Tuberous sclerosis: a review of the past, present, and future

Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem disorder that is characterized by cellular and tissue dysplasia in several organs. With the advent of genetic and molecular techniques, mutations in the TSC1 or TSC2 genes were discovered to be responsible for mTOR overactivation, which is the underlying mechanism of pathogenesis. TSC is a highly heterogenous clinical entity with variable presentations and severity of disease. The brain, heart, skin, eyes, kidneys, and lungs are commonly involved in this syndrome, with neurologic symptoms comprising a significant source of morbidity and mortality. In 2012, the diagnostic criteria for TSC were revised by the International Tuberous Sclerosis Complex Consensus panel, and genetic testing was incorporated into the guidelines. Early detection of cardiac rhabdomyomas or TSC-associated skin lesions can suggest the diagnosis and underlie the importance of clinical vigilance. Animal studies have demonstrated the benefit of using mTOR inhibitors for various symptoms of TSC, and they have been successfully translated into clinical trials with significant improvement in symptom burden. Subependymal giant cell astrocytomas, renal angiomyolipomas, and epilepsy are the three FDA-approved indications in relation to TSC for the use of everolimus, which is a first generation mTOR inhibitor. Rapamycin has been FDA approved for lymphangioleiomyomatosis. Other TSC symptoms that could potentially benefit from this class of medication are currently under investigation. TSC constitutes a unique combination of protean physical symptoms and neurobehavioral abnormalities. TSC associated neuropsychiatric disorders (TAND), including intellectual disability, mood disorders, and autism spectrum disorder, represent significant challenges but remain underdiagnosed and undertreated. The TAND checklist is a useful tool for routine use in the clinical evaluation of TSC patients. A multidisciplinary treatment plan, based on the specific problems and needs of individuals, is the key to management of this genetic condition. Ongoing research studies have been providing promising leads for developing novel mechanistic strategies to address the pathophysiology of TSC.

Diagnostic features of tuberous sclerosis complex: case report and literature review

“…Rarely, TSC is associated with a severe early onset polycystic kidney phenotype due to a large deletion mutation spanning parts of both TSC2 and PKD1 genes on chromosome 16p13 (78). The combination of AMLs and cysts is highly indicative of TSC (79). Our patient did in fact have multiple renal lesions.…”

“…Retinal astrocytic hamartomas (RAHs), (Figure 1; feature 5) were reported in 9 out of 65 cases. Northrup et al and Uysal et al reported that retinal hamartomas are a major feature that were observed in up to 50% of TSC patients, and they also reported that retinal achromic patch is another manifestation (4,79). RAHs are a potential cause of visual deficits in TSC patients (82).…”

“…Northrup et al (4) and von Ranke et al (5) reported that cortical dysplasia and cortical tubers were present in 90% and 95% of TSC patients, respectively. In addition, 80-90% of TSC patients were reported to have cortical tubers and SENs (79).…”

“…The majority were renal AMLs (Figure 1 80% of patients with TSC, and they report that the most serious complication is rupture and haemorrhage frequently associated with aneurysm (5). AML is a type of benign tumour that consists of variable numbers of vascular cells, smooth-muscle cells, epithelioid cells, and fat cells (1,79).…”

Management of genetic diseases: Present and future

“…La esclerosis tuberosa (MIM #PS191100) tiene manifestaciones clínicas muy heterogéneas y la FDA ha aprobado el uso de inhibidores mTOR como el everolimus para la epilepsia, rabdomiosarcomas, astrocitomas, angiomiolipomas; y la rapamicina para linfangioleiomatosis (93) .…”