bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2021‒05‒30
fourteen papers selected by
Marti Cadena Sandoval

  1. Epilepsia Open. 2021 Feb 27.
      OBJECTIVE: Tuberous sclerosis complex (TSC) is a genetic disorder primarily characterized by the development of multisystem benign tumors. Epilepsy is the most common neurologic manifestation, affecting 80%-90% of TSC patients. The diffuse structural brain abnormalities and the multifocal nature of epilepsy in TSC pose diagnostic challenges when evaluating patients for epilepsy surgery.METHODS: We retrospectively reviewed the safety experience and efficacy outcomes of five adult TSC patients who were treated with direct brain-responsive neurostimulation (RNS System, NeuroPace, Inc).
    RESULTS: The average follow-up duration was 20 months. All five patients were responders (≥50% disabling seizure reduction) at last follow-up. The median reduction in disabling seizures was 58% at 1 year and 88% at last follow-up. Three of the five patients experienced some period of seizure freedom ranging from 3 months to over 1 year.
    SIGNIFICANCE: In this small case series, we report the first safety experience and efficacy outcomes in patients with TSC-associated drug-resistant focal epilepsy treated with direct brain-responsive neurostimulation.
    Keywords:  refractory epilepsy; responsive neurostimulation; tuberous sclerosis complex
  2. NMR Biomed. 2021 May 27. e4563
      The homeostasis of various metabolites is impaired in epilepsy secondary to the tuberous sclerosis complex (TSC). Chemical exchange saturation transfer (CEST) imaging is an emerging molecular MRI technique that can detect various metabolites and proteins in vivo. However, the role of CEST imaging for TSC-associated epilepsy has not been assessed. Here, we aim to investigate the feasibility of applying CEST imaging to TSC-associated epilepsy, optimize the CEST acquisition parameters, and provide an analysis method for exploring the dominant molecular contributors to the CEST signal measured. Nine TSC epilepsy patients were scanned on a 3-T MRI system. The CEST saturation frequencies were swept from -6 to 6 ppm with 12 different combinations of saturation power (4, 3, 2 and 1 μT) and duration (1000, 700 and 400 ms). Furthermore, a two-stage simulation method based on the seven-pool Bloch-McConnell model was proposed to assess the contribution of each exchangeable pool to the CEST signal in normal-appearing white matter and cortical tubers, which avoided the complexity and uncertainty of full Bloch-McConnell fitting. The results showed that under the optimal saturation duration of 1000 ms, the greatest contrast between tubers and normal tissues occurred around 3, 2.5, 1.75 and 3.5 ppm for B1 of 4, 3, 2 and 1 μT, respectively. At the optimal frequency offsets, the CEST values of tubers were significantly higher than those in the normal brain tissues (P < 0.01). Furthermore, the two-stage analysis suggested that the amine pool played a dominant role in yielding the contrast between cortical tubers and normal tissues. These results indicate that CEST MRI may serve as a potentially useful tool for identifying tubers in TSC, and the two-stage analysis method may provide a route for investigating the molecular contributions to the CEST contrast in biological tissues.
    Keywords:  Bloch-McConnell simulation; chemical exchange saturation transfer; epilepsy; saturation power; saturation time; tuberous sclerosis complex
  3. Front Endocrinol (Lausanne). 2021 ;12 678869
      Phakomatoses encompass a group of rare genetic diseases, such as von Hippel-Lindau syndrome (VHL), neurofibromatosis type 1 (NF1), tuberous sclerosis complex (TSC) and Cowden syndrome (CS). These disorders are due to molecular abnormalities on the RAS-PI3K-Akt-mTOR pathway for NF1, TSC and CS, and to hypoxia sensing for VHL. Phakomatoses share some phenotypic traits such as neurological, ophthalmological and cutaneous features. Patients with these diseases are also predisposed to developing multiple endocrine tissue tumors, e.g., pheochromocytomas/paragangliomas are frequent in VHL and NF1. All forms of phakomatoses except CS may be associated with digestive neuroendocrine tumors. More rarely, thyroid cancer and pituitary or parathyroid adenomas have been reported. These susceptibilities are noteworthy, because their occurrence rate, prognosis and management differ slightly from the sporadic forms. The aim of this review is to summarize current knowledge on endocrine glands tumors associated with VHL, NF1, TSC, and CS, especially neuroendocrine tumors and pheochromocytomas/paragangliomas. We particularly detail recent advances concerning prognosis and management, especially parenchyma-sparing surgery and medical targeted therapies such as mTOR, MEK and HIF-2 α inhibitors, which have shown truly encouraging results.
    Keywords:  Cowden syndrome; digestive neuroendocrine tumors; neurofibromatosis type 1; paraganglioma; pheochromocytoma; tuberous sclerosis complex; von Hippel-Lindau
  4. BMJ Case Rep. 2021 May 26. pii: e241635. [Epub ahead of print]14(5):
      Bladder perivascular epithelioid cell tumours (PEComas) associated with tuberous sclerosis complex (TSC) are rare, with only one other case report in the literature to date. We present our case of a bladder PEComa in a young adult female with TSC arising de novo. Histopathology showed features in keeping with an angiomyolipoma and confirmatory immunohistochemical stains were positive for both melanocytic and smooth muscle markers. She was well at the 6-month follow-up post-surgical resection. Given the rarity of such lesions in the bladder, we discuss the diagnostic and prognostic challenges, clinical implications and a brief review of the literature to date.
    Keywords:  genetics; urological cancer; urology
  5. Epilepsia. 2021 May 29.
      OBJECTIVE: Cannabidiol (CBD) has been shown to reduce seizures among patients with refractory epilepsies of various etiologies in recent clinical trials and an expanded access program (EAP). Most studies report efficacy over short time periods (<1 year), with little published on longer term efficacy. Here, we investigate the efficacy of CBD for a treatment period of up to 60 months (median = 45.5 months).METHODS: We conducted a retrospective review of patient-reported seizure logs and medical records for 54 subjects with refractory epilepsy who enrolled in the Massachusetts General Hospital's open-label EAP for CBD as a new treatment for epilepsy. We analyzed the effect of CBD on seizure frequencies and concomitant antiepileptic drug (AED) use at 1 year after starting treatment and the most recent study visit.
    RESULTS: Our results indicate that CBD maintains its efficacy for controlling seizures from Year 1 to the most recent study visit. The percentage of seizure responders remained similar at these time points (41.7%-42.6%), and the seizure response rate was also maintained (p = .12). Efficacy was also seen over a broad dose range, and up to 50 mg/kg/day. CBD was particularly effective for controlling seizures in the setting of tuberous sclerosis complex and for reducing epileptic spasms and absence seizures. Although CBD use did not lead to an overall decrease in concomitant AEDs, most subjects reduced the dose of at least one concomitant AED compared to baseline. CBD was generally well tolerated, with drowsiness and diarrhea as the primary adverse reactions.
    SIGNIFICANCE: This study demonstrates CBD does not lose its efficacy in controlling seizures over a treatment period of up to 60 months. Taken alongside other results on the efficacy and tolerability of CBD in the treatment of refractory epilepsies, our results provide evidence that CBD is an effective, safe, and well-tolerated AED for long-term use.
    Keywords:  antiepileptic drugs; refractory epilepsy; seizures; tolerability; tuberous sclerosis complex
  6. Cureus. 2021 Apr 19. 13(4): e14565
      Cardiac rhabdomyoma is a hamartoma comprised of cardiac myocytes. It is the classic cardiac manifestation of tuberous sclerosis complex (TSC) which is an autosomal dominant genetic syndrome with multi-organ involvement, but highly variable phenotype. Cardiac rhabdomyoma is most commonly diagnosed in infancy, 70 to 90% of whom have TSC. However, TSC-associated cardiac rhabdomyoma usually shows spontaneous regression within the first two years of life and hence is extremely rare in adults. We present a 34-year-old woman with TSC who was found to have a cardiac rhabdomyoma when she was referred to the cardiology clinic for evaluation and to establish care. Cardiac rhabdomyoma is usually asymptomatic. However, depending on size and location, it can cause outflow or inflow tract obstruction and aberrant electrical conduction. Hence, appropriate surveillance is important.
    Keywords:  benign cardiac tumor; cardiac tumor in adults; surveillance for cardiac rhabdomyoma; tsc-associated cardiac rhabdomyoma; tuberous sclerosis complex
  7. Int J Pharm. 2021 May 25. pii: S0378-5173(21)00541-X. [Epub ahead of print] 120736
      Facial angiofibromas are benign tumors characteristic of tuberous sclerosis complex. The disease involves the mTOR pathway and the cutaneous manifestation responds to topical treatment with sirolimus (SIR). However, there are no approved topical SIR products and extemporaneous formulations have been sub-optimal. The aims of this study were (i) to develop aqueous formulations of SIR loaded in polymeric micelles prepared using D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and (ii) to use the cutaneous biodistribution method, in conjunction with a new statistical approach, to investigate the feasibility of SIR delivery to the viable epidermis. Optimized micelle solutions and hydrogels (0.2%) were developed and stable at 4°C for at least 6 and 3 months, respectively. Cutaneous delivery experiments (infinite and finite dose) using porcine skin demonstrated that both formulations increased SIR cutaneous bioavailability as compared to the control (ointment 0.2%). Moreover, studies with the micellar hydrogel 0.2% demonstrated SIR deposition in the viable epidermis with no transdermal permeation. These encouraging results confirmed that polymeric micelles enabled development of aqueous SIR formulations capable of targeted epidermal delivery. Furthermore, the cutaneous biodistribution provided a detailed insight into drug bioavailability in the different skin compartments that could complement/explain clinical observations of formulation efficacy.
    Keywords:  TPGS; facial angiofibromas; polymeric micelles; sirolimus; skin; thermodynamic activity; topical delivery
  8. World J Gastroenterol. 2021 May 21. 27(19): 2299-2311
      First reported in 1976, hepatic angiomyolipoma (HAML) is a rare mesenchymal liver tumor occurring mostly in middle-aged women. Diagnosis of the liver mass is often incidental on abdominal imaging due to the frequent absence of specific symptoms. Nearly 10% of HAMLs are associated with tuberous sclerosis complex. HAML contains variable proportions of blood vessels, smooth muscle cells and adipose tissue, which renders radiological diagnosis hazardous. Cells express positivity for HMB-45 and actin, thus these tumors are integrated into the group of perivascular epithelioid cell tumors. Typically, a HAML appears on magnetic resonance imaging (or computed tomography scan) as a hypervascular solid tumor with fatty areas and with washout, and can easily be misdiagnosed as other liver tumors, particularly hepatocellular carcinoma. The therapeutic strategy is not clearly defined, but surgical resection is indicated for symptomatic patients, for tumors showing an aggressive pattern (i.e., changes in size on imaging or high proliferation activity and atypical epithelioid pattern on liver biopsy), for large (> 5 cm) biopsy-proven HAML, and if doubts remain on imaging or histology. Conservative management may be justified in other conditions, since most cases follow a benign clinical course. In summary, the correct diagnosis of HAML is challenging on imaging and relies mainly on pathological findings.
    Keywords:  Angiomyolipoma; Imaging; Liver; Pathology; Potentially malignant; Tuberous sclerosis complex
  9. PLoS Biol. 2021 May 26. 19(5): e3001279
      Hyperactivation of the mammalian target of rapamycin (mTOR) pathway can cause malformation of cortical development (MCD) with associated epilepsy and intellectual disability (ID) through a yet unknown mechanism. Here, we made use of the recently identified dominant-active mutation in Ras Homolog Enriched in Brain 1 (RHEB), RHEBp.P37L, to gain insight in the mechanism underlying the epilepsy caused by hyperactivation of the mTOR pathway. Focal expression of RHEBp.P37L in mouse somatosensory cortex (SScx) results in an MCD-like phenotype, with increased mTOR signaling, ectopic localization of neurons, and reliable generalized seizures. We show that in this model, the mTOR-dependent seizures are caused by enhanced axonal connectivity, causing hyperexcitability of distally connected neurons. Indeed, blocking axonal vesicle release from the RHEBp.P37L neurons alone completely stopped the seizures and normalized the hyperexcitability of the distally connected neurons. These results provide new evidence of the extent of anatomical and physiological abnormalities caused by mTOR hyperactivity, beyond local malformations, which can lead to generalized epilepsy.
  10. Pediatr Int. 2021 May 26.
    Keywords:  cardiac rhabdomyoma; everolimus; tuberous sclerosis complex; very-low-birthweight infant
  11. Brain. 2021 May 28. pii: awab173. [Epub ahead of print]
      Phosphatase and tensin homolog (PTEN) regulates cell growth and survival through inhibition of the mammalian target of rapamycin (MTOR) signaling pathway. Germline genetic variation of PTEN is associated with autism, macrocephaly, and PTEN hamartoma tumor syndromes (PHTS). The effect of developmental PTEN somatic mutations on nervous system phenotypes is not well understood, although brain somatic mosaicism of MTOR pathway genes is an emerging cause of cortical dysplasia and epilepsy in the pediatric population. Here we report two somatic variants of PTEN affecting a single patient presenting with intractable epilepsy and hemimegalencephaly that varied in clinical severity throughout the left cerebral hemisphere. High-throughput sequencing analysis of affected brain tissue identified two somatic variants in PTEN. The first variant was present in multiple cell lineages throughout the entire hemisphere and associated with mild cerebral overgrowth. The second variant was restricted to posterior brain regions and affected the opposite PTEN allele, resulting in a segmental region of more severe malformation, and the only neurons in which it was found by single-nuclei RNA-seq had a unique disease-related expression profile. This study reveals brain mosaicism of PTEN as a disease mechanism of hemimegalencephaly and furthermore demonstrates the varying effects of single- or bi-allelic disruption of PTEN on cortical phenotypes.
    Keywords:  brain development; epilepsy; hemimegalencephaly (HME); somatic mosaicism
  12. Nat Commun. 2021 May 24. 12(1): 3059
      Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease in the world, however, no drug treatment has been approved for this disease. Thus, it is urgent to find effective therapeutic targets for clinical intervention. In this study, we find that liver-specific knockout of PPDPF (PPDPF-LKO) leads to spontaneous fatty liver formation in a mouse model at 32 weeks of age on chow diets, which is enhanced by HFD. Mechanistic study reveals that PPDPF negatively regulates mTORC1-S6K-SREBP1 signaling. PPDPF interferes with the interaction between Raptor and CUL4B-DDB1, an E3 ligase complex, which prevents ubiquitination and activation of Raptor. Accordingly, liver-specific PPDPF overexpression effectively inhibits HFD-induced mTOR signaling activation and hepatic steatosis in mice. These results suggest that PPDPF is a regulator of mTORC1 signaling in lipid metabolism, and may be a potential therapeutic candidate for NAFLD.
  13. Mol Cell Oncol. 2021 ;8(3): 1919006
      Ferroptosis is a cell death mechanism triggered by lipid peroxidation. Our recent study linked cyst(e)ine availability with glutathione peroxidase 4 (GPX4) protein synthesis and ferroptosis mitigation via a Rag-mechanistic target of rapamycin complex 1 (mTORC1) axis, and proposed that co-targeting mTORC1 and ferroptosis is a promising strategy for cancer therapy.
    Keywords:  GPX4; SLC7A11; cancer therapy; cysteine; cystine; ferroptosis; lipid peroxidation; mTORC1
  14. EMBO Rep. 2021 May 27. e53232
      Lowe syndrome is a rare, developmental disorder caused by mutations in the phosphatase, OCRL. A study in this issue of EMBO Reports shows that OCRL is required for microtubule nucleation and that mutations in this protein lead to an inability to activate mTORC1 signaling and consequent cell proliferation in the presence of nutrients. These defects are the result of impaired microtubule-dependent lysosomal trafficking to the cell periphery and are independent of OCRL phosphatase activity.