Tuberous sclerosis complex: neurological, renal and pulmonary manifestations

Abstract

Tuberous sclerosis complex (TSC) is an important cause of epilepsy and autism, as well as renal and pulmonary disease in adults and children. Affected individuals are subject to hamartomas in various organ systems which result from constitutive activation of the protein kinase mTOR (mammalian target of rapamycin). The clinical course, prognosis and appropriate therapy for TSC patients are often different from that for individuals with epilepsy, renal tumors, or interstitial lung disease, from other causes. Additionally, TSC serves as a model for other conditions in which the mTOR pathways are also up-regulated. This article reviews the molecular pathophysiology and management of neurological, renal and pulmonary manifestations of the disorder. The use of mTOR inhibitors such as rapamycin and everolimus is discussed and recent clinical trials of these drugs in TSC are reviewed.

Fig. 1

The mTOR pathway. mTOR1 and mTOR2 are distinguished by their co-factors – raptor and rictor respectively. The tuberous sclerosis gene products function through the GAP protein Rheb (Ras homolog enhanced in brain) to inhibit mTOR, and thereby protein synthesis, cellular growth and division. Rapamycin mimics this by causing the dissociation of raptor from mTOR, resulting in inactivation of the complex. mTOR1 is also inhibited by nutrient deprivation (by courtesy of G. Thomas, Ph.D).

Fig. 2

Large calcified area of cortical dysplasia in the left medial frontal lobe. This area grew in size over 1½ – 2 years, herniating across the mid-line. This was associated with a clinical reduction in seizure frequency. The lesion then regressed spontaneously over the next several years (cranial MRI).

Fig. 3

Multifocal areas of abnormal T ₂ -weighted signal at the gray-white junction represent cortical tubers. Dystrophic calcification is present in the frontal white matter, left greater than right. Prominent calcifications led to consideration of congenital infection and possible child abuse as possible diagnoses, before the child was recognized as having TSC (cranial MRI).

Fig. 4

Subependymal giant cell astrocytoma in the region of the left foramen of Monro. Once these lesions begin to grow they inexorably continue to do so, eventually producing hydrocephalus (cranial MRI).

Fig. 5

Non-contrast computer tomography image demonstrating a large left renal angiomyolipoma and hemorrhage.

Fig. 6

Diffuse thin walled cysts and bilateral chylous effusions (blue vertical arrows posteriorly) in a patient with lymphangioleiomyomatosis (non-contrast CT).