ABSTRACT
We conducted a retrospective chart review of 142 patients with tuberous sclerosis complex (TSC) seen in a multidisciplinary clinic between 2008 and 2023 to describe patients' clinical and genetic characteristics, disease severity, therapy, and genetic variations. The most common manifestations of TSC were neurological, dermatological, and renal involvements. Among 100 patients who underwent genetic testing, 26% and 62% were positive for TSC1 and TSC2 variants, respectively, and 12% had no pathogenic variant identified. Specific disease‐causing variants in the TSC gene were characterized in 62.0% of patients. As shown in previous studies, patients in our cohort carrying TSC2 variants tended to have more severe and earlier onset symptoms, including higher rates of skin and renal involvement, infantile spasms, and TSC‐associated neuropsychiatric disorders. We also identified two distinct clinical subgroups: one characterized by predominant renal involvement and the other by more pronounced neurological manifestations. These groups seem to follow different disease courses, suggesting potential for more personalized monitoring and treatment approaches. Our study revealed key differences between TSC patients with TSC1 and TSC2 variants, but the retrospective analysis warrants further research to identify early indicators predicting TSC disease course.
Keywords: epilepsy, renal, TSC1, TSC2, tuberous sclerosis complex
We found key differences between tuberous sclerosis patients with TSC1 and TSC2 variants. Patients carrying TSC2 variants had more severe and earlier‐onset symptoms. We also identified two distinct clinical subgroups which follow different disease courses: one characterized by predominant renal involvement and the other by more pronounced neurological manifestations.
1. Introduction
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by multisystem involvement in various organs such as the brain, kidneys, skin, lungs, and heart [1]. The disorder is caused by pathogenic variants in the TSC1 or TSC2 genes encoding the hamartin and tuberin proteins, respectively [2]. Although the disorder is primarily diagnosed by clinical features [3], next‐generation sequencing enables molecular confirmation when a pathogenic variant is identified in TSC1/TSC2 [4].
Individuals with TSC2 variants often exhibit a more severe phenotype compared to those with TSC1 variants, characterized by an increased prevalence of neurological symptoms such as epilepsy and cognitive impairment [5, 6, 7, 8, 9], as well as a greater likelihood for severe renal manifestations, including renal cysts and angiomyolipoma (AML) [10, 11]. An additional group with no pathogenic variant identified (NPVI) was found to have a higher incidence rate of AML compared to individuals with TSC1 variants but lower than that of individuals with TSC2 variants. However, less severe neurological manifestations were observed in individuals with NPVI compared to those with a known variant on TSC1 or TSC2 [12]. The main theory is that individuals with NPVI have mosaic or deep intronic TSC1/TSC2 pathogenic variants [13].
Safra Children's Medical Center (Sheba Medical Center, Ramat Gan, Israel) has a specialized multidisciplinary clinic dedicated to children and adults with TSC, living in Israel, the West Bank, and Gaza. The clinic brings together experts from various disciplines, including neurology, dermatology, nephrology, ophthalmology, and other specialists based on patient needs. Approximately 160 patients aged 0–45 years are followed up at this clinic.
In this study, we aimed to describe the clinical and genetic characteristics of the patients seen at the TSC clinic, including the severity of the disease, therapy, and genetic variations. Additionally, we aimed to find correlations between patients' genotype and phenotype, to investigate whether TSC1 versus TSC2 precise variant location could imply different disease trajectories. We also examined distinct features of two clinical subgroups within the cohort: (1) renal without epilepsy (Group 1), consisting of individuals with TSC and renal disease but without epilepsy (although additional systemic manifestations could be present), and (2) all other patients (Group 2), which included the remainder of the cohort—the majority of whom had epilepsy.
2. Methods
2.1. Setting and Patients
We conducted a retrospective review of the electronic medical records of patients who were diagnosed clinically or genetically with TSC and were seen at the clinic between 2008 and 2023.
The study was approved by the Institutional ethics committee (approval number 0129‐23‐SMC). The requirement for informed consent was waived due to the study's retrospective design. All data were deidentified.
2.2. Data Collection
The data collected included patients who met the 2021 clinical criteria for TSC or carried a confirmed pathogenic variant associated with the disease [14]. The study population included children living in Israel, the West Bank, and Gaza. Patients under clinic follow‐up without a definitive clinical or genetic diagnosis of TSC were excluded. Most analyses were performed by sequencing of the TSC1/TSC2 genes, while in some cases targeted gene panels, whole exome sequencing, or multiplex ligation–dependent probe amplification (MLPA) were used. In other instances, only brief notes documenting a pathogenic variant, as recorded by the treating physician, were available. Each variant was either reported by a certified laboratory or documented more generally by a clinic physician, allowing reliable assignment to the relevant exonic region (with approximate placement when precise coordinates were unavailable). Variant classification followed validated systems in accordance with the guidelines of the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP). Importantly, formal laboratory diagnostic reports were available for 50 patients only, whereas no formal laboratory reports could be accessed for the rest.
2.3. Statistical Analysis
SPSS software version 28 (IBM Corporation, Armonk, New York, USA) was used for all statistical analysis. To summarize the data, we employed descriptive statistics. Categorical variables were presented as number and frequency (%) and compared using the chi‐square test and Fisher's exact test. To assess the distribution of variables, histograms were used. Since all continuous variables showed nonnormal distribution, they were presented as medians and interquartile ranges (IQR) and compared using the Mann–Whitney test. All statistical tests were two‐sided and p < 0.05 was considered statistically significant.
2.4. Visualization of TSC1 and TSC2 Variants
We used SMART (Simple Modular Architecture Research Tool; https://smart.embl.de) to visualize genetic data by identifying and annotating protein domains and analyzing protein domain architecture [15]. As not all genetic reports were available in Human Genome Variation Society (HGVS)‐compliant notation, we displayed the variants on schematic gene figures. The figure includes all patients with any documented variant, and a Supporting Information: Table S1 lists those with full HGVS specifications.
3. Results
3.1. Patient Demographic and Clinical Characteristics
Approximately 160 patients had available medical records. Eighteen were excluded due to uncertain diagnoses or limited follow‐up data. In total, the medical records of 142 children and adults were included in the study. The patients' demographic and clinical characteristics are summarized in Table 1.
TABLE 1.
Patient demographic and clinical characteristics.
| Characteristic | Study population N = 142 |
|---|---|
| Male, n (%) | 76 (53.5%) |
| Age at diagnosis, years, median (IQR) | 1 (0.3–7.0) |
| Age at first clinic visit, years, median (IQR) | 10.2 (3.1–21.1) |
| Genetic testing, n (%) | 100 (70.4%) |
| Family history of TSC, n (%) | 39 (27.5%) |
| Neurologic manifestations | 136 (95.5%) |
| Epilepsy | 114 (80.3%) |
| Infantile spasms | 30 (21.1%) |
| Brain tubers | 120 (84.5%) |
| Subependymal giant cell astrocytoma | 44 (31.0%) |
| Developmental delay | 67 (47.2%) |
| TSC‐associated neuropsychiatric disorders a | 68 (47.9%) |
| Renal manifestations | 91 (64.1%) |
| Angiomyolipoma | 77 (54.2%) |
| Polycystic kidney disease | 8 (5.6%) |
| Renal cysts | 34 (23.9%) |
| Other manifestations | |
| Skin involvement | 127 (89.4%) |
| Lymphangioleiomyoma | 20 (14.1%) |
| Rhabdomyoma | 45 (31.7%) |
| Ocular | 34 (23.9%) |
Abbreviations: IQR, interquartile range; TSC, tuberous sclerosis complex.
Including anxiety, depression, behavioral problems, and autism.
3.2. Comparison of the Clinical Characteristics of Patients With TSC1 and TSC2 Pathogenic Variants
Among 100 patients (70.4%) in our cohort who underwent genetic testing, 26% had a TSC1 variant, 62% had a TSC2 variant, and 12% had NPVI.
No difference in the male to female ratio was observed between TSC1 variant and TSC2 variant groups. A significantly higher proportion of patients with TSC1 variants had a family history of TSC (57.7% vs. 24.2%, p = 0.002). Patients with TSC2 variants were diagnosed at a statistically significantly earlier median age (0.7 vs. 6.5 years, p < 0.001); also, the median age at first clinic visit differed significantly between groups (5.8 vs. 8.3 years, p < 0.036) (Table 2).
TABLE 2.
Comparison of the demographic and clinical characteristics of patients with TSC1 and TSC2 variants.
| Variable | TSC1 N = 26 | TSC2 N = 62 | Total N = 88 | p |
|---|---|---|---|---|
| Male, n (%) | 12 (46.2%) | 37 (59.7%) | 49 (55.7%) | 0.244 |
| Family history of TSC, n (%) | 15 (57.7%) | 15 (24.2%) | 30 (34.1%) | 0.002 |
| Age at diagnosis, years, median (IQR) | 6.5 (0.7–12.8) | 0.7 (0.1–1.6) | 0.8 (0.3–5.0) | < 0.001 |
| Age at first clinic visit years, median (IQR) | 8.3 (2.5–17.9) | 5.8 (1.0–17.0) | 6.9 (1.3–16.9) | 0.036 |
Abbreviations: IQR, interquartile range; TSC, tuberous sclerosis complex.
3.2.1. Neurological Manifestations
Most patients with TSC variants (95.5%) exhibited neurologic manifestations (epilepsy, radiographic findings, TSC‐associated neuropsychiatric disorders [TAND], and developmental delay) (Table 3). Analysis by neurological manifestations showed that the rate of patients with infantile spasms and TAND was statistically significantly higher in the TSC2 group. Although not statistically significant, there was a trend toward a higher prevalence of patients with developmental delays in the TSC2 group.
TABLE 3.
Comparison of neurological manifestations and epilepsy treatments and responses between patients with TSC1 and TSC2 variants.
| TSC1 N = 26 n (%) | TSC2 N = 62 n (%) | Total N = 88 n (%) | p | |
|---|---|---|---|---|
| All neurological manifestation | 23 (88.5%) | 61 (98.4%) | 84 (95.5%) | 0.076 |
| Epilepsy | 21 (80.8%) | 54 (87.1%) | 75 (85.2%) | 0.515 |
| Infantile spasms | 0 (0%) | 19 (30.6%) | 19 (21.6%) | 0.001 |
| Brain tubers | 20 (76.9%) | 57 (91.9%) | 77 (87.5%) | 0.076 |
| Subependymal giant cell astrocytoma | 6 (23.1%) | 18 (29.0%) | 24 (27.3%) | 0.567 |
| TSC‐associated neuropsychiatric disorders a | 9 (34.6%) | 37 (59.7%) | 46 (52.2%) | 0.037 |
| Developmental delays | ||||
| None | 17 (65.4%) | 26 (41.9%) | 43 (48.9%) | 0.059 |
| Mild | 5 (19.2%) | 21 (33.9%) | 26 (29.5%) | |
| Moderate | 4 (15.4%) | 12 (19.4%) | 16 (18.2%) | |
| Severe | 0 (0%) | 3 (4.8%) | 3 (3.4%) | |
| Antiseizure treatments | ||||
| Number of antiseizure medications used, median (IQR) | 2 (0.8–5.0) | 3.5 (1.0–6.0) | 3 (1.0–5.0) | 0.406 |
| Ketogenic diet | 1 (3.8%) | 13 (21%) | 14 (15.9%) | 0.057 |
| Vagus nerve stimulation | 4 (15.4%) | 8 (12.9%) | 12 (13.6%) | 0.743 |
| Epileptic surgery | 1 (3.8%) | 4 (6.5%) | 5 (5.6%) | 1.00 |
| Deep brain stimulation | 1 (3.8%) | 0 (0%) | 1 (1.1%) | 0.295 |
| mTOR inhibitor | 3 (11.5%) | 14 (22.6%) | 17 (19.3%) | 0.231 |
| mTOR inhibitor response rate | 0 (0%) | 3/14 (21.4%) | 3/17 (17.6%) | 1.00 |
| CBD oil | 2 (7.7%) | 9 (14.5%) | 11 (12.5%) | 0.496 |
| CBD oil response rate | 1/2 (50%) | 4/8 (50%) | 5/10 (50%) | 1.00 |
| Epidiolex | 3 (11.5%) | 15 (24.2%) | 18 (20.5%) | 0.179 |
| Epidiolex response rate | 3/3 (100%) | 10/15 (66.7%) | 13/18 (72.2%) | 0.522 |
Abbreviations: CBD, cannabidiol; IQR, interquartile range; mTOR, mammalian target of rapamycin; TSC, tuberous sclerosis complex.
Including TSC‐associated anxiety, depression, behavioral problems, and autism.
3.2.2. Therapy and Response to Antiepileptic Treatment
We treat epilepsy in patients with TSC using both pharmacological and nonpharmacological approaches [16] (Table 3). No statistically significant difference between TSC groups was observed in the use of any of the regimens or neuromodulation, but a trend toward more frequent use of the ketogenic diet was noted among patients with TSC2 variants.
A positive response to treatment, described as a decline in seizure burden, was observed in 50% of patients treated with artisanal CBD oil and 72.2% of patients treated with Epidiolex; 17.6% of patients treated with an mTOR inhibitor prescribed for neurological reasons showed a positive response to treatment. No statistically significant differences in response rates were found between patients with TSC1 and TSC2. Due to limited data, we could not assess treatment response rates for epileptic surgery, neuromodulation, or ketogenic diet between the two TSC groups.
3.2.3. Renal Manifestations
Over half of patients with TSC variants (58.0%) had renal manifestations (Table 4), including AML, renal cysts, and polycystic kidney disease (PKD). Patients with TSC2 variants had a statistically significantly higher prevalence of these manifestations compared to those with TSC1 variants (69.4% vs. 30.8%, p < 0.01). The prevalence of each renal manifestation was also higher among patients with TSC2 variants compared to those with TSC1 variants, but only AML had a statistically significantly higher prevalence (61.3% vs. 19.2%, p < 0.01). Two patients in our cohort were documented with a TSC2‐PKD1 contiguous gene variant. Both presented with severe epilepsy, including infantile spasms, and PKD. Another patient was identified with mosaicism involving the TSC2‐PKD1 region and presented with a compatible clinical phenotype. Her daughter exhibited a similar clinical presentation; however, no PKD1 deletion variant was detected, including by MLPA analysis.
TABLE 4.
Comparison of renal manifestations and treatments between patients with TSC1 and TSC2 variants.
| TSC1 N = 26 n (%) | TSC2 N = 62 n (%) | Total N = 88 n (%) | p | |
|---|---|---|---|---|
| Any renal manifestation | 8 (30.8%) | 43 (69.4%) | 51 (58.0%) | < 0.01 |
| Angiomyolypoma | 5 (19.2%) | 38 (61.3%) | 43 (48.9%) | < 0.01 |
| Polycystic kidney disease | 0 (0%) | 6 (9.7%) | 6 (6.8%) | 0.174 |
| Renal cysts | 5 (19.2%) | 15 (24.2%) | 20 (22.7%) | 0.612 |
| Renal treatments | ||||
| Renal surgery | 0 (0%) | 3 (4.8%) | 3 (3.4%) | 0.552 |
| Renal endovascular treatment | 0 (0%) | 6 (9.7%) | 6 (6.8%) | 0.174 |
| mTOR inhibitor treatment | 0 (0%) | 10 (16.1%) | 10 (11.4%) | 0.03 |
| mTOR inhibitor response | 0 (0%) | 5/10 (50.0%) | 5/10 (50.0%) | 1.00 |
Abbreviation: mTOR, mammalian target of rapamycin.
Treatment for renal manifestations included renal surgery, renal endovascular treatment, and mTOR inhibitors. None of the patients with TSC1 variants received treatment for renal manifestations. Among the 10 patients with TSC2 variants who were treated with a low dose of the mTOR inhibitor everolimus (5 mg/day [17]), 50% showed a good response. Notably, good response was defined at our clinic as a reduction in AML diameter in contrast to the typical assessment of response based on at least a 50% reduction in AML volume [18].
3.2.4. Skin Manifestations
Skin manifestations, including major and minor criteria of TSC (hypomelanotic macules, facial angiofibroma, shagreen patch, ungual fibromas, confetti skin lesions), were documented in 89.8% (79/88) of patients with TSC variants. Patients with TSC2 variants had a statistically significant higher prevalence of skin manifestations compared to those with TSC1 variants (95.2% vs. 76.9%, p = 0.018).
3.2.5. Lung Manifestations
Among the 88 patients with TSC variants, 9 (10.2%) had lung manifestations (LAM), with no statistically significant differences between those with TSC2 and TSC1 (11.3% vs. 7.7%, p = 1).
3.2.6. Cardiac Manifestations
About a third of patients with TSC variants (30/88, 34.1%) had cardiac involvement (rhabdomyoma). A trend for higher prevalence of cardiac involvement was observed among patients with TSC2 variants compared to those with TSC1 variants (40.3% vs. 19.2%, p = 0.057).
3.2.7. Ocular Manifestations
A quarter of patients with TSC variants (22/88, 25.0%) had ocular involvement, with a statistically significantly higher prevalence observed among patients with TSC2 variants compared to those with TSC1 variants (33.9% vs. 3.8%, p = 0.003).
3.2.8. Variants on the TSC Loci
The TSC variants identified in the cohort are shown in Figure 1 with further details provided in Table S1. As mentioned, specific disease‐causing variants in the TSC gene were characterized in 88 of 142 patients. Overall, 47 (53%) of the variants were single‐nucleotide variants (SNVs) or small insertions/deletions (indels); eight (9%) were large deletions or duplications. No data were available for 33 cases (38%). According to the ACMG classification, 55 (62.5%) of the variants were designated as pathogenic or likely pathogenic, three (3.5%) were reported as variants of uncertain significance (VUS), one as likely benign, and 29 (33%) had no available classification data. All VUS were identified in TSC1; two of them were identical and detected in siblings. A large number of the pathogenic variants were located principally in the GAP‐related domain of TSC2 encoded in exons 36–40. Small truncating lesions were distributed across the TSC1 and TSC2 genes.
FIGURE 1.
A graphic representation of the TSC1 (A) and TSC2 (B) genes as displayed in the SMART database. Information on the different variants in our cohort is displayed on the graphical representations. A total of 46 variants are shown, representing all patients who underwent genetic testing with a positive result that was documented either fully or partially. Recurrent variants were identified among additional family members (details are provided in Table S1). Black—pathogenic/likely pathogenic; Orange—variant of uncertain significance; Blue—benign/likely benign.
3.3. Characterization of TSC Patients With Renal Involvement
TSC is a multiorgan disease, commonly affecting the brain and kidneys. In our clinic, we identified a subgroup of patients with prominent renal disease but minimal or no neurological symptoms. Using epilepsy as an indicator of neurological involvement, we categorized our cohort into two groups: Group 1 (n = 20) with renal involvement but no epilepsy and Group 2 (n = 122) comprising all other patients. The male to female ratio was similar between the two groups. A family history of TSC was significantly less common in Group 1 than in Group 2 (5% vs. 31.1%, p = 0.015). The median age at diagnosis and the median age at the first clinic visit were significantly higher in Group 1 compared to Group 2 (14.0 years [IQR 6.3–21.8] vs. 1.0 year [IQR 0.3–5.0] and 29.7 years [IQR 15.5–39.7] vs. 9.1 years [IQR 2.5–16.8], respectively, p < 0.001 for both comparisons).
3.3.1. Genetic Testing Results
Among the patients who underwent genetic testing, a statistically significant higher prevalence of TSC1 and TSC2 variants was found in Group 2 compared to Group 1 (TSC1: 14.3% vs. 27.9%; TSC2: 35.7% vs. 66.3%, p < 0.001 for both comparisons). In contrast, a higher prevalence of patients with NPVI was observed in Group 1 compared to Group 2 (50.0% vs. 5.8%, p < 0.001).
3.3.2. Neurological Manifestations
Although the patients in Group 1 had renal manifestations and no epilepsy, 75% of them had other neurological manifestations, compared to 99.2% of Group 2 patients (p < 0.001). These neurological symptoms included the presence of brain tubers, subependymal giant cell astrocytomas, and TAND. Brain tubers and TAND were significantly more prevalent in Group 2 compared to Group 1 (p = 0.004 and p < 0.001, respectively) (Table 5). Patients in Group 1 had a lower rate of developmental delays than those in Group 2 (p < 0.001).
TABLE 5.
Comparison of neurological manifestations between patients with renal involvement without epilepsy (Group 1) and all other patients (Group 2).
| Group 1 N = 20 n (%) | Group 2 N = 122 n (%) | Total N = 142 n (%) | p | |
|---|---|---|---|---|
| Any neurological manifestation | 15 (75.0%) | 121 (99.2%) | 136 (95.8%) | < 0.001 |
| Brain tubers | 12 (60.0%) | 108 (88.5%) | 120 (84.5%) | 0.004 |
| Subependymal giant cell astrocytoma | 3 (15.0%) | 41 (33.6%) | 44 (31.0%) | 0.095 |
| TSC‐associated neuropsychiatric disorders a | 3 (15.0%) | 65 (53.3%) | 68 (47.9%) | < 0.001 |
| Developmental delays | ||||
| None | 18 (90.0%) | 57 (46.7%) | 75 (52.8%) | < 0.001 |
| Mild | 1 (5.0%) | 33 (27.1%) | 34 (23.9%) | |
| Moderate | 1 (5.0%) | 20 (16.4%) | 21 (14.8%) | |
| Severe | 0 (0%) | 12 (9.8%) | 12 (8.5%) | < 0.001 |
Including anxiety, depression, behavioral problems, and autism.
3.3.3. Renal Manifestations
As Group 1 included patients with renal manifestations, the prevalence of overall renal involvement, AML, and renal cysts was statistically significantly higher in this group compared to Group 2. In contrast, PKD showed similar prevalence in both groups (Table 6). The rates of all treatments for renal manifestations were higher in Group 1 compared to Group 2; however, only renal endovascular treatment was statistically significantly higher in Group 1 compared to Group 2 (p = 0.03). The response rate to treatment with an mTOR inhibitor for renal reasons was statistically significantly higher in Group 1 compared to Group 2 (25.0% vs. 6.6%, p = 0.021).
TABLE 6.
Comparison of renal manifestations and treatments between patients with renal involvement without epilepsy (Group 1) and all other patients (Group 2).
| Group 1 n = 20 | Group 2 N = 122 | Total N = 142 | p | |
|---|---|---|---|---|
| Any renal manifestation | 20 (100.0%) | 71 (58.2%) | 91 (64.1%) | 0.001 |
| Angiomyolypoma | 18 (90.0%) | 59 (48.4%) | 77 (54.2%) | 0.001 |
| Polycystic disease | 1 (5.0%) | 7 (5.7%) | 8 (5.6%) | 1.000 |
| Renal cysts | 9 (45.0%) | 25 (20.5%) | 34 (23.9%) | 0.02 |
| Treatments | ||||
| Renal surgery | 2 (10.0%) | 4 (3.3%) | 6 (4.2%) | 0.200 |
| Renal endovascular treatment | 5 (25.0%) | 9 (7.4%) | 14 (9.9%) | 0.03 |
| mTOR inhibitor treatment | 6 (30.0%) | 16 (13.1%) | 22 (15.5%) | 0.088 |
| mTOR inhibitor response | 5 (25.0%) | 8 (6.6%) | 13 (9.2%) | 0.021 |
Abbreviation: mTOR, mammalian target of rapamycin.
3.3.4. Other Manifestations
Comparison of other manifestations between patients with renal involvement but no epilepsy (Group 1) and all other patients (Group 2) showed a statistically significant difference in LAM (50% vs. 8.2%, p < 0.001), whereas no difference was observed for other manifestations.
4. Discussion
Our cohort represents a large group of patients with TSC who are seen at a multidisciplinary clinic. This clinic provides enhanced patient follow‐up, enabling clinicians to deliver more effective treatment and facilitating broader research opportunities.
In line with previous reports [4, 7, 19], neurological, dermatological, and renal involvements were the most common manifestations of TSC.
In our cohort, 39 patients (27.5%) had a family history of TSC. Among these, 24 were index cases and 15 were secondarily ascertained through family genetic testing. All patients had some clinical manifestations in addition to genetic findings. Consistent with previous reports [20], most of the secondarily ascertained patients exhibited a milder phenotype. Notably, one large family had seven affected members carrying the same variant, showing variable expressivity: two with severe epilepsy, while the others presented with milder neurological symptoms alongside multisystem involvement including skin, cardiac, and renal manifestations. The most common neurological manifestation was epilepsy with a median of two antiseizure medications, emphasizing the high rates of drug‐resistant epilepsy in these patients [21, 22]. In addition to pharmacological treatment, patients were treated with neuromodulation (mainly vagal nerve stimulation) and neurosurgery. One young adult patient in our cohort was treated with deep brain stimulation. While the literature discusses this method mainly for adults, we believe it should be considered for children with refractory epilepsy who cannot undergo epileptic surgery [23, 24, 25].
Patients in our cohort showed a good clinical response both to artisanal CBD oil and Epidiolex. Similar response rates to Epidiolex among patients with TSC were reported in previous studies [26, 27, 28], which could make it more suitable for this patient population [29].
The prevalence of kidney involvement in our cohort was lower than described in the literature (50% vs. 80%) [30]. This observation may be attributed to the relatively young age of patients in our cohort, as the average age for diagnosing renal involvement is 7 years [31]. The prevalence of lung involvement in our cohort was 14.1%. When considering only the female population, the prevalence was 27%, which is comparable to that described in the literature (30%–40% among females over 18 years) [7, 32]. It should be noted, however, that our cohort includes many females under the age of 18, and as the prevalence of LAM increases with age, this likely accounts for the lower overall frequency observed in our study. The slightly lower percentage may also reflect patients receiving care outside our referral clinic, possibly due to less extensive organ involvement or delayed diagnosis. This is consistent with previous reports suggesting that TSC patients with LAM tend to have milder neurological manifestations [33].
4.1. Comparison of the Characteristics of Patients With TSC1 Variants With Those With TSC2 Variants
Patients with TSC2 variants often present with more severe and early symptoms [34, 35]. This may explain the younger age at first clinic visit and the higher proportion of patients with TSC2 variants in our cohort.
Our cohort includes a large family of seven patients with a TSC1 variant, with a broad interfamilial severity of symptoms [36], two of whom did not have a formal genetic test result. This may explain the statistically significantly higher rate of patients with TSC1 variants and a first‐degree relative with TSC compared to patients with TSC2 variants. Furthermore, de novo variants are often observed in the TSC2 gene, increasing the likelihood of cases with no family history.
Although the prevalence of neurological manifestations was higher among patients with TSC2 variants, they were not statistically significantly different from the rates observed among patients with TSC1 variants. Notably, infantile spasms were significantly more common in the TSC2 group, together with a trend toward a higher rate of developmental delays. Higher rates of infantile spasms were reported in patients with TSC, in correlation with more severe developmental delays [4, 5, 19, 35] and a higher tuber load [35]. Published data suggest that TSC2‐specific variants impact neurodevelopmental and cognitive outcomes in children [8, 37], and influence the risk for epilepsy and infantile spasms [9].
Brain tubers, one of the major neurological signs of TSC, can cause epileptic activity [38]. The prevalence of brain tubers was similar among patients with TSC1 and TSC2 variants in our cohort. The characterization of tuber load in our cohort, including tuber burden, size, and location, was previously reported [35]. TAND, including anxiety, depression, behavioral problems, and autism (not including attention deficit hyperactivity disorder [ADHD]/attention deficit disorder [ADD] and learning disorders), was significantly more prevalent in the TSC2 group. These neurological manifestations impose a high morbidity burden on patients, families, and society [39]. It should be noted that, in our study, the prevalence of TAND was approximately 50% of patients, compared with 80%–90% reported in the literature [39]. This difference is likely attributable to the fact that developmental delay was reported separately and that children with ADHD/ADD and learning disorders were not included in this category. No significant differences were found between antiseizure treatment and response to treatment between the two gene groups. However, the use of a ketogenic diet among patients with TSC2 variants was higher compared to its use among patients with TSC1 variants, suggesting higher rates of patients with drug‐resistant epilepsy in this group.
Patients with TSC2 often experience more severe disease affecting multiple organs, including renal AMLs, LAMs, as well as skin, cardiac, and ocular manifestations [5, 6]. We observed statistically significant higher rates of AML, skin involvement, LAM, rhabdomyomas, and ocular involvement among patients with TSC2 variants compared to those with TSC1 variants.
4.2. Comparison of Patients With Renal Manifestations and no Epilepsy With all Other Patients
The subgroup characterized by renal manifestations with no epilepsy (Group 1) was diagnosed at a later median age, probably due to the absence of seizures in infancy and childhood, which often leads to earlier admissions to medical care [40]. This group had a low rate of patients with a family history of TSC and a higher rate of NPVI. Fifty percent of patients who underwent genetic testing within this group had no identified variant. As described in previous studies, this is most likely attributable to mosaicism or deep intronic alterations [13].
Although this subgroup had statistically significantly fewer tubers observed on magnetic resonance imaging scans, 60% had tubers. The number of tubers, their size, and location could potentially influence the occurrence of seizures and their severity [41]. This group was also characterized by a significantly lower rate of TAND and developmental delays. Up to 90% of patients in this group had normal development during childhood. This difference could indicate a lower involvement of brain tissue in this group but can also be secondary to the association between epilepsy and neurodevelopmental disorders [34, 42]. This observation may be useful for prognosis and predicting future complications. The renal manifestations in this group were more severe, with a greater prevalence of AML and renal cysts.
The effectiveness of mTOR inhibitors in the treatment of AML is well established [11, 18]. The response rate to this treatment was higher in Group 1. The prevalence of LAM in this group was also higher. This relationship between lung and renal manifestations in TSC has been described in several studies [43, 44]. Cardiac manifestations were less prevalent in Group 1. There is a known correlation between cardiac rhabdomyomas and epilepsy in TSC [45]. Cardiac rhabdomyomas can be seen in prenatal ultrasound and in echocardiogram during infancy, which could help in diagnosing patients at an early age.
4.3. Strengths and Limitations
The strength of this study lies in the relatively large cohort of 142 patients with TSC, over 15 years. Despite our relatively large cohort, TSC is a rare disease, and the sample size remains small, making it challenging to derive statistically significant conclusions.
This study's retrospective design is an inherent limitation due to the lack of standardized data collection. The information was gathered from hospital records, and some records had missing data or the summaries were variably detailed.
In addition, our clinic has a large population of younger patients. As some of the TSC symptoms are age‐related, this caused a bias toward manifestations seen at younger ages.
Another limitation of this study is the variability in genetic testing methods and the availability of results, as different commercial laboratories were used, each employing distinct technologies. While most patients underwent targeted gene sequencing, others underwent whole genome sequencing, or epilepsy panels or MLPA. This inconsistency may have influenced the sensitivity and scope of variant detection, potentially leading to underdiagnosis or variability in genotype classification across the cohort. Additionally, comprehensive laboratory diagnostic documentation was obtainable for only 50 patients, while no formal laboratory reports were available for the rest, which may have further limited the uniformity and completeness of genetic data. As for the NPVI group, low‐level mosaicism for TSC genes cannot be ruled out because designated deep sequencing was not performed systematically.
5. Conclusions
Our study revealed key differences between TSC patients with TSC1 and TSC2 variants based on a large cohort of Israeli and Palestinian patients. Patients carrying TSC2 variants tended to have more severe and earlier‐onset symptoms, including higher rates of skin, renal, and lung involvement, as well as drug‐resistant epilepsy, infantile spasms, and TAND. Considering their higher drug‐resistance rates, we recommend more intensive clinical‐neurological monitoring for these patients, with early referrals for treatments such as neuromodulation, neurosurgery, and treatment with cannabidiol. Psychiatric needs should be addressed early in the disease course.
Tailored treatment strategies based on variant type are essential for optimizing care for both groups and for using wisely and efficiently the medical resources. Genetic testing allows for earlier diagnosis of TSC, even before clinical criteria and complications manifest.
We also identified two distinct clinical subgroups: one characterized by predominant renal involvement and the other by more pronounced neurological manifestations. These groups seem to follow different disease courses, suggesting potential for more personalized monitoring and treatment approaches. However, as this observation is based on retrospective data, further research is needed to identify early indicators that could predict future disease course.
Author Contributions
Hila Weisblum Neuman: conceptualization, methodology, resources, data curation, formal analysis, writing – review and editing, writing – original draft. Sara Via Dorembus: conceptualization, methodology, resources, data curation, formal analysis, writing – review and editing, writing – original draft. Omer Shlomovitz: conceptualization, methodology, resources, data curation, formal analysis, writing – review and editing. Shoshana Greenberger: conceptualization, methodology, resources, data curation, formal analysis, writing – review and editing. Einat Lahav: conceptualization, methodology, resources, data curation, formal analysis, writing – review and editing. Sharon Mini‐Goldberger: conceptualization, methodology, resources, data curation, formal analysis, writing – review and editing. Michal Tzadok: conceptualization, methodology, resources, data curation, formal analysis, writing – review and editing. All authors read and approved the final manuscript.
Ethics Statement
The study was approved by Sheba Medical Center's ethics committee (approval number 0129‐23‐SMC). The requirement for informed consent was waived due to the study's retrospective design. All data were deidentified.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Table S1: cge70096‐sup‐0001‐TableS1.docx. TSC variants identified in the TSC clinic cohort.
Acknowledgments
The authors would like to thank Amit Safran from the Morris Kahn Laboratory of Human Genetics at the Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences and National Institute for Biotechnology in the Negev, Ben Gurion University (Beer Sheva, Israel) for assembling the gene's schemes, and Tomer Ziv‐Baran from the Department of Epidemiology and Preventive Medicine, The Faculty of Medical and Health Sciences at Tel Aviv University (Tel Aviv, Israel) for statistical analysis. The authors would also like to thank Yishay Ben‐Moshe from Texas Children's Hospital and Baylor College of Medicine (Houston, Texas, USA), and Ben Pode‐Shakked from the Institute of Rare Diseases at the Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel, for assisting with the revision of this manuscript.
Weisblum Neuman H., Via Dorembus S., Shlomovitz O., et al., “A Retrospective Cross‐Sectional Study of 142 Patients in a Multidisciplinary Tuberous Sclerosis Clinic,” Clinical Genetics 109, no. 4 (2026): 697–706, 10.1111/cge.70096.
Funding: The authors received no specific funding for this work.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1: cge70096‐sup‐0001‐TableS1.docx. TSC variants identified in the TSC clinic cohort.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.