Rapamycin and dexamethasone during pregnancy prevent tuberous sclerosis complex-associated cystic kidney disease.

Chronic kidney disease is the main cause of mortality in patients with tuberous sclerosis complex (TSC) disease. The mechanisms underlying TSC cystic kidney disease remain unclear, with no available interventions to prevent cyst formation. Using targeted deletion of TSC1 in nephron progenitor cells, we showed that cysts in TSC1-null embryonic kidneys originate from injured proximal tubular cells with high mTOR complex 1 activity. Injection of rapamycin to pregnant mice inhibited the mTOR pathway and tubular cell proliferation in kidneys of TSC1-null offspring. Rapamycin also prevented renal cystogenesis and prolonged the life span of TSC newborns. Gene expression analysis of proximal tubule cells identified sets of genes and pathways that were modified secondary to TSC1 deletion and rescued by rapamycin administration during nephrogenesis. Inflammation with mononuclear infiltration was observed in the cystic areas of TSC1-null kidneys. Dexamethasone administration during pregnancy decreased cyst formation by not only inhibiting the inflammatory response, but also interfering with the mTORC1 pathway. These results reveal mechanisms of cystogenesis in TSC disease and suggest interventions before birth to ameliorate cystic disease in offspring.

Therapeutic Targeting of the Secreted Lysophospholipase D Autotaxin Suppresses Tuberous Sclerosis Complex-Associated Tumorigenesis.

Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by multiorgan hamartomas, including renal angiomyolipomas and pulmonary lymphangioleiomyomatosis (LAM). TSC2 deficiency leads to hyperactivation of mTOR Complex 1 (mTORC1), a master regulator of cell growth and metabolism. Phospholipid metabolism is dysregulated upon TSC2 loss, causing enhanced production of lysophosphatidylcholine (LPC) species by TSC2-deficient tumor cells. LPC is the major substrate of the secreted lysophospholipase D autotaxin (ATX), which generates two bioactive lipids, lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P). We report here that ATX expression is upregulated in human renal angiomyolipoma-derived TSC2-deficient cells compared with TSC2 add-back cells. Inhibition of ATX via the clinically developed compound GLPG1690 suppressed TSC2-loss associated oncogenicity in vitro and in vivo and induced apoptosis in TSC2-deficient cells. GLPG1690 suppressed AKT and ERK1/2 signaling and profoundly impacted the transcriptome of these cells while inducing minor gene expression changes in TSC2 add-back cells. RNA-sequencing studies revealed transcriptomic signatures of LPA and S1P, suggesting an LPA/S1P-mediated reprogramming of the TSC lipidome. In addition, supplementation of LPA or S1P rescued proliferation and viability, neutral lipid content, and AKT or ERK1/2 signaling in human TSC2-deficient cells treated with GLPG1690. Importantly, TSC-associated renal angiomyolipomas have higher expression of LPA receptor 1 and S1P receptor 3 compared with normal kidney. These studies increase our understanding of TSC2-deficient cell metabolism, leading to novel potential therapeutic opportunities for TSC and LAM. SIGNIFICANCE: This study identifies activation of the ATX-LPA/S1P pathway as a novel mode of metabolic dysregulation upon TSC2 loss, highlighting critical roles for ATX in TSC2-deficient cell fitness and in TSC tumorigenesis.

Mourning Dr. Alfred G. Knudson: the two-hit hypothesis, tumor suppressor genes, and the tuberous sclerosis complex.

On July 10, 2016, Alfred G. Knudson, Jr., MD, PhD, a leader in cancer research, died at the age of 93 years. We deeply mourn his loss. Knudson's two-hit hypothesis, published in 1971, has been fundamental for understanding tumor suppressor genes and familial tumor-predisposing syndromes. To understand the molecular mechanism of two-hit-initiated tumorigenesis, Knudson used an animal model of a dominantly inherited tumor, the Eker rat. From the molecular identification of Tsc2 germline mutations, the Eker rat became a model for tuberous sclerosis complex (TSC), a familial tumor-predisposing syndrome. Animal models, including the fly, have greatly contributed to TSC research. Because the product of the TSC2/Tsc2 gene (tuberin) together with hamartin, the product of another TSC gene (TSC1/Tsc1), suppresses mammalian/mechanistic target of rapamycin complex 1 (mTORC1), rapalogs have been used as therapeutic drugs for TSC. Although significant activity of these drugs has been reported, there are still problems such as recurrence of residual tumors and adverse effects. Recent studies indicate that there are mTORC1-independent signaling pathways downstream of hamartin/tuberin, which may represent new therapeutic targets. The establishment of cellular models, such as pluripotent stem cells with TSC2/Tsc2 gene mutations, will facilitate the understanding of new aspects of TSC pathogenesis and the development of novel treatment options. In this review, we look back at the history of Knudson and animal models of TSC and introduce recent progress in TSC research.

Esclerosis tuberosa / Tuberous sclerosis

Se presenta el caso de paciente masculino de 15 años de edad que es llevado a sala de urgencia s del Hospital Roosevelt por convulsiones tónico clónico generalizadas de 2 minutos de duración, con período postictal, con antecedentes familiares de convulsiones mostradas en el árbol genealógico (grafico 2 ). Además presenta antecedente de síndrome convulsivo desarrollado a los tres años de edad, tratado con múltiples anticonvulsivantes sin llegar a un dia gnóstico. Paciente al examen físico se presenta normocéfalo, cabello adecuada implantación, alerta, orientado en tiempo, espacio y persona, escleras y mucosas normales, con lesiones angiofibromatosas de distribución en alas de mariposa en región de puente nasal, alas nasales, mejillas y frente , frecuencia respiratoria de 14 por minuto, con ruidos respiratorios conservados, frecuencia cardíaca 70 por minuto, presión arteria l 100/60 mmHg, ritmo cardíaco normal, sincrónico con el pulso, abdomen sin alteraciones, extremidades y evaluación de sistema nervioso central sin presentar alteraciones...(AU)

We present the case of a 15-year-old male patient who is taken to the emergency room s Roosevelt Hospital for generalized 2-minute clonic tonic convulsions, with a period postictal, with family history of seizures shown in the pedigree (chart 2). It also presents a history of convulsive syndrome developed at three years of age, treated with multiple anticonvulsants without reaching a Gnostic day. Patient to the physical examination presents normocephalus, adequate hair implantation, alert, oriented in time, space and person, normal scleras and mucous membranes, with angiofibromatosis lesions of distribution in butterfly wings in nasal bridge region, nasal wings, cheeks and forehead, frequency respiratory rate of 14 per minute, with preserved respiratory sounds, heart rate 70 per minute, artery pressure l 100/60 mmHg, normal heart rate, synchronous with the pulse, abdomen without alterations, extremities and evaluation of the central nervous system without presenting alterations. . (AU)

Mammalian target of rapamycin (mTOR) inhibition as a potential antiepileptogenic therapy: From tuberous sclerosis to common acquired epilepsies.

Most current treatments for epilepsy are symptomatic therapies that suppress seizures but do not affect the underlying course or prognosis of epilepsy. The need for disease-modifying or "antiepileptogenic" treatments for epilepsy is widely recognized, but no such preventive therapies have yet been established for clinical use. A rational strategy for preventing epilepsy is to target primary signaling pathways that initially trigger the numerous downstream mechanisms mediating epileptogenesis. The mammalian target of rapamycin (mTOR) pathway represents a logical candidate, because mTOR regulates multiple cellular functions that may contribute to epileptogenesis, including protein synthesis, cell growth and proliferation, and synaptic plasticity. The importance of the mTOR pathway in epileptogenesis is best illustrated by tuberous sclerosis complex (TSC), one of the most common genetic causes of epilepsy. In mouse models of TSC, mTOR inhibitors prevent the development of epilepsy and underlying brain abnormalities associated with epileptogenesis. Accumulating evidence suggests that mTOR also participates in epileptogenesis due to a variety of other causes, including focal cortical dysplasia and acquired brain injuries, such as in animal models following status epilepticus or traumatic brain injury. Therefore, mTOR inhibition may represent a potential antiepileptogenic therapy for diverse types of epilepsy, including both genetic and acquired epilepsies.

Seguimiento a largo plazo de angiofibromas tratados con láser de CO2 en 23 pacientes con esclerosis tuberosa / Long-term follow up of angiofibromas treated with CO2 laser in 23 patients with tuberous sclerosis

Introducción. La esclerosis tuberosa es una enfermedad autosómica dominante que determina la formación de hamartomas en múltiples órganos. Los cambios cutáneos son una de las características primarias de esta enfermedad. Dentro de éstos, los angiofibromas constituyen una forma común de presentación que causa importantes problemas cosméticos y médicos. El láser de CO2 se ha utilizado satisfactoriamente en el tratamiento de estas lesiones, pero existen escasos estudios que evalúen sus resultados a largo plazo. El objetivo de nuestro estudio es valorar la respuesta del tratamiento de los angiofibromas en el largo plazo. Métodos. Se realizó un estudio retrospectivo en 23 pacientes con angiofibromas tratados con láser de CO2. Los pacientes fueron tratados entre los años 1991 y 2000 inclusive con láser de CO2 continuo o superpulsado. Clasificamos los angiofibromas de acuerdo a su tamaño, resultados iniciales del tratamiento y edad de los pacientes (< 20 años y 20 años o más). Resultados. El rango de edad varió entre 12 y 39 años, con una media de 22,5 años. Después del tratamiento los pacientes fueron controlados durante un periodo de 6 meses a 10 años. En el análisis a largo plazo encontramos que un 30,1 % mantuvo el resultado inicial y el 60,9 % mostró diferentes grados de recidiva con un tiempo medio de recurrencia de 3 años. Cuando analizamos los resultados a largo plazo según tamaños de angiofibromas, resultado inicial y edad de los pacientes, no encontramos diferencias estadísticamente significativas entre los diferentes grupos. El análisis de supervivencia, con curvas de Kaplan-Meier, de los grupos de edad mostró que los pacientes más jóvenes (< 20 años) recayeron antes que los de mayor edad (rango logarítmico 4,01 y p < 0,05). Conclusiones. El tratamiento con láser de CO2 logra buenos resultados a corto plazo. Por otro lado, uno de los mayores problemas es la recaída en el largo plazo, ya que probablemente debido a la naturaleza de las lesiones, éstas no se pueden eliminar permanentemente. Este trabajo coincide con estudios previos que no han encontrado factores que permitan predecir la recurrencia de las lesiones. Sin embargo, podemos concluir que los pacientes de mayor edad recaen más tardíamente y tienen por tanto mejores resultados cosméticos a largo plazo

Introduction. Tuberous sclerosis is an autosomal dominant disease in which hamartomas form in multiple organs. Cutaneous changes are one of the primary characteristics of this disease. These include angiofibromas (AF), a common form of presentation that causes significant cosmetic and medical problems. The CO2 laser has been used satisfactorily in treating these lesions, but there are few studies that evaluate its long-term results. The aim of our study is to assess the long-term response of the treatment of angiofibromas. Methods. A retrospective study was carried out on 23 patients with angiofibromas treated with CO2 laser. The patients were treated between 1991 and 2000, inclusive, with continuous or superpulsed CO2 laser. We classified the angiofibromas by size, initial treatment results and patients' ages (< 20 years and 20 years or older). Results. Ages ranged from 12 to 39 years, with a median age of 22.5 years. After treatment, patients were followed up for a period of six months to 10 years. In the long-term analysis, we found that 30.1 % maintained the initial result, and 60.9 % showed different degrees of recurrence, with a mean recurrence time of 3 years. When we analyzed the long-term results by the size of the angiofibromas, initial result and patients' ages, we found no statistically significant differences among the different groups. The survival analysis of the age groups, with Kaplan-Meier curves, showed that the youngest patients (< 20 years) had earlier recurrences than the older ones (logarithmic range 4.01 and p < 0.05). Conclusions. CO2 laser treatment achieves good short-term results. On the other hand, one of the biggest problems is recurrence over the long term; this is probably due to the fact that, because of their nature, these lesions cannot be eliminated permanently. This work coincides with earlier studies which found no factors that would make it possible to predict the recurrence of the lesions. However, we can conclude that recurrence takes place at a later date in older patients, and therefore they have better cosmetic results over the long term

Enfermedad de Lhermitte-Duclos asociada a esclerosis tuberosa. Presentación de un caso y revisión de la literatura / Lhermitte-Duclos disease associated with tuberous sclerosis. A case report and review of the litarature

Introduction. Lhermitte-Duclos disease is a rare disorder of the cerebellum of unknown origin in which dysplasic thickening of the cerebellar convolutions is seen. It usually occurs in young adults. Currently it is included in the phacomatosis group of disorders. Clinical case. A 19 year old woman attended the Emergency Department complaining of progressive orthostatic headache for the previous three months. On examination there were striking facial micronodular lesions suggestive of angiofibromas, a hypo-pigmented macula in the inframammary region and a hyperpigmented ‘café-au-lait’ macula in the right hypochondrium. On computerized tomography there was tetraventricular hydrocephalia. Cerebral magnetic resonance showed significant descent of the tonsils, hypertensive hydrocephalia and a lesion in the left cerebellum, apparently laminar hyperintensity in DP and T2, with thickening of some folia, not enhanced by intravenous contrast and suggestive of a dysplasic gangliocytoma. Laboratory investigations showed subclinical hypothyroidism. Other investigations were normal. The patient was treated by implanting a ventriculo-peritoneal shunt which has relieved the symptoms to date. Conclusions. Lhermitte-Duclos disease is probably not a single anatomo-clinical condition,assuming that it may be a cerebellar hamartoma associated with a phacomatosis with few clinical signs, whether it be Cowden’s disease, tuberous sclerosis as in this case or an ‘overlapping’ syndrome. The magnetic resonance findings are necessary and sufficient for the diagnosis of Lhermitte-Duclos disease (AU)

Introducción. La enfermedad de LhermitteDuclos es una rara afectación cerebelosa, de causa desconocida y que consiste en el engrosamiento displásico de las circunvoluciones cerebelosas. Se presenta típicamente en adultos jóvenes. En la actualidad, se incluye dentro del espectro de las facomatosis. Caso clínico. Paciente de 19 años que acudió al Servicio de Urgencias por presentar cefalea ortostática progresiva de tres meses de evolución. En la exploración llamaba la atención la presencia de lesiones micronodulares faciales sugerentes de angiofibromas, una mácula hipopigmentada en la región inframamaria y otra hiperpigmentada ‘café con leche’ en el hipocondrio derecho. La tomografía computarizadamostraba una hidrocefalia tetraventricular. La resonancia magnética cerebral evidenciaba un descenso amigdalar significativo, hidrocefalia hipertensiva y una lesión localizada en el hemisferio cerebeloso izquierdo, hiperintensa en DP y T2, de apariencia laminar, con engrosamiento de alguna folia y sin realce tras el contraste intravenoso, sugerente de gangliocitoma displásico. El estudio analítico demostró un hipotiroidismo subclínico. El resto de las pruebas complementarias fueron normales. La paciente fue sometida a una derivación ventrículo-peritoneal tras la cual cedieron los síntomas hasta la actualidad. Conclusiones. Probablemente la enfermedad de LhermitteDuclos no constituya una entidad anatomoclínica aislada, asumiendo que pueda tratarse de un hamartoma cerebeloso enmarcado dentro de una facomatosis con poca expresividad clínica, ya sea la enfermedad de Cowden, la esclerosis tuberosa, como ocurre en este caso, o un síndrome de ‘solapamiento’. Los hallazgos en resonancia magnética son necesarios y suficientes para el diagnóstico de enfermedad de LhermitteDuclos (AU)

Genetic aspects of tuberous sclerosis in the west of Scotland.

Complete ascertainment of tuberous sclerosis was attempted in the west of Scotland (population 2,763,000). A total of 101 patients was identified, giving an overall minimum prevalence of 1 in 27,000, but for children under 10 years of age the minimum prevalence was 1 in 12,000. Both parents of 84 of the ascertained cases were assessed for signs of tuberous sclerosis. In 51 pairs of parents no evidence of the condition was seen, indicating that up to 60% of the cases were new mutations. The mutation rate was estimated at 2.5 X 10(-5) mutations per gene per generation. Analysis of parental ages for the new mutations did not show a significant age effect. Thirty-five patients occurred in 13 families containing other affected subjects. The pattern of inheritance was consistent with an autosomal dominant trait in these families. In one sibship, non-penetrance or gonadal mosaicism resulted in affected sibs with normal parents. Of two further sibships where non-penetrance was suspected, one was shown to represent a single new mutation in monozygotic twins and the other to involve non-paternity.

[Clinical aspects (especially nephropathologic) and genetic counseling in tuberous sclerosis. Presentation of a case with polycystic kidney]. / Aspetti clinici (in particolare nefropatologici) e consiglio genetico nella sclerosi tuberosa. Presentazione di un caso esordito come rene policistico.

Tuberous sclerosis (TS) represents a relatively frequent inherited disorder of the skin and neurological tissues. Defects of other organs may also be present, but subjects differ significantly in their individual involvement. Usually, white leaf - shaped macules, even though most subtle, are the first precocious sign of the disease in young patients. Other signs tend to appear when the patient grows older. Visceral disorders include renal angiomyolipomata; clinical behavior of these solid tumors is almost always benign. Sometimes the renal lesions present themselves as polycystic kidneys, and may be the earliest sign and the only manifestation of TS, such as the case here described. This unusual form of renal involvement may be a severe potential complication of TS for the possible blood hypertension, recurrent urinary sepsis and chronic renal failure. It is of the utmost importance to search for the classical stigmata of TS in any patient who has cystic renal enlargement as only apparent abnormality. Careful inquiry into the family history cannot be overemphasized. The authors believe that, failing availability of adequate therapy for TS, the role in genetic counseling is to provide as much informations as possible to enable the involved family to make an intelligent decision about future children.