July 2026 Research Update

Across these papers, the main message is that a genetic result can be missed or remain unclear with standard testing, and newer approaches can add information. Two approaches stood out: testing that looks more deeply into non-coding parts of the genes, and lab-based tests that measure whether a specific gene change seems to disrupt normal cell signaling. Even with these tools, some types of changes (such as very low-level mosaicism) can still be hard to detect, and some results need confirmation in broader patient groups. [1] [2]

In a small retrospective series of 7 people who clearly met clinical criteria for tuberous sclerosis complex (TSC) but had no answer after standard gene testing, high-depth targeted sequencing found disease-causing or likely disease-causing TSC2 variants in 4 of 7. All of the identified variants were deep intronic or splice-altering changes, meaning they could be missed if testing focuses mainly on the typical coding regions. The authors also reported that the people with these confirmed TSC2 variants tended to have more severe brain and multi-system involvement in this selected group. [1]

A separate functional genomics study tested thousands of possible TSC2 missense variants in the lab, including measures of the amount of TSC2 protein and how strongly the mTOR pathway was turned on. When these functional results were calibrated and applied to a clinical cohort, 212 of 276 TSC2 missense variants previously labeled as variants of uncertain significance were reclassified. In plain language, this kind of testing is aimed at reducing the number of genetic reports that end with "uncertain" for TSC2 missense changes. [2]

For patients and families, this body of work mainly affects how a genetic result might be interpreted when earlier testing did not find a clear answer or reported an uncertain TSC2 change. Some studies suggest that deeper DNA sequencing (including intronic regions) and lab-based functional testing may clarify a portion of these situations, but the evidence still has limits: some changes may remain undetected (especially low-level mosaicism), and functional tests are not yet the same as long-term clinical outcome data.

Together, the prenatal studies emphasized that diagnosis before birth often relies on putting multiple pieces together: ultrasound and fetal echocardiography, fetal magnetic resonance imaging (MRI) of the brain and heart, and genetic testing for TSC1 and TSC2. The overall direction was that using more than one tool increased the chance of reaching a clearer prenatal diagnosis and describing what organs were involved, although the studies were small and follow-up was limited. [3] [4]

In a retrospective study of 24 fetuses diagnosed with TSC or fetal cardiac rhabdomyomas, fetal brain MRI showed abnormalities in 15 of 23 scanned, most often multiple lesions affecting the area lining the brain ventricles. The authors described a "bright spot" pattern on MRI that helped point toward TSC, and they reported that some diagnoses were made based on imaging alone while others were made genetically. The paper also described how fetal cardiac MRI characterized rhabdomyomas as having a consistent appearance compared with surrounding heart muscle. [3]

A separate case series described three pregnancies with fetal cardiac rhabdomyoma where genetic testing results differed: one involved an inherited TSC2 variant from the father, one involved a new (de novo) TSC1 variant, and one pregnancy declined testing. The report highlighted how genetic information can change recurrence risk discussions and help clarify whether a finding is likely part of TSC, but it reflects only three cases and cannot predict outcomes for most families. [4]

One exploratory database-based analysis looked for links between specific parts (exons) of TSC1 and TSC2 and the presence of cardiac rhabdomyoma. It reported enrichment signals in certain exons (TSC1 exons 15 and 18, and TSC2 exons 37, 38, and 41), suggesting that some genetic locations might be more commonly reported with this heart finding. The authors noted important limitations, including reporting bias in databases and the need for validation. [5]

For families facing suspected TSC during pregnancy, these papers mostly add background on what clinicians may look for and how different tests can complement each other (ultrasound, fetal MRI, and genetic testing). The imaging descriptions may help explain why some fetuses show brain signs on MRI while others are diagnosed mainly through genetics. What remains uncertain is how well specific prenatal imaging patterns or specific gene regions predict later health and development, because studies were small, retrospective, and often had limited long-term follow-up.

Across these studies, a consistent pattern is that many children with tuberous sclerosis complex (TSC) show early and ongoing differences in development and behavior, though the exact mix can vary by child. Evidence from longitudinal cohorts suggests that delays in motor skills can appear in the first year of life and that thinking and daily living skills often remain below age expectations over time. Smaller exploratory work also suggests that epilepsy features and brain lesion burden may relate to cognitive and behavior outcomes, but uncertainty remains because these analyses were limited by sample size and design. [6] [7] [8]

In a prospective study that followed infants from 3 to 12 months, infants with TSC had persistently lower gross motor scores and slower gains than other infants at elevated autism risk and low-likelihood controls. The differences were seen in multiple motor areas, including prone, sitting, and standing skills. This points to motor delay as an early, measurable part of development for some infants with TSC. [6]

In a separate longitudinal cohort of 32 children with TSC, cognitive and adaptive functioning (skills used in everyday life) were generally delayed and relatively stable over time, and 48% met criteria for autism spectrum disorder (ASD) at the most recent assessment. ASD diagnoses were largely stable, and lower adaptive functioning was linked to ASD and to greater social and behavioral impairment. After adjustment, girls showed higher levels of social impairment than boys in this sample. [7]

A small cross-sectional study of 18 children and adolescents with TSC described high epilepsy rates and reported ASD and attention-deficit/hyperactivity disorder (ADHD) in 16.7% each. Earlier epilepsy onset and a higher number of cortical tubers showed trends toward worse cognitive and emotional/behavior outcomes, but these were not statistically significant in this exploratory work. Aggressive behavior scores were higher in participants with ASD compared with ADHD in this sample. [8]

Two additional papers focused on how families participate in research on TSC-related neuropsychiatric and behavioral concerns. In a randomized waitlist-control telehealth caregiver-mediated behavioral program for children aged 12 to 39 months, higher seizure severity and enrollment during the COVID era were linked to completing fewer sessions, and interviews highlighted medical crises and caregiver burden as key reasons families could not finish. Separately, a process paper described how patient advocacy groups and clinicians helped design a decentralized trial for TSC-associated neuropsychiatric disorders, including remote assessments and a structured self-report checklist. [9] [10]

For patients and caregivers, these studies mainly help set expectations about what researchers commonly measure in TSC over time: early motor development in infancy, and later learning, daily living skills, and social/behavior functioning through childhood. They also show that autism-related diagnoses and social challenges can be persistent for many children with TSC, and that seizure severity and medical crises can affect a family ability to stay engaged with time-intensive programs and studies. What remains uncertain is how well findings from smaller or single-center studies apply to all families with TSC, and which specific medical factors most strongly predict an individual childs long-term developmental path.

Across these studies, a consistent pattern was that seizure severity early in life mattered for later outcomes, and that for some people whose seizures do not respond to medicines, non-medication options (devices or procedures) can reduce seizures in carefully selected situations. Evidence ranged from moderate-strength clinical cohort studies to exploratory lab research, so some questions remain about who benefits most and why. [11] [12] [13] [14] [15]

In a single-center adult cohort with tuberous sclerosis complex (TSC) and epilepsy, about 41% were seizure-free at last follow-up, but about 35% had significant disability. Childhood drug-resistant epilepsy was the strongest predictor of persistent seizures in adulthood, and both childhood drug-resistant epilepsy and spasms at seizure onset were linked with disability in adulthood. [11]

For people with TSC-related drug-resistant epilepsy who did not have a removable seizure-causing brain lesion, a multicenter prospective cohort compared vagus nerve stimulation (VNS) plus medicines versus medicines alone for up to 3 years. VNS had higher seizure response rates over time, along with fewer anti-seizure medicines and better measured thinking scores and quality of life at 2 years, with only mild surgical complications reported and no permanent adverse events. [12]

For children with TSC and drug-resistant epilepsy evaluated for epilepsy surgery using stereotactic electroencephalography (sEEG), seizure outcomes were broadly similar whether one sEEG study or multiple sEEG studies were needed, despite greater complexity in the multiple-sEEG group. The study also noted that agreement between initial noninvasive testing (video-EEG and magnetoencephalography) related to whether repeat invasive monitoring was needed. [13]

In a retrospective series of MR-guided laser interstitial thermal therapy (MRgLITT) procedures in children and young adults, most procedures were for brain tumors and about 1 in 5 were for seizure-causing lesions or TSC; results were not given separately for people with TSC. Over half of the epilepsy patients achieved the best seizure outcome category reported (Engel class I), and permanent treatment-related problems were uncommon but did occur (including hearing loss and a visual field deficit). The authors described safety features of newer MRI-guided workflows and reported no trajectory-related bleeding events in this series. [16]

Exploratory work in two TSC mouse models suggested that seizure-related death events occurred after seizure-related breathing stoppage (apnea), most often following tonic seizures. In the same study, vigabatrin reduced clonic seizures but did not prevent tonic seizures or apnea, and treated mice showed heart-signal declines hours before death events. [14]

A conference review summarized early seizure-outcome data for 13 investigational epilepsy treatments being studied across different epilepsy causes, including TSC. Because this was an overview of preliminary reports rather than a single controlled trial, it mainly serves as background on the breadth of therapies under development rather than definitive evidence for any one option. [15]

For patients and caregivers, these papers add context on two fronts: (1) long-term risk, where difficult-to-control seizures and spasms early in life were linked with more ongoing seizure and disability burden in adulthood, and (2) treatment possibilities when medicines are not enough, where VNS and certain surgical or minimally invasive procedures were reported with seizure improvement in selected groups. The animal study helps researchers understand possible body processes involved in seizure-related death, but it does not by itself show what will happen in people. Many results come from retrospective or non-randomized studies, so it is still uncertain how well these outcomes apply across all ages, seizure types, and care settings.

Together, these papers show that kidney involvement is frequent in tuberous sclerosis complex (TSC) and can range from stable findings to bleeding and long-term loss of kidney function. In a real-world clinic population, kidney blood vessel tumors called angiomyolipomas were very common, and older age and larger lesions lined up with more kidney complications. Two single-patient reports add that risk may not always be captured by lesion size alone, especially when lesions are widespread or when someone has only one kidney. [17] [18] [19]

In a retrospective study of 172 people with TSC seen at two Brazilian university hospitals, angiomyolipomas were reported in 91.7% and kidney cysts in 45.2%. Kidney bleeding was reported in 16.6%, invasive kidney procedures in 27.9%, and more advanced chronic kidney disease in 9.9%. Older age was linked to a higher chance of prior kidney bleeding, and more advanced chronic kidney disease was linked to older age, larger angiomyolipomas, and prior bleeding or invasive procedures. [17]

The same study also reported that, among people who met kidney-related indications in that health system, 41.9% were using an mTOR inhibitor (a type of medicine that targets an overactive growth pathway in TSC). When compared at similar ages, female patients had slightly lower estimated kidney filtration on average, with a trend toward larger angiomyolipomas and more kidney procedures. [17]

One case report described a 28-year-old woman with TSC whose kidney function worsened from advanced chronic kidney disease to kidney failure requiring long-term dialysis in about 30 months. Early imaging did not show large angiomyolipomas, but later scans showed the kidneys replaced by many diffuse fat-containing nodules consistent with widespread angiomyolipomas; during pregnancy she had marked protein in the urine and blood in the urine. The authors used this case to highlight that angiomyolipoma size alone may miss some higher-risk situations. [18]

A second case report described a 14-year-old boy with TSC and a congenital solitary right kidney, with multiple angiomyolipomas and cysts but normal kidney function at last follow-up. The report frames having one kidney as a higher-stakes situation for long-term kidney health and describes multidisciplinary follow-up with ongoing surveillance, with discussion of mTOR inhibitors as a possible option to reduce angiomyolipoma burden. [19]

For patients and caregivers, this group of papers mainly reinforces that kidney monitoring in TSC is important because problems can include bleeding, procedures, and gradual loss of kidney function, and these risks can change over time. The larger study suggests that age and kidney lesion burden tend to track with higher complication rates, but the case reports illustrate that an individual can have either unexpectedly rapid decline or stable kidney function depending on their specific kidney pattern (for example, diffuse small lesions or having a single kidney). What remains uncertain from this set of papers is how to best predict, for an individual person, who will progress quickly and which signals (such as urine protein/blood or imaging patterns beyond size) should weigh most heavily in risk assessment.

Across three case reports, heart rhabdomyomas (non-cancerous heart tumors) in infants or a fetus either got smaller on their own over time or shrank after treatment with medicines that target the mTOR pathway (everolimus or sirolimus). These reports suggest that changes in tumor size can happen over months to years, and that close heart monitoring was central to care, but the evidence is limited because each report describes only one patient. [20] [21] [22]

One newborn had a large right-ventricle rhabdomyoma (a heart tumor often linked to TSC, though TSC was not confirmed in this case: genetic testing was not performed and screening for other TSC features was negative) that did not block blood flow or trigger abnormal heart rhythms, and it steadily shrank during conservative management over 2 years. Imaging was used to assess the tumor and track heart function, and no arrhythmias or obstruction were reported during follow-up. [20]

In one 5-month-old infant without symptoms and with negative genetic testing for TSC, an isolated cardiac rhabdomyoma was linked to marked ST-segment elevation on electrocardiogram (ECG) despite no evidence of heart muscle injury on blood tests. Earlier, about 3 months of sirolimus had shrunk the heart tumors and was stopped because of raised liver enzymes; the tumor later disappeared completely, and then a similar mass reappeared without affecting blood flow. The child remained clinically well, with persistent but stable ECG changes, at 10-month follow-up. [21]

One report described prenatal (during pregnancy) maternal everolimus given for a large fetal heart rhabdomyoma that was causing obstruction, in a fetus with a TSC2 mutation. The tumor size decreased before birth and was reported as completely regressed by 5 months after birth; a neonatal blood level supported that the medicine crossed the placenta, and short-term maternal and infant outcomes were reported as normal. The authors emphasized that dosing approaches, safety, and long-term effects still need larger studies. [22]

For families affected by TSC, these reports add real-world examples of the range of ways heart rhabdomyomas can behave: some may shrink over time without invasive treatment, and in select situations medicines that target the mTOR pathway have been used to reduce tumor size, including in pregnancy. Because these are single-patient reports, they cannot show how often these outcomes happen or fully define risks, especially for prenatal treatment and longer-term child development. The consistent takeaway is that serial heart checks (and sometimes lab monitoring with mTOR medicines) were used to watch for obstruction, rhythm problems, side effects, and changes in tumor size. [20] [21] [22]

This group of papers highlights that tuberous sclerosis complex (TSC) can show up in multiple organs beyond the more commonly discussed brain and kidneys. The overall pattern is that careful screening can help detect eye and dental changes that may otherwise be missed, while rare blood vessel problems can present suddenly and require urgent care. Most evidence here is from case reports (single patients or one family), plus one guideline-style review, so the details may not apply to everyone. [23] [24] [25]

An ophthalmology guideline-review covering TSC and other related genetic conditions emphasized structured eye checks to find and track ocular lesions, including retinal astrocytic hamartomas in TSC. It also described eye imaging tools that can help document lesion size and changes over time, while noting gaps in long-term data and differences between published screening schedules. [23]

In a report of two siblings with TSC, the older child had multiple enamel pits, gum fibromas, and dental x-ray signs of pulpal calcifications, while the younger sibling had enamel pits only, showing that even within one family TSC features can differ. Both children had brain imaging that showed subependymal nodules despite neither having seizures, underscoring that visible signs in the mouth may coexist with less obvious findings elsewhere. [24]

A separate case described a 14-year-old girl with TSC who presented with a ruptured abdominal aortic aneurysm and had an uncomplicated recovery after open surgical repair with a graft, with the repair intact on follow-up imaging. The authors stressed that pediatric TSC-related aortic aneurysms are rare and that evidence is limited because most published information comes from isolated cases. [25]

For patients and caregivers, these papers mainly add background about the range of organs TSC can affect and the types of screening clinicians may consider, especially eye exams and dental assessments that can document TSC-related changes. The aortic aneurysm report is a reminder that rare vascular complications have been described, but it does not establish how common they are or exactly who is at risk. Overall, the evidence here is not strong enough to define a single best screening plan for everyone, and the guideline-review itself notes that long-term data and standardized schedules are still limited. [23] [24] [25]

The remaining papers are a mix of uncommon clinical scenarios and early-stage laboratory work. Together, they show how TSC-related questions can arise in very specific situations (like lung surgery decisions, breastfeeding while taking sirolimus, or tumor classification), while preclinical studies focus on tools and cautions for interpreting brain-related immune experiments. Evidence strength is mostly exploratory, dominated by case reports and animal studies, so these reports are best viewed as context rather than general rules. [26] [27] [28] [29] [30]

One case report described robot-assisted removal of the left upper lung lobe for very early-stage lung cancer in a woman with TSC-associated lymphangioleiomyomatosis (LAM), using techniques intended to reduce air leaks. Recovery was uneventful and lung function was reported as preserved at 1 year, with no cancer recurrence reported at just over 1 year. [26]

Another case report measured sirolimus levels in breast milk from a lactating person with TSC taking sirolimus and found detectable levels in all collected samples, while the maternal blood level was much higher. The authors estimated infant exposure would be far below therapeutic levels, but infant blood levels were not measured and safety could not be confirmed from this single report. [27]

A separate single-patient report described a subependymal giant cell astrocytoma (SEGA) in a teenager without clinical signs of TSC, and emphasized the role of lineage-focused tumor staining tests to avoid mislabeling it as a more aggressive brain tumor. The authors noted that without molecular testing they could not definitively prove the tumor was truly sporadic (not related to TSC). [28]

In mouse experiments, researchers found evidence that a gene tool often used to target immune cells (RORgamma-Cre) can also label neurons during embryonic brain development. They argued this could mean some previously reported brain and seizure effects from RORgamma-Cre-driven loss of a TSC gene (TSC1) may have come from changes in neurons, not only immune cells, which could affect how older studies are interpreted. [29]

A zebrafish protocol paper described a method to trigger whole-body inflammatory signaling in a TSC-model larva by injecting an immune messenger (interleukin-6) into the bloodstream, aimed at studying how inflammation might interact with TSC during development. Because this is a methods paper in an animal model, it does not provide direct information about patient outcomes. [30]

For patients, these reports are most relevant when a very specific situation comes up, such as surgery for lung cancer in someone with TSC-related lung cysts, questions about medication transfer into breast milk, or clarifying the diagnosis of a particular brain tumor type. The animal studies mainly matter as background: they may influence how researchers design and interpret future TSC brain and immune studies, but they do not directly change current clinical care. Across all these papers, the biggest uncertainty is how much their results generalize beyond the individual cases or experimental models. [26] [27] [28] [29] [30]