Our TSC cohort had a total of 291 patients, of which 117 (40.21%) were 6-16 years old. After excluding 16 cases, 86.32% (101/117) parents signed the informed consent, but 6 cases did not complete all the questionnaires (withdrew halfway). 95 cases (81.20%, 95/117) completed the questionnaire, including 46 females (48.42%) and 49 male (51.58%), whose average age was 10.02±3.10 years old. All of them are Han people (Table 1). In addition, 95 children with normal development (male: female = 51:44, age 10.3±2.4 years) were recruited (Table 1).
Table 1
Sociodemographic comparison of TSC patients and normal controls
Sociodemographic feature
|
TSC
|
NC
|
χ2/F
|
P value
|
N
|
95
|
95
|
|
|
Male
|
49 (51.58)
|
51 (53.68)
|
0.08
|
0.17
|
Age at interview (years)
|
10.12±3.10
|
10.32±2.41
|
1.66
|
036
|
Paternal education (years)
|
|
|
0.33
|
0.72*
|
≤9
|
35 (36.84)
|
35 (36.84)
|
|
|
9-12
|
20 (21.05)
|
23 (24.21)
|
|
|
>12
|
40 (42.11)
|
37 (38.95)
|
|
|
Maternal education (years)
|
|
|
2.75
|
0.57
|
≤9
|
38 (40.00)
|
30 (31.58)
|
|
|
9-12
|
18 (18.95)
|
27 (28.42)
|
|
|
>12
|
39 (41.05)
|
38 (40.00)
|
|
|
Family income (RMB)
|
|
|
3.42
|
0.09
|
<5000
|
16 (16.84)
|
5 (5.26)
|
|
|
5000-10000
|
51 (53.68)
|
63 (66.32)
|
|
|
>10000
|
28 (29.47)
|
27 (28.42)
|
|
|
Residence
|
|
|
1.37
|
0.11
|
Suburban or rural
|
50 (52.63)
|
58 (61.05)
|
|
|
Urban
|
45 (47.37)
|
37 (38.95)
|
|
|
TSC: tuberous sclerosis complex; NC: normal controls (children with normal nervous system development);
Data were presented as mean ± SD and n (%).
ANOVA F-test for continuous variables, chi-square test for categorical values.
All 95 children were genetically tested, and the TSC1:TSC2: NMI (no mutation identified) ratio was 27:58:10. There were more sporadic cases than familial cases (n = 55 VS n = 40). Sixty-seven children had an intellectual disability (IQ≤70) (70.53%), 34 (35.79%) had mild to moderate intellectual disability (IQ 35-70), and 33 (34.74%) had severe intellectual disability (IQ<35). Of the 95 children, 76 had epilepsy (80.00%). The average age at seizure onset was 2.50±3.59 years, and the duration was 7.65±4.37 years. Eighty-seven patients had cortical tubers, 86 children had subependymal nodules (SENs), and 3 patients had subependymal giant cell astrocytoma (SEGA).
Incidence of neuropsychiatric disorders in TSC patients and normal controls
A total of 77 (81.05%) children with TSC developed TAND. Among children with TAND, the male: female ratio was 39:38. A total of 85.19% (23/27) of the TSC1 gene mutation group, 81.03% (47/58) of the TSC2 gene mutation group and 70.00% (7/10) of NMI group had neuropsychiatric disorders, but there was no significant difference (p = 0.578). 11 cases (11.58%) occurred in control group. It was significantly lower than in the TSC group (P <0.001).
A total of 15 neuropsychiatric diseases were diagnosed, the most common of which was attention-deficit/hyperactivity disorder (ADHD) (51.58%, 49/95), followed by social anxiety disorder (41.05%, 39/95), panic disorder (26.32%, 25/95), specific phobia (26.32%, 25/95), (mild) manic episodes (22.11%, 21/95), agoraphobia (16.84%, 16/95), tic disorder (15.79%, 15/95) and separation anxiety disorder (10.53%, 10/95) (Table 2). ADHD, social anxiety disorder, panic disorder, specific phobia, (mild) manic episodes, agoraphobia, tic disorder, separation anxiety disorder, major depressive episode, suicide and obsessive-compulsive disorder were significantly different between the TSC and the control group (p<0.05)(Table 2). Among TSC patients, 70.53% had two or more TAND. Patients with TSC1/TSC2 mutations were more likely to have multiple TAND (≥2) than children with NMI (p = 0.004).
Table 2
Distribution of neuropsychiatric disorders of TSC patients and normal controls
Neuropsychiatric disorders
|
TSC
|
Normal
|
p value
|
N
|
95
|
95
|
|
ADHD
|
49(51.58)
|
6 (6.32)
|
<0.01
|
Inattentive type
|
27(28.43)
|
3(3.16)
|
|
Combined type
|
13(13.68)
|
2(2.11)
|
|
Hyperactive impulsive
|
9(9.47)
|
1(1.05)
|
|
Social anxiety disorder
|
39(41.05)
|
2(2.11)
|
<0.01
|
Panic disorder
|
25(26.32)
|
0(0.00)
|
<0.01
|
Specific phobia
|
25(26.32)
|
1(1.05)
|
<0.01
|
(Mild) manic episodes
|
21(22.11)
|
0(0.00)
|
<0.01
|
Agoraphobia
|
16(16.84)
|
0(0.00)
|
<0.01
|
Tic disorder
|
15(15.79)
|
0(0.00)
|
<0.01
|
Separation anxiety disorder
|
10(10.53)
|
1(1.05)
|
0.01
|
Oppositional defiant disorder
|
7(7.37)
|
1(1.05)
|
0.07
|
Major depressive episode
|
6(6.32)
|
0(0.00)
|
0.03
|
Suicide
|
6(6.32)
|
0(0.00)
|
0.03
|
Obsessive-compulsive disorder
|
6(6.32)
|
0(0.00)
|
0.03
|
Dysthymia
|
4(4.21)
|
0(0.00)
|
0.12
|
Posttraumatic stress disorder
|
3(3.16)
|
0(0.00)
|
0.25
|
Conduct disorder
|
1(1.05)
|
0(0.00)
|
0.32
|
ADHD: attention-deficit/hyperactivity disorder; Normal: children with normal nervous system development
Data were presented as n (%). Chi-square or Fisher's exact tests for categorical values.
Analysis of TAND-related risk factors
Ninety-five children with TSC were divided into a combined TAND group and an uncombined TAND group. Logistic regression models found that earlier age of onset (<2 years) (P = 0.019), longer duration of epilepsy (≥ 2 years) (P = 0.003), more frequent seizure frequency (more than once a month) (P = 0.024) and use of a greater number of antiepileptic drugs (≥2) (P = 0.029) were closely related to the occurrence of TAND (Table 3). We additionally adjusted for gender (male/female), maternal education (years) (≤9/9-12/>12), paternal education (years) (≤9/9-12/>12), family income (RMB) (<5000/5000-10000/>10000) and residence (suburban or rural/urban) (Table 4). However, there was no significant correlation with seizure type, TSC gene type, hypomelanotic macules, angiofibromas, shagreen patches, ungual fibromas, cardiac rhabdomyomas, renal angiomyolipoma, or lymphangioleiomyomatosis (LAM). No significant correlation was found with neoplastic disease, cortical tubers, SENs, or SEGA (p>0.05) (Table 3).
Table 3
Analysis of factors associated with TAND incidence
Predictor
|
TAND
|
Without TAND
|
p value
|
N
|
77
|
18
|
|
Male
|
39(41.05)
|
10(10.53)
|
0.71
|
Paternal education (years)
|
|
|
0.74
|
≤9
|
29(30.53)
|
6(6.32)
|
|
9~12
|
17(17.89)
|
3(3.16)
|
|
>12
|
31(32.63)
|
9(9.47)
|
|
Maternal education (years)
|
|
|
0.94
|
≤9
|
31(32.63)
|
7(7.37)
|
|
9~12
|
15(15.79)
|
3(3.16)
|
|
>12
|
31(32.63)
|
8(8.42)
|
|
Family income (RMB)
|
|
|
0.36
|
<5000
|
11(11.58)
|
5(5.26)
|
|
5000-10000
|
42(44.21)
|
9(9.47)
|
|
>10000
|
24(25.26)
|
4(4.21)
|
|
Residence
|
|
|
0.07*
|
Suburban or rural
|
37(38.95)
|
13(13.68)
|
|
Urban
|
40(42.11)
|
5(5.26)
|
|
Epilepsy
|
64(67.37)
|
12(12.63)
|
0.12
|
Age at seizure onset(<2y)
|
45(47.37)
|
5(5.26)
|
0.02
|
Duration of epilepsy(≥2y)
|
51(53.68)
|
5(5.26)
|
0.003
|
Seizure frequency ≥ 1/month
|
30(31.58)
|
2(2.11)
|
0.02
|
Spasm
|
20(26.32)
|
1(1.32)
|
0.1
|
Gene
|
|
|
0.58
|
NMI
|
7(7.37)
|
3(3.16)
|
|
TSC1
|
23(24.21)
|
4(4.21)
|
|
TSC2
|
47(49.47)
|
11(11.58)
|
|
Family history
|
36(37.89)
|
4(4.21)
|
0.06
|
Mutation type
|
|
|
0.78
|
Nonsense
|
20(23.53)
|
6(7.06)
|
|
Missense
|
16(18.82)
|
3(3.53)
|
|
Frame shift
|
21(24.71)
|
3(3.53)
|
|
Splicing
|
7(8.24)
|
2(2.35)
|
|
Small deletion
|
2(2.35)
|
1(1.18)
|
|
Large deletion
|
4(4.71)
|
0(0)
|
|
Polytherapy(≥2 AEDs)
|
55(57.89)
|
8(8.42)
|
0.03
|
Hypomelanotic macules
|
72(75.79)
|
18(18.95)
|
0.27
|
Angiofibromas
|
32(33.68)
|
8(8.42)
|
0.82
|
Shagreen patches
|
39(41.05)
|
12(12.63)
|
0.22
|
Ungual fibromas
|
7(7.37)
|
0(0)
|
0.18
|
RAMLs
|
52(54.74)
|
13(13.68)
|
0.7
|
Cardiac rhabdomyomas
|
64(67.37)
|
14(14.74)
|
0.6
|
LAM
|
17(17.89)
|
7(7.37)
|
0.14
|
SENs
|
69(72.63)
|
17(17.89)
|
0.53
|
Cortical tubers
|
70(73.68)
|
17(17.89)
|
0.63
|
SEGA
|
3(3.16)
|
0(0)
|
0.4
|
TAND: tuberous sclerosis-associated neuropsychiatric disorders; TSC: tuberous sclerosis complex;
AED: antiepileptic drugs; NMI: no mutation identified; RAML: Renal angiomyolipoma; LAM: Lymphangioleiomyomatosis; SENs: Subependymal nodules; SEGA: Subependymal giant cell astrocytoma;
Data were presented as n (%). Logistic regression models were used to explore the risk factors for TAND.
Table 4
Risk factors associated with TAND
Predictor
|
TAND
|
Without TAND
|
Crude
|
Adjusted
|
OR (95% CI)
|
OR (95% CI)*
|
Age at seizure onset(<2y)
|
45(47.37)
|
5(5.26)
|
3.66 (1.19, 11.28)
|
4.17 (1.19, 14.66)
|
Duration of epilepsy(≥2y)
|
51(53.68)
|
5(5.26)
|
5.10 (1.64, 15.86)
|
7.44 (1.92, 28.92)
|
Seizure frequency ≥ 1/month
|
30(31.58)
|
2(2.11)
|
5.11 (1.10, 23.81)
|
4.94 (1.98, 24.86)
|
Polytherapy(≥2 AEDs)
|
55(57.89)
|
8(8.42)
|
3.125 (1.09, 8.96)
|
2.98 (1.93, 9.46)
|
TAND: tuberous sclerosis-associated neuropsychiatric disorders;
Data were presented as n (%).
*: adjust for gender (male/female), maternal education (years) (≤9/9-12/>12), paternal education (years) (≤9/9-12/>12), family income (RMB) (<5000/5000-10000/>10000) and residence (suburban or rural/urban).