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Objective:To improve clinicians′ understanding of developmental and epileptic encephalopathy (DEE) caused by PPP3CA gene mutation. Methods:Clinical data of a patient with DEE diagnosed in the First Department of Neurology, Hebei Children′s Hospital in September 2018 were collected. The whole-exome sequencing of the proband′s family was performed, and the characteristics of gene mutation were analyzed. Literature review was carried out based on the reported cases related to PPP3CA gene. Results:The proband, a 3 months and 20 days old girl, was admitted to the hospital with a history of paroxysmal confusion with extremities shaking for 2 days. The clinical manifestations included frequent epilepsy seizures and hypoevolutism. Brain magnetic resonance imaging showed that the bilateral frontotemporal extracerebral space was slightly wider. The video electroencephalography showed hyperarrhythmia and a cluster of spastic seizures. Whole exome sequencing of the family revealed that the proband had a heterozygous de novo frameshift truncating mutation in the PPP3CA gene: c.1255-1256delAG (p.Ser419Cysfs*31). From the establishment of the database to May 2022, 8 foreign literatures and 1 Chinese literature were retrieved, and a total of 21 children with PPP3CA gene mutation were reported, with clinical developmental delay, cognitive dysfunction and abnormal electroencephalography activity. Conclusions:The frameshift truncating mutation of the PPP3CA gene (c.1255-1256delAG) is the hereditary etiology of this patient. For cases of frequent seizures with poor efficacy of antiepileptic drugs, and developmental delay, genetic testing should be performed to confirm diagnosis and treatment.
ABSTRACT
Objective@#To investigate the efficacy and safety of rapamycin in children with tuberous sclerosis complex (TSC) associated renal disease.@*Methods@#A prospective self-control study was conducted. The clinical data of 92 children diagnosed with tuberous sclerosis complex associated kidney disease at the People′s Liberation Army General Hospital from January 2011 to January 2019 were collected. The long-term rapamycin treatment for all patients initiated at 1 mg/(m2·d), which was gradually adjusted to reach a blood concentration of 5-10 μg/L. The changes of the maximum diameter of renal lesions in children after rapamycin treatment were observed and analyzed with Wilcoxon test.@*Results@#Ninety-two children, including 52 males and 40 females, who met the criteria were analyzed. Sixty patients had only renal angiomyolipoma(RAML), while 24 patients had only multiple renal cysts(MRC), and 8 patients had both lesions. The age of TSC diagnosis was 16.0 (7.0, 42.0) months, and the age of initial treatment with rapamycin was 63.5 (21.0, 103.0) months. The follow-up lasted for 12.0 (4.0, 23.0) months. Sequencing of TSC1 and TSC2 genes was performed in 54 children with TSC, including 3 patients (6%) with mutations in TSC1 gene and 51 patients (94%) with mutations in TSC2 gene. The maximum RAML diameter before treatment was 7.0 (4.0, 9.0) mm. The best effect reached at 3 months of treatment, with the diameter of 4.0 (0,7.0) mm. The maximum diameters at 6 months, 1 year and 1-2 years were 5.0 (0,9.8) mm, 5.0 (1.5, 8.5) mm, 5.5 (3.0, 9.0) mm, respectively, and were significantly different from the baseline (Z=-2.404,-2.350,-2.750,P=0.016,0.019,0.006, respectively). The maximum diameter after 2-3 years, and ≥3 years were 5.0 (3.9,7.0) mm and 6.0 (1.0, 11.0) mm, without significant difference from the baseline (Z=-0.856,-0.102,P=0.393,0.919, respectively).The maximum diameters of MRC after 3 months, 6 months, 1 year,1-2 years, 2-3 years, and ≥3 years were 11.0 (5.0, 14.0) mm,3.0 (0.0,11.0) mm,5.0 (0,21.0) mm,0 (0,14.0) mm,0 (0,10.0) mm, and 0 (0,18.3) mm, respectively, but were not significantly different rom the baseline (7.0 (5.0, 15.7) mm)(Z=-0.944,-1.214,-1.035,-1.896,-1.603,-1.214,P=0.345,0.225,0.301,0.058,0.109,0.225, respectively).Twenty-nine patients (32%) had oral ulcers during the entire treatment period, and no serious adverse reactions were observed.@*Conclusions@#Rapamycin could decrease the diameter of TSC-related RAML, but could not inhibit the growth of cysts. It is well tolerated in the treatment of renal diseases associated with tuberous sclerosis complex.
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Objective@#To investigate the status of immunization of National Immunization Program (NIP) and its adverse reaction rate in children with tuberous sclerosis.@*Method@#Questionnaire survey was adopted to identify the vaccination coverage and its adverse events; 72 cases of children with tuberous sclerosis and 78 normal controls (healthy children completing age-appropriate NIP) admitted to Chinese People′s Liberation Army General Hospital from December 2014 to November 2015 were involved into this study.@*Result@#The age-appropriate NIP coverage rate of tuberous sclerosis was 36%(26/72). The coverage rate of bacillus calmette-guerin (BCG), hepatitis B vaccine 1st to 3rd doses (HepB1-3), oral poliovaccine 1st dose (OPV1), diphtheria, pertussis and tetanus 1st dose (DPT1), DPT1-3, meningococcal polysaccharide vaccine group A (MPVA), measles amd rubella vaccine/measles vaccine 1st dose (MRV/MCV1), and Japanese encephalitis vaccine 1st dose (JEV1) were 100%(72 cases), 75%(51 cases), 97%(66 cases), 91%(62 cases), 82%(56 cases), 66%(45 cases), 69%(42 cases), and 61%(37 cases) respectively. The reasons why the children did not complete the vaccination plan were that parents were concerned about vaccination-induced seizures or seizures had not been controlled. Among 72 children with TSC, the rate of adverse events or suspected adverse events after vaccination was 17% (12 cases), which was higher than the normal control children (2 cases, 3%) (χ2=8.799, P<0.05). The main adverse events were seizure events, which accounted for 92%(11 cases).@*Conclusion@#The age-appropriate NIP coverage rate among children with tuberous sclerosis is low. The high incidence of adverse events may be associated with a fact that there are some nervous system abnormalities in cases with tuberous sclerosis. TSC children vaccination is relatively safe, with no serious adverse events.
ABSTRACT
<p><b>OBJECTIVE</b>To evaluate the therapeutic effect and safety of rapamycin in treatment of children with tuberous sclerosis complex (TSC) complicated with epilepsy.</p><p><b>METHOD</b>This was an open-label, prospective, self-controlled study. From Sep. 2011 to Sep. 2013, 52 patients with the diagnosis of tuberous sclerosis complicated with epilepsy receiving rapamycin treatment for at least 24 weeks were enrolled.</p><p><b>RESULT</b>Of the 52 children, 34 were male and 18 female. The median age at onset of epilepsy was 4.8 months (4 days-49 months), the median age for treatment with rapamycin was 27 months (4.5-172.5 months). Ten children had a family history of TSC. In 24 children TSC gene detection was carried out, among whom TSC1 mutation was detected in 4 cases and TSC2 mutation in 20. Before rapamycin therapy, 59.62%, (31/52) patients took more than 3 antiepileptic drugs, of whom 10 cases even took more than 5 kinds of antiepileptic drugs. Fifty-two patients received rapamycin treatment for 24 weeks, seizure free rate was 25.00% (13 cases), the total effective rate was 73.08% (38 cases); 31 cases received treatment for 48 weeks, seizure free 6 cases, total effective 23 cases; 17 cases accepted treatment for 72 weeks, seizure free 5 cases, total effective 13 cases; 12 cases received treatment for 96 weeks, seizure free 3 cases, total effective 9 cases. With the decrease of seizure attacks, use of antiepileptic drug types were reduced simultaneously, they had a negative correlation. Before rapamycin therapy, the average frequency of seizures was 70.27 times/d, the number of antiepileptic drug kinds was 1.30. After 24, 48, 72, 96 weeks' treatment, the average seizure frequency was reduced to 1.94-2.80 times /d and the antiepileptic drugs were reduced to 0.83-0.97 kinds. On every visit during the follow-up, blood and urine routine tests, liver and kidney function test showed no abnormality in the 52 cases. The drug dosage was 1 mg/(m(2)×d), average 0.7 mg/d (0.35-1.20 mg/d). Blood concentrations of rapamycin remained below 10 µg/L (average 6.5 µg/L). The main side effect was oral ulcer which happened in 23.08% (12/52). The oral ulcer would disappeared 2-3 days later. 17.31% (9/52 cases) had upper respiratory infection.</p><p><b>CONCLUSION</b>Rapamycin was effective in children with tuberous sclerosis and epilepsy with few adverse reactions. The daily dose of rapamycin for children patients is 1 mg/m(2), which has a certain effect on seizures and a good safety profile.</p>