total cholesterol (5.46-6.95mmo / L), accounting for 6.56%, of which 5 presented after treatment for 3 months; 13 presented increased high density lipoprotein (3.47-4.5 mmol / L), accounting for 10.66%, of which 6 presented after treatment for 3 months; 22 presented increased high density lipoprotein(1.61-2.4mmol / (1.82mmol/ L), accounting for 0.82%. The other side effects included loss of appetite(3,28%), oral ulcers(5.74%), abnormal liver function(4.92%).All the level of the side effect were 1-2, and all were transient and returned to normal after symptomatic treatment. No thrombocytopenia and neutropenia, no blood sugar abnormalities and renal dysfunction were observed. The therapy efficiency was then analysed before and after the one-year treatment of rapamycin, and all the symptoms showed no significant difference except for epilepsy, heart disease, depigmentation spots, shagreen patch, and multiple renal nodules.Conclusion: Long-term treatment of rapamycin in children with TSC could alleviate the symptoms of epilepsy, heart disease, depigmentation spots, shagreen patch,multiple renal nodules, and it had no effect on height, weight, body mass index, height annual growth rate, no bone marrow suppression, no abnormal renal function, no blood sugar abnormalities. In our study, we found that the application of rapamycin presented side effects of lipid metabolism, mainly in the total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol. In total cholesterol and LDL cholesterol in children, 52.38 percent appeared elevated number in the early treatment, and there was no cumulative effect during the duration of treatment.63.64% of patients with TSC treated with rapamycin presented increased high-density and lipoprotein cholesterol after the treatment for more than six months. The rest of the drug side effects were mostly transient. There was a transient liver function damage in infants and young children, without sustained liver damage. Therefore in the application of rapamycin in infants and young children, we requires to closely monitor the liver function and the occurrence of other side effects.