September 2026 Research Update

This group of studies adds detail to how changes in TSC1 or TSC2 may lead to tuberous sclerosis complex features in different organs. Overall, one paper showed how a change in the TSC2 gene can disrupt how that gene's own RNA is processed, and the others point to multiple downstream effects of TSC2 loss, including overactive mTOR growth signaling, altered behavior of brain cells and brain support cells, and altered gene control programs in kidney cyst lining cells. Most of the evidence here comes from lab-based work (cells, organoids, and mice), so how directly each result maps to symptoms in people is still uncertain. [1] [2] [3] [4] [5]

One report showed that a DNA change in TSC2 that does not alter the amino acid code (a "synonymous" change) can still be harmful by disrupting RNA splicing, which is the step where cells stitch RNA pieces together before making protein. In this single patient, RNA testing and a lab splicing model both showed abnormal skipping of TSC2 exons, and the authors reclassified the variant as likely disease-causing. [5]

Several lab studies focused on how TSC2 loss affects brain biology. In human stem cell derived neurons, TSC2 knockout cells showed reduced activity of synapse-related genes. When both FMR1 and TSC2 were knocked out, the double knockout cells showed abnormal network activity described as hyperexcitable, along with overactive mTOR signaling, and mostly resembled TSC2 loss rather than showing a correction of these changes. [1]

In human brain organoids and in resected tuber tissue, another study suggested that glial cells (especially astrocytes) may actively contribute to brain changes in tuberous sclerosis complex, not just react to them. Loss of TSC2 pushed developing cells toward enlarged, reactive astrocytes that showed lower glutamate transporter expression and higher release of inflammatory signals, along with higher APOE and CLU expression. [2]

A mouse study focused on kidney cysts and found that the cyst lining cells were mainly a specific kidney cell type (A-intercalated cells) that was actively proliferating. The researchers found increased expression of the transcription factors (gene-control proteins) FOXI1, FOXP1, and DMRT2 in cyst lining cells, and saw FOXP1 and DMRT2 in the cell nucleus. They also found lower HMX2 expression and a loss of B-intercalated cells in the cyst lining. These findings suggest that this gene-control network may help drive cyst development in these TSC mouse models, although the roles of FOXP1 and DMRT2 were not directly tested. [3]

Finally, a computational study screened thousands of possible protein-changing variants in TSC1 and TSC2 and nominated sets of "high-risk" variants predicted to destabilize the proteins or disrupt important regions, including sites related to phosphorylation and protein structure. Because these were computer predictions without direct biological testing, the results are best viewed as a shortlist of variants and mechanisms to confirm in future experiments. [4]

For patients and caregivers, these studies mainly matter as background research that explains why different genetic changes can lead to problems in the brain and kidneys, and why some variants that look "silent" on a DNA report may still affect how the gene works by altering RNA splicing. The lab studies suggest multiple cell-level pathways downstream of TSC2 loss, including neuron network overactivity, reactive astrocyte behavior, and kidney cyst cell identity programs, but it remains uncertain which of these pathways best predicts a person's symptoms or course. Over time, this kind of work can help refine genetic variant interpretation and point researchers toward which cell types and pathways to study more closely in people.

Across three real-world (mostly retrospective) studies, adding purified cannabidiol (CBD) to existing seizure medicines was linked to substantial seizure reduction for many people, including those with tuberous sclerosis complex (TSC). Overall, results suggest roughly half (and in some pediatric settings closer to two-thirds) had their seizures drop by at least half, while others had smaller or no improvements. Side effects were reported fairly often, but the studies described them as mostly mild, and many patients stayed on CBD for a year or longer. [6] [7] [8]

In a multicenter adult cohort that included people with TSC, nearly half had at least a 50% seizure reduction at both 6 months (48.6%) and 12 months (45.9%), and about 6 in 10 had at least a 25% reduction at 12 months. Some caregivers also reported better thinking or behavior (29.7%), and the typical number of other seizure medicines decreased from 4 to 3 over follow-up. Side effects occurred in 64.9%, were mostly mild, and 81.1% of adults were still taking CBD at 12 months. [6]

In a multicenter pediatric cohort of treatment-resistant focal epilepsies that included TSC, 54.4% had at least a 50% seizure reduction and 5.1% became seizure-free during an average follow-up of 30 months. Response rates were reported as similar in TSC compared with non-TSC causes, and abnormal brain-wave activity between seizures improved among responders. Side effects were reported in 29.1%, were mainly mild and temporary, and no serious treatment-related side effects were reported. [7]

A single-center pediatric chart review compared children with FDA-labeled CBD indications (including TSC) to children treated outside those labeled diagnoses, and the proportion with at least 50% seizure reduction was similar (65% vs 63%). The most commonly noted side effects included stomach and bowel symptoms (19%), agitation (7.6%), insomnia (4.9%), and weight loss (6.3%), and drooling or extra secretions (2.8%) were only seen in children also taking clobazam. This study suggests that, in that clinic, tolerability and seizure response looked broadly similar across different epilepsy diagnoses, including TSC. [8]

For families affected by TSC-related seizures, these studies add real-world context to what CBD may look like in day-to-day care: many patients had large seizure reductions, some had smaller changes, and side effects (especially sleepiness or stomach-related symptoms) were not rare. Because these were observational studies without a control group, they cannot prove that CBD caused the improvements or predict who will respond. They are most useful for understanding the range of seizure outcomes seen in clinics over 1 to 2+ years, and what types of side effects clinicians commonly monitor. [6] [7] [8]

This group of papers suggests that treatments affecting the mTOR pathway can help some tuberous sclerosis complex (TSC) problems, but results vary by organ system and person, and the strongest evidence here is still limited. Long-term real-world data supported seizure reduction for some people using everolimus as an add-on treatment, while a single prenatal case showed that shrinking fetal heart tumors did not guarantee stable heart function after birth or improved brain outcomes. Two animal studies explored non-drug brain stimulation and a dietary approach aimed at serotonin-related biology, with behavior changes in rodents that cannot yet be assumed to translate to people. [9] [10] [11] [12]

In a small retrospective cohort of 21 people with TSC-associated epilepsy, everolimus used alongside anti-seizure medicines was linked to responder rates of 53.8% to 64.7% over long follow-up, and seizure-free rates of 33.3% to 41.2%. People who responded tended to have fewer organ systems involved at baseline and were taking fewer anti-seizure medicines at the start, and younger starting age showed a trend toward better response. Because this was a real-world, non-randomized study, it cannot prove everolimus caused the changes for every individual, but it adds information about long-term patterns. [9]

A single case report described a fetus with TSC and severe cardiac rhabdomyomas treated during pregnancy with transplacental sirolimus. The report described marked prenatal tumor shrinkage and improved fetal heart function, but after birth the newborn developed severe left-ventricular dysfunction requiring intensive cardiac support, and later had ongoing epilepsy and developmental delays even though the heart tumors fully regressed by 5 months with postnatal everolimus. This one-patient experience highlights that different TSC features (heart tumors vs brain-related symptoms) may respond differently, and that prenatal improvement may not predict newborn stability. [10]

Two preclinical studies tested approaches not focused on tumor size or seizures, but on autism-relevant social behaviors in Tsc2 models. In rats, repeated anodal transcranial direct current stimulation (tDCS) reduced social avoidance and partially improved some social behaviors, alongside normalization of serotonin levels in brain regions involved in social function. In mice, dietary tryptophan supplementation produced sex-specific social changes (improved sociability in females and social novelty in males) and increased cortical tryptophan, while brain spectroscopy did not show major changes in an excitation/inhibition balance measure. These are laboratory findings in animals and do not establish effectiveness or safety for people with TSC. [11] [12]

For patients and caregivers, this set of studies mainly adds context about how mTOR inhibitors may affect different TSC symptoms over time. The everolimus epilepsy study provides longer-term real-world numbers that some families may find useful as background, but it does not predict what will happen for any one person. The prenatal sirolimus case shows that even when fetal heart tumors shrink before birth, newborn heart function and long-term neurodevelopment can still be complicated, so this evidence is best viewed as an example rather than a general expectation. The brain-stimulation and dietary tryptophan papers are early animal research that may guide future human studies, but they are not evidence of benefit in people yet, and many questions remain about translation, safety, and which outcomes would matter most in daily life. [9] [10] [11] [12]

Across this month s papers, epilepsy procedures for tuberous sclerosis complex (TSC) were reported to help some people reach seizure freedom, but outcomes varied by study and by what was measured. A larger evidence summary suggested MRI guided laser therapy and open surgery had broadly similar seizure control and complication rates, while a smaller pediatric study highlighted that changes in behavior, attention, and language can improve or worsen after surgery and may not track with seizure results. [13] [14]

In a systematic review and meta analysis of 36 studies in MRI visible focal cortical dysplasia type II and TSC, seizure freedom rates were similar between MR guided laser interstitial thermal therapy (MRgLITT) and resective (open) surgery when results were pooled. In the TSC-only analysis, seizure freedom was 50% with MRI-guided laser treatment and 59% with open surgery, a difference that was not statistically significant. Complication rates were reported for the combined TSC and focal cortical dysplasia type II group, where no significant difference was found. Age did not appear to change these overall comparisons in subgroup analyses. [13]

In a retrospective single center study of children with TSC who had epilepsy surgery and at least 12 months of follow up, 13 of 21 surgeries led to complete seizure freedom. Most children improved in at least one neurobehavioral area documented in the TSC associated neuropsychiatric disorders (TAND) framework, especially language and attention, but many also had worsening in at least one area, most often repetitive behaviors or tantrums. These neurobehavioral changes were not clearly related to whether a child became seizure free. [14]

For patients and caregivers, these papers add context for what outcomes can be discussed after epilepsy procedures in TSC: seizure control and procedure related complications are not the only outcomes that may change. The comparison of laser therapy and open surgery comes from pooled results across many studies (with far fewer laser patients than open surgery patients), so the overall message is about broad similarity rather than a guarantee for any one person. The pediatric behavior study suggests some children may see gains in areas like attention or language after surgery, while others may have new or worse challenges such as repetitive behaviors or tantrums, and these shifts may happen even when seizures improve, which remains an area of uncertainty needing more structured, prospective assessment. [13] [14]

Across these studies, kidney and pancreas involvement in tuberous sclerosis complex (TSC) showed wide variation in how aggressive disease can look on imaging and how it behaves over time. One small imaging study highlighted a distinct subgroup with very large cystic kidneys plus angiomyolipomas (benign kidney tumors made of blood vessels, muscle, and fat), while a separate cohort plus literature review described pancreatic neuroendocrine tumors that were usually non-hormone producing and often followed with imaging or treated with surgery or targeted medicines. [15] [16]

In 9 adults with genetically confirmed TSC2/PKD1 contiguous gene deletion syndrome, kidney scans often showed markedly enlarged polycystic kidneys with a high number of cysts, and angiomyolipomas were common (including fat-poor types that can be harder to recognize on imaging). In this small group, many reached kidney failure at a young age, and some had kidney bleeding or needed kidney procedures related to angiomyolipomas. [15]

In a multicenter series of 26 people with TSC and pancreatic neuroendocrine tumors (pNETs), plus a review of 80 published cases, most tumors did not produce hormones (nonfunctioning), and management varied between surgery, medicines that target the mTOR pathway, and active surveillance. Many non-surgical cases stayed stable over time, but some tumors progressed to metastatic disease, and recurrence or metastasis also occurred in some people after surgery. [16]

For patients and caregivers, these papers add detail about two less common but important organ issues in TSC: a specific genetic subtype (TSC2/PKD1 contiguous gene deletion) may come with a heavy kidney cyst burden plus angiomyolipomas and earlier kidney failure, and pancreatic neuroendocrine tumors in TSC are often found on imaging and may remain stable but sometimes spread or return. The kidney report is based on only 9 adults, and the pancreas report combines retrospective data across centers and published cases, so the exact chances of different outcomes remain uncertain.

This months papers show that tuberous sclerosis complex (TSC) may first come to attention through problems in a single organ system, even in adulthood, and only later be recognized as a multi-organ condition. Alongside these medical clues, a separate interview study emphasized that living with TSC often involves ongoing, practical and emotional challenges for both the person affected and their family. Overall, the evidence includes several single-patient case reports and one qualitative interview study, so the details may not apply to everyone but they illustrate real-world pathways to diagnosis and lived experience. [17] [18] [19]

One case report described a 28-year-old woman whose long-standing seizures were already present, but TSC was diagnosed only after evaluation for heavy and irregular uterine bleeding and anemia. Her work-up identified multiple typical TSC features across organs, including facial skin changes, kidney angiomyolipomas, lung involvement, and brain findings, with uterine PEComas considered a likely cause of the bleeding. The authors framed abnormal uterine bleeding as an uncommon first sign that can trigger broader evaluation when other TSC features are also present. [17]

Another single-patient report described a 29-year-old woman who presented with vitreous hemorrhage (bleeding inside the eye) and abnormal blood vessel growth linked to a retinal astrocytic hamartoma. After eye evaluation and genetic testing, she was found to have TSC with a TSC1 gene change, showing how an eye problem can be the doorway to identifying a whole-body condition. In that case, the eye bleeding improved and retinal changes stayed stable during a year of follow-up after a single injection into the eye. [18]

A retrospective case series looked at 12 people with musculoskeletal PEComas (a rare tumor type) and described MRI patterns and outcomes. Most tumors in this series were not linked to TSC and were large, deep, and sometimes extended across tissue compartments, and the reported outcomes included a high rate of spread and death from the tumor over a median 19 months of follow-up. The one TSC-associated tumor in the series looked different on MRI, appearing well-defined and without strong contrast enhancement, but this is based on a single TSC case within the series. [20]

In 34 interviews with people with TSC and family members in Ireland, experiences varied widely, but many described the day-to-day work of managing a condition that can affect multiple organs. Difficult-to-control seizures and TSC-associated learning, behavior, and mental health differences (often grouped as TAND) were described as especially disruptive, and families reported emotional strain, stress, and isolation. Participants also described care as fragmented, felt that health, social, and educational services were often inadequate, and felt that awareness of TSC among healthcare professionals was poor. [19]

For patients and caregivers, this set of studies mainly provides context about how TSC may be recognized and what living with it can feel like, rather than offering new tests or treatments to seek out. The case reports and small series underline that TSC can be identified after an eye problem, unusual uterine bleeding, or a PEComa, but they cannot show how often these paths happen. The interview study adds that beyond medical monitoring, many families experience coordination burdens and emotional stress, and it highlights gaps that may depend on local services and awareness. Uncertainty remains about how generalizable these individual diagnostic stories are, and how widely the reported care-fragmentation experience applies outside the setting studied. [17] [18] [19] [20]