Tuberous Sclerosis Research Articles

Хирургические методы лечения заболевания почек при туберозном склерозе у детей: серия клинических случаев

Туберозный склероз – это полисистемное, генетически детерминированное, аутосомно-доминантное орфанное заболевание, которым страдает примерно 1 из 10 000 человек во всем мире. Поражение почек при туберозном склерозе является основной причиной смертности, которая обусловлена серьезными осложнениями, самым частым из которых является кровотечение из ангиомиолипом. Особенностью ангиомиолипом почек является то, что они начинают прогрессировать и увеличиваться в объеме с раннего возраста, приводя к прогрессированию хронической болезни почек, при этом риску кровотечения подвергаются ангиомиолипомы более 30 мм в диаметре. Также наиболее значимым поражением почек при туберозном склерозе является наличие поликистоза почек. Большие кисты почек могут также приводить к серьезным осложнениям, таким как сдавление паренхимы почек, выраженное нарушение уродинамики, разрыв кисты. Как правило, для лечения осложнений кист и ангиомиолипом почек используют хирургические методы лечения, о чем будет говориться в статье на примере клинических случаев. Tuberous sclerosis is a multisystem, genetically determined, autosomal dominant orphan disease that affects approximately 1 in 10,000 people worldwide. Kidney damage in tuberous sclerosis is the main cause of mortality, which is caused by serious complications, the most common of which is bleeding from angiomyolipomas. A feature of renal angiomyolipomas is that they begin to progress and increase in volume from an early age, leading to the progression of chronic kidney disease, while angiomyolipomas more than 30 mm in diameter are at risk of bleeding. Also, the most significant kidney damage in tuberous sclerosis is the presence of polycystic kidney disease. Large kidney cysts can also lead to serious complications, such as compression of the kidney parenchyma, severe disturbances in urodynamics, and rupture of the cyst. As a rule, surgical methods of treatment are used to treat complications of cysts and angiomyoliposis of the kidneys, which will be discussed in the article using the example of clinical cases.

Retrospective Analysis of Canadian Adults with Tuberous Sclerosis Complex.

Our study goal was to characterize the relative frequencies of molecular and phenotypic traits of tuberous sclerosis complex (TSC) in a Canadian adult population. Previous studies have sought to identify TSC-related genotypic and phenotypic trends in pediatric cohorts, but little is known about clinical manifestations and severity when it presents in adults. We conducted a retrospective chart review of adult patients seen at the TSC clinic at the University Health Network genetics clinics (Toronto, Ontario) to compare trends in the relative frequency of TSC manifestations with genotype. Fifty-one patients were eligible for this study. Eight patients had a pathogenic/likely pathogenic variant in the tuberous sclerosis complex 1 (TSC1) gene, 18 had a tuberous sclerosis complex 2 (TSC2) pathogenic/likely pathogenic variant, 6 patients had multiple variants identified in TSC1/TSC2 or TSC2/PKD1, 11 had no mutation identified (NMI) and 8 had no genetic testing done. Patients with a pathogenic/likely pathogenic variant in TSC2 presented with an increased involvement of multiple systems and a higher frequency of TSC-related manifestations relative to the other mutation groups. Previous studies comparing the wide phenotypic variability with TSC genotype have mainly comprised pediatric cohorts. With a focus on adults, we found trends to be similar across previous literature. An informed multidisciplinary approach should be taken to ensure proper surveillance and management of adults with TSC until a correlation between genotype and phenotype, especially past infancy, is better understood.

A Case of Tuberous Sclerosis Presenting with Gelastic Seizures

A Case of Tuberous Sclerosis Presenting with Gelastic Seizures

Hyperactive mTORC1 in lung mesenchyme induces endothelial cell dysfunction and pulmonary vascular remodeling.

Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease caused by tuberous sclerosis complex 1/2 (TSC1/2) gene mutations in pulmonary mesenchymal cells, resulting in activation of the mechanistic target of rapamycin complex 1 (mTORC1). A subset of patients with LAM develop pulmonary vascular remodeling and pulmonary hypertension. Little, however, is known regarding how LAM cells communicate with endothelial cells (ECs) to trigger vascular remodeling. In end-stage LAM lung explants, we identified EC dysfunction characterized by increased EC proliferation and migration, defective angiogenesis, and dysmorphic endothelial tube network formation. To model LAM disease, we used an mTORC1 gain-of-function mouse model with a Tsc2 KO (Tsc2KO) specific to lung mesenchyme (Tbx4LME-Cre Tsc2fl/fl), similar to the mesenchyme-specific genetic alterations seen in human disease. As early as 8 weeks of age, ECs from mice exhibited marked transcriptomic changes despite an absence of morphological changes to the distal lung microvasculature. In contrast, 1-year-old Tbx4LME-Cre Tsc2fl/fl mice spontaneously developed pulmonary vascular remodeling with increased medial thickness. Single-cell RNA-Seq of 1-year-old mouse lung cells identified paracrine ligands originating from Tsc2KO mesenchyme, which can signal through receptors in arterial ECs. These ECs had transcriptionally altered genes including those in pathways associated with blood vessel remodeling. The proposed pathophysiologic mesenchymal ligand-EC receptor crosstalk highlights the importance of an altered mesenchymal cell/EC axis in LAM and other hyperactive mTORC1-driven diseases. Since ECs in patients with LAM and in Tbx4LME-Cre Tsc2fl/fl mice did not harbor TSC2 mutations, our study demonstrates that constitutively active mTORC1 lung mesenchymal cells orchestrated dysfunctional EC responses that contributed to pulmonary vascular remodeling.

Predictive model for epileptogenic tubers from all tubers in patients with tuberous sclerosis complex based on 18F-FDG PET: an 8-year single-centre study

BackgroundMore than half of patients with tuberous sclerosis complex (TSC) suffer from drug-resistant epilepsy (DRE), and resection surgery is the most effective way to control intractable epilepsy. Precise preoperative localization of epileptogenic tubers among all cortical tubers determines the surgical outcomes and patient prognosis. Models for preoperatively predicting epileptogenic tubers using 18F-FDG PET images are still lacking, however. We developed noninvasive predictive models for clinicians to predict the epileptogenic tubers and the outcome (seizure freedom or no seizure freedom) of cortical tubers based on 18F-FDG PET images.MethodsForty-three consecutive TSC patients with DRE were enrolled, and 235 cortical tubers were selected as the training set. Quantitative indices of cortical tubers on 18F-FDG PET were extracted, and logistic regression analysis was performed to select those with the most important predictive capacity. Machine learning models, including logistic regression (LR), linear discriminant analysis (LDA), and artificial neural network (ANN) models, were established based on the selected predictive indices to identify epileptogenic tubers from multiple cortical tubers. A discriminating nomogram was constructed and found to be clinically practical according to decision curve analysis (DCA) and clinical impact curve (CIC). Furthermore, testing sets were created based on new PET images of 32 tubers from 7 patients, and follow-up outcome data from the cortical tubers were collected 1, 3, and 5 years after the operation to verify the reliability of the predictive model. The predictive performance was determined by using receiver operating characteristic (ROC) analysis.ResultsPET quantitative indices including SUVmean, SUVmax, volume, total lesion glycolysis (TLG), third quartile, upper adjacent and standard added metabolism activity (SAM) were associated with the epileptogenic tubers. The SUVmean, SUVmax, volume and TLG values were different between epileptogenic and non-epileptogenic tubers and were associated with the clinical characteristics of epileptogenic tubers. The LR model achieved the better performance in predicting epileptogenic tubers (AUC = 0.7706; 95% CI 0.70–0.83) than the LDA (AUC = 0.7506; 95% CI 0.68–0.82) and ANN models (AUC = 0.7425; 95% CI 0.67–0.82) and also demonstrated good calibration (Hosmer‒Lemeshow goodness-of-fit p value = 0.7). In addition, DCA and CIC confirmed the clinical utility of the nomogram constructed to predict epileptogenic tubers based on quantitative indices. Intriguingly, the LR model exhibited good performance in predicting epileptogenic tubers in the testing set (AUC = 0.8502; 95% CI 0.71–0.99) and the long-term outcomes of cortical tubers (1-year outcomes: AUC = 0.7805, 95% CI 0.71–0.85; 3-year outcomes: AUC = 0.8066, 95% CI 0.74–0.87; 5-year outcomes: AUC = 0.8172, 95% CI 0.75–0.87).ConclusionsThe 18F-FDG PET image-based LR model can be used to noninvasively identify epileptogenic tubers and predict the long-term outcomes of cortical tubers in TSC patients.

Cerebral vascular and blood brain-barrier abnormalities in a mouse model of epilepsy and tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a genetic disorder, characterized by tumor formation in the brain and other organs, and severe neurological symptoms, such as epilepsy. Abnormal vascular endothelial growth factor (VEGF) expression may promote angiogenesis in kidney and lung tumors in TSC and has been identified in brain specimens from TSC patients, but the role of VEGF and vascular abnormalities in neurological manifestations of TSC is poorly defined. In this study, we investigated abnormalities in brain VEGF expression, cerebral blood vessel anatomy, and blood-brain barrier (BBB) structure and function in a mouse model of TSC. Tsc1GFAP CKO mice were used to investigate VEGF expression and vascular abnormalities in the brain by Western blotting and immunohistochemical analysis of vascular and BBB markers. Invivo two-photon imaging was used to assess BBB permeability to normally impenetrable fluorescently labeled compounds. The effect of mechanistic target of rapamycin (mTOR) pathway inhibitors, VEGF receptor antagonists (apatinib), or BBB stabilizers (RepSox) was assessed in some of these assays, as well as on seizures by video-electroencephalography. VEGF expression was elevated in cortex of Tsc1GFAP CKO mice, which was reversed by the mTOR inhibitor rapamycin. Tsc1GFAP CKO mice exhibited increased cerebral angiogenesis and vascular complexity in cortex and hippocampus, which were reversed by the VEGF receptor antagonist apatinib. BBB permeability was abnormally increased and BBB-related tight junction proteins occludin and claudin-5 were decreased in Tsc1GFAP CKO mice, also in an apatinib- and RepSox-dependent manner. The BBB stabilizer (RepSox), but not the VEGF receptor antagonist (apatinib), decreased seizures and improved survival in Tsc1GFAP CKO mice. Increased brain VEGF expression is dependent on mTOR pathway activation and promotes cerebral vascular abnormalities and increased BBB permeability in a mouse model of TSC. BBB modulation may affect epileptogenesis and represent a rational treatment for epilepsy in TSC.

Distribution of shagreen patches and fibrous cephalic plaques in patients with tuberous sclerosis complex: A retrospective cohort study

Distribution of shagreen patches and fibrous cephalic plaques in patients with tuberous sclerosis complex: A retrospective cohort study

Cancer Predisposition Syndromes in Neuro-oncology.

Although most primary central and peripheral nervous system (NS) tumors occur sporadically, there are a subset that may arise in the context of a cancer predisposition syndrome. These syndromes occur due to a pathogenic mutation in a gene that normally functions as a tumor suppressor. With increased understanding of the molecular pathogenesis of these tumors, more people have been identified with a cancer predisposition syndrome. Identification is crucial, as this informs surveillance, diagnosis, and treatment options. Moreover, relatives can also be identified through genetic testing. Although there are many cancer predisposition syndromes that increase the risk of NS tumors, in this review, we focus on three of the most common cancer predisposition syndromes, neurofibromatosis type 1, neurofibromatosis type 2, and tuberous sclerosis complex type 1 and type 2, emphasizing the clinical manifestations, surveillance guidelines, and treatment options.

Tuberous sclerosis with lung involvement

Tuberous sclerosis with lung involvement

Efficacy and Safety of Topical Sirolimus for the Treatment of Angiofibromas in Tuberous Sclerosis: a Systematic Review and Meta-analysis

Efficacy and Safety of Topical Sirolimus for the Treatment of Angiofibromas in Tuberous Sclerosis: a Systematic Review and Meta-analysis

Tuberous sclerosis complex, Clinic and pathology manifestations, Mini -review

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous syndrome that affects almost all of the organs of the body, including the brain, heart, lungs, liver, and kidneys. Brain tumors in TSC patients include cortical tubers, subependymal nodules (SENs), and Subependymal giant cell astrocytomas (SEGAs). Seizures that occur in 92% of patients with TSC are an important cause of sudden deaths in them. Other organ involvement includes renal angiomyolipomas, lymphangioleiomyomatosis, cardiac rhabdomyomas, and cutaneous manifestations (hypomelanotic macules, angiofibroma, ungual fibromas, shagreen patch, and ‘confetti’ skin lesions). There is a criterion for tuberous sclerosis complex that consists of 11 major and 6 minor clinical features that diagnosis occurs based on it. The best way for a definitive diagnosis of TSC in a patient is by using genetic tests and histopathology. Immunohistochemistry is a helpful method in confirming the diagnosis of brain tumors in TSC. Immunostaining of SEGA shows positivity for GFAP and S-100 protein while neurofilament and synaptophysin are negative. Ki-67, which indicates nuclear proliferation, has a low proliferation index in immunostain. In an aggressive tumor, hydrocephalus, rising intracranial pressure and focal neurologic deficit, surgery is a necessity and can improve outcomes. Brain and kidney involvement in this disease is life-threatening. Brain involvement in these patients can lead to extensive neuropsychological complications, so the aim of this study is a concise review of the variable manifestations of this disease with a focus on the histopathological findings of brain involvement.

Early development of the Tsc1 Purkinje cell specific mouse knockouts.

Tsc1 is a gene which expression results in hamartin, a protein involved in regulation of the mTOR1 pathway. Inactivation of Tsc1 gives rise to hyperactivation of the mTOR1 machinery, increased proliferation and growth of cells with subsequent cell degeneration and cell death. In humans, mutations of Tsc1 result in an inherited disorder ‑ tuberous sclerosis complex (TSC) with the concomitant multiorgan non‑malignant tumors (tubers), epileptic seizures and autistic‑like manifestations. General mouse knock‑outs, homozygous for the inactivated Tsc1 alleles do not survive and die at early embryonal stages. To circumvent this problem, we utilized the Cre/loxP system and removed Tsc1 specifically in Purkinje cells using the pcp2/L7Cre mouse strain and the Tsc1tmDjk/J strains. Because of the published results showing the autistic‑like symptoms after the same crossbred, we have decided to look closer at the early postnatal period of these mutants. Surprisingly no evidence of any behavioral alterations were found, including the ultrasonic vocalizations of newborns. We decided to focus more attention on the interpretation of data, including a more detailed statistical evaluation of our results.

Clinical characteristics and genetic analysis of two children with Tuberous sclerosis complex

To explore the clinical characteristics and genetic variants in two children with Tuberous sclerosis complex (TSC). Two children who had presented at the Children's Hospital Affiliated to Zhengzhou University respectively in June 2020 and July 2021 were selected as the study subjects. Clinical data of the children were collected, and potential pathogenic variants were screened by whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing of their family members. Child 1 was a 7-month-and-29-day-old male, and child 2 was a 2-year-and-6-month-old male. Both children had shown symptoms of epileptic seizures and multiple hypomelanotic macules. Genetic testing revealed that both children had harbored de novo variants of the TSC2 gene, namely c.3239_3240insA and c.3330delC, which were unreported previously. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were rated as pathogenic (PVS1+PS2+PM2_Supporting). This study has uncovered the genetic etiology for two children with TSC. Above findings have also enriched the phenotypic and mutational spectrum of TSC in the Chinese population.

Subependymal giant cell astrocytoma, report of a rare case

Tuberous sclerosis complex (TSC) is a rare genetic disease that is inherited autosomal dominantly and may be associated with subependymal giant cell astrocytoma (SEGA) in 10-20% of cases. Different phenotypes are related to the form of lesions in different parts of the body, including skin, brain, kidneys, lungs, and heart. The age of the patient, the location of the tumor, and associated skin or neurological lesions may guide the pathologist for a definite diagnosis. Here we report a case of SEGA in an adolescent with TSC. Neurological clues including seizure and mental retardation, facial angiofibroma, renal mass, and histopathology examination of the brain tumor culminated in the diagnosis of TSC and SEGA.

Clinical outcomes of fetuses with cardiac rhabdomyoma: A case series from a tertiary center.

The study aims to evaluate the genetic and clinical outcomes of fetal cardiac rhabdomyoma in our tertiary center. Data of cases with cardiac rhabdomyoma detected by fetal echocardiography during antenatal follow-up were analyzed retrospectively. Nine cases were included in the study. The incidence of cardiac rhabdomyoma was 0.003%. The median fetal diagnosis time was 26th weeks, the most common location was the LV. There was no hemodynamic disorder requiring cardiovascular intervention in any of the cases. Of the eight genetically tested cases, four were tuberous sclerosis complex (TSC) gene-negative, one hereditary TSC2, one de novo TSC1, and two de novo TSC2 gene mutants. Postnatal first-year survival rate of the cases was 88.8%. Cardiac rhabdomyoma is a rare fetal and pediatric pathology that generally is a remarkable finding in the clinical process of TSC. Therefore, cases should be evaluated multisystemically and genetic counseling should be given to the family.

The Evolving Landscape of Therapeutics for Epilepsy in Tuberous Sclerosis Complex.

Tuberous sclerosis complex (TSC) is a rare multisystem genetic disorder characterized by benign tumor growth in multiple organs, including the brain, kidneys, heart, eyes, lungs, and skin. Pathogenesis stems from mutations in either the TSC1 or TSC2 gene, which encode the proteins hamartin and tuberin, respectively. These proteins form a complex that inhibits the mTOR pathway, a critical regulator of cell growth and proliferation. Disruption of the tuberin-hamartin complex leads to overactivation of mTOR signaling and uncontrolled cell growth, resulting in hamartoma formation. Neurological manifestations are common in TSC, with epilepsy developing in up to 90% of patients. Seizures tend to be refractory to medical treatment with anti-seizure medications. Infantile spasms and focal seizures are the predominant seizure types, often arising in early childhood. Drug-resistant epilepsy contributes significantly to morbidity and mortality. This review provides a comprehensive overview of the current state of knowledge regarding the pathogenesis, clinical manifestations, and treatment approaches for epilepsy and other neurological features of TSC. While narrative reviews on TSC exist, this review uniquely synthesizes key advancements across the areas of TSC neuropathology, conventional and emerging pharmacological therapies, and targeted treatments. The review is narrative in nature, without any date restrictions, and summarizes the most relevant literature on the neurological aspects and management of TSC. By consolidating the current understanding of TSC neurobiology and evidence-based treatment strategies, this review provides an invaluable reference that highlights progress made while also emphasizing areas requiring further research to optimize care and outcomes for TSC patients.

Solitary atrial Rhabdomyoma in an infant with tuberous sclerosis: a case report and review of the literature

BackgroundDespite its rare incidence of 1/40,000, fetal cardiac rhabdomyoma (CR) represents the prevailing type of benign cardiac fetal tumors, which commonly affects the ventricles. Fetal CRs rarely occur in the right atrium. Thus, the presentation of atrial fibrillation and premature atrial contractions (PAC) due to a solitary cardiac rhabdomyoma is an extremely rare scenario. Our literature review found that only 2% (1 out of 61) of rhabdomyoma cases were found in the right atrium. The majority of fetal cardiac rhabdomyomas are associated with tuberous sclerosis complex (TSC).Case presentationA 7-day-old male neonate presented with arrhythmias and an atrial mass for further evaluation. Echocardiography revealed a hyperechoic, round, uniform right atrial mass (25 mm). An abdominal and testicular ultrasound showed multiple thin-walled cortical cysts in both kidneys and a scrotal hydrocele, respectively. His laboratory workup was insignificant except for hypomagnesemia. Electrocardiography revealed junctional rhythm and PACs with wave distortions. A brain magnetic resonance imaging scan revealed multiple subependymal lesions on the frontal and occipital horns of the lateral ventricles. These findings (Fig. 1), along with a family history of TSC, confirmed the diagnosis of TSC with associated CR. The patient was treated symptomatically with an anti-convulsant and monitored with regular follow-ups. Surgical resection was not required.ConclusionDespite CR’s predominance in the ventricles, a diagnosis of rhabdomyoma should be kept in mind in the presence of a solitary atrial mass and PACs. Physicians should evaluate systemic findings related to TSC and provide appropriate follow-up and family screening. Surgical resection is not always required, and symptom management can be achieved through medical treatment alone.

Effectiveness and safety of everolimus treatment in patients with tuberous sclerosis complex in real-world clinical practice

BackgroundThe randomised double-blinded placebo-controlled EXIST-1–3 studies have showed everolimus effective with adverse effects reported as acceptable in treatment of symptoms in patients with tuberous sclerosis complex (TSC), although evidence of outcomes in clinical practice remains limited. This study aimed to investigate, in clinical practice, the effectiveness and safety of everolimus for epilepsy, renal angiomyolipoma (rAML), and subependymal giant cell astrocytoma (SEGA) in patients with TSC.ResultsThe study included 64 patients with TSC (median age: 19, range 0.9–54 years) receiving everolimus treatment (Norway: n = 35; Denmark: n = 29). Among 45 patients with epilepsy, 14 (31%) were responders experiencing ≥ 50% reduction in seizure frequency in the last 3 months of treatment compared with the last 3 months before treatment. Nineteen (42%) patients changed their anti-seizure medications (ASMs). Responders were more common among patients < 18 years (46%) than among patients ≥ 18 years (14%, p = 0.03). In 29 patients with rAML, everolimus reduced (≥ 30% decrease) and stabilized (< 20% increase, ≤ 30% decrease) longest diameter of rAML in 38% and 59%, respectively, after a mean treatment duration of 37 months. SEGA volume was reduced in three patients by 71%, 43%, and 48% after 39, 34, and 82 months. Adverse effects were reported in 61 of 64 patients (95%) after a median treatment duration of 31 months (range 0–106), with oral ulceration/stomatitis (63%) and upper respiratory tract infections (38%) being the most common. The most common laboratory abnormalities were increased cholesterol (41%), anaemia (30%), and leucopoenia (25%). Grade 3–4 adverse effects were reported in 36% of cases, and life-threatening conditions were reported in two patients. Nine patients discontinued everolimus treatment.ConclusionsSeizure reduction in this study sample was consistent with results from EXIST, but might be lower than expected, given that changes in concomitant ASMs are part of clinical practice. Seizure reduction was associated with younger age. As with EXIST, everolimus reduced or stabilised rAML size in most patients. SEGA volume was reduced in all three patients. Close follow-up is needed for this group, especially for children and patients who may not be able to report adverse effects.

Aberrant DJ‐1 expression underlies L‐type calcium channel hypoactivity in dendrites in Alzheimer’s disease (AD) and tuberous sclerosis complex (TSC)

AbstractBackgroundL‐type voltage‐dependent Ca2+ channels (L‐VGCC) dysfunction is implicated in several neurological and psychiatric diseases. While a popular therapeutic target, it is unknown if molecular mechanisms leading to disrupted L‐VGCC across neurodegenerative disorders is conserved. Importantly, L‐VGCC integrate synaptic signals to facilitate a plethora of cellular mechanisms; however, mechanisms that regulate L‐VGCC channel density and subcellular compartmentalization are understudied.MethodThe following methods were used: bioinformatics; RNA immunoprecipitation; Surface Sensing of Translation–Proximity Ligation Assay (SUnSET‐PLA); calcium imaging, immunocytochemistry; Western blots, dissociated hippocampal neurons and acute hippocampal slices from APP/PS1 mouse mode of AD and Tsc1 conditionally knockout mice; Postmortem human prefrontal cortex tissue.ResultHerein, we report that in disease models with overactive mammalian target of rapamycin complex 1 (mTORC1) signaling (or mTORopathies), deficits in dendritic L‐VGCC activity are associated with increased expression of the RNA‐binding protein (RBP) DJ‐1. DJ‐1 binds the mRNA coding for the alpha and auxiliary Ca2+ channel subunits CaV1.2 and alpha2delta2 (α2δ2), and represses their mRNA translation, only in the disease states, specifically preclinical models of Alzheimer’s disease (AD) and tuberous sclerosis complex (TSC). In agreement, DJ‐1 mediated repression of CaV1.2/α2δ2 protein synthesis in dendrites is exaggerated in mouse models of AD and TSC, resulting in deficits in dendritic L‐VGCC calcium activity. These preclinical findings are recapitulated in the synaptic and dendritic regions of prefrontal cortices of humans diagnosed with AD.ConclusionDiscovery of DJ‐1 regulated L‐VGCC activity in dendrites in TSC and AD provides a new signaling pathway that can be targeted in clinical mTORopathies.

Optimization, Formulation, and Stability of Topical Rapamycin Used for Rare Tuberous Sclerosis Disease: from Ointment to Liposomes

IntroductionTopical rapamycin has been established as an effective and safe therapy for facial angiofibromas in tuberous sclerosis. Different formulations have been tested for this skin disease, most using an ointment as a vehicle.PurposeTo improve the classical formulation of topical rapamycin and to determine the validity period of the proposed options based on chemical, physical, and microbiological stability studies.MethodsFour different 0.4% rapamycin formulations were prepared (ointment, emulsion, gel, and liposomes). The stability studies for each formulation over 56 days were as follows: (1) chemical: extraction with different solvents and high-performance liquid chromatography assay; (2) physical: pH, uniformity, extensibility, absence of crystals, absence of phase separation, and only for liposomal formulation, particle size, zeta potential, and encapsulation efficiency were determined; and (3) microbiological: culture samples in blood-agar media.ResultsOnly liposomes were chemically, physically, and microbiologically stable after 8 weeks. Ointment, emulsion, and gel formulations lost their chemical or physical stability before 56 days.ConclusionsThe authors describe four new formulations to improve the previous treatment for facial angiofibromas in tuberous sclerosis. The liposome-based formulation was the most appropriate according to chemical, physical, and microbiological stability studies. However, it would be necessary to carry out clinical studies to ensure the effectiveness and safety of this formulation and also guarantee an improvement in the quality of life of patients.