Characteristics of the study population
Our TSC cohort had a total of 291 patients, of which 117 (40.21%) were 6-16 years old. Sixteen people declined to participate, 86.32% (101/117) of parents signed informed consent, but 6 patients did not complete all the questionnaires (withdrew halfway). Ninety-five patients (81.20%, 95/117) completed the questionnaire, including 46 females (48.42%) and 49 males (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).
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 a history of epilepsy (80.00%), and 49 of the patients with TSC and epilepsy developed drug-resistant epilepsy (64.47%). 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).
Rate of neuropsychiatric disorders in TSC patients and normal controls
A total of 79 (83.16%) children with TSC developed TANDs. Among children with TANDs, the male:female ratio was 41:38. A total of 85.19% (23/27) of the TSC1 gene mutation group, 84.48% (49/58) of the TSC2 gene mutation group and 70.00% (7/10) of the NMI group had neuropsychiatric disorders, but there was no significant difference (p = 0.546). 11 cases (11.58%) occurred in control group. It was significantly lower than in the TSC group (p <0.001).
A total of 16 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), pervasive developmental disorder (PDD) (22.11%, 21/95), (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, PDD, (mild) manic episodes, agoraphobia, tic disorder, separation anxiety disorder, major depressive episode, suicide and obsessive-compulsive disorder were significantly different between the TSC and control groups (p<0.05) (Table 2). Among TSC patients, 73.68% had two or more TANDs. The rates of psychiatric disorders in those with different levels of ID and different genotypes are shown in Supplementary Table 1 and Supplementary Table 2.
Analysis of TAND-related risk factors
Ninety-five children with TSC were divided into the TAND group (n=79) and the without TAND group (n=16). Multivariate logistic regression models found that earlier age of onset (<2 years) (p = 0.03), more frequent seizure frequency (more than once a month) (p =0.04) and use of a greater number of antiepileptic drugs (≥2) (p = 0.04) were closely related to the occurrence of TANDs (Table 3). No significant correlation was found with neoplastic disease (RAML, LAM and cardiac rhabdomyomas), cortical tubers, SENs, or SEGA (p>0.05) (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 (spasm, generalized and focal seizures), TSC gene type, hypomelanotic macules, angiofibromas, shagreen patches, ungual fibromas, cardiac rhabdomyomas, renal angiomyolipoma (RAML), or lymphangioleiomyomatosis (LAM).