Genotype–phenotype correlations in tuberous sclerosis: Who and how to treat

Tuberous sclerosis complex (TSC) is an autosomal dominant hamartomatous syndrome characterized by lesions of the skin, most prominently hypopigmented macules and facial angiofibromas (adenoma sebaceum), hamartomatous lesions of the brain (cortical tubers, subependymal nodules, and subependymal giant cell tumors), optic gliomas, and benign tumors of the eyes, heart, and lungs.1, 2 Tumors of the kidney are also common and may rarely progress to malignancy (<2%) in the form of malignant angiomyolipomas or renal cell carcinomas. TSC occurs in about 1 in 6,000 to 10,000 individuals.3, 4 One third of cases are familial, whereas the majority are sporadic. Early descriptions of the dermatological features were recorded by Rayer in 1835 (végétations vasculaires)30 and by Pringle in 1890 (adenoma sebaceum).5 In 1880, Bourneville described the cerebral pathology and proposed the term sclérose tubéreuse.6 For most of the twentieth century, Vogt's triad of epilepsy, mental retardation, and adenoma sebaceum has served as a framework. It was not until 1979 that the spectrum of clinical and pathological findings was fully described.1, 7 Phenotypic variation in TSC is well documented. Among the most severe neurological manifestations of TSC are intractable seizures, mental retardation, optic glioma, and obstructive hydrocephalus. The frequency and severity of involvement of other organs is also highly variable. Renal angiomyolipoma, cardiac rhabdomyoma, and pulmonary lymphangioleiomyomatosis may be absent or may be severe enough to cause organ failure. The decreased life expectancy associated with TSC is primarily due to neurological manifestations, followed by renal, pulmonary, and cardiovascular disease.8 The neuropathology of TSC is attributed to abnormalities in proliferation, differentiation, migration, and cytoarchitecture of neurons, starting early in fetal development and resulting from the disruption of either hamartin (TSC1 9q34) or tuberin (TSC2 16p13). Biochemical and genetic analyses in Drosophila melanogaster showed that Tsc1 and Tsc2 proteins were sensors of nutrient and growth factor signaling, linking these extracellular cues to the activity of the mammalian target of rapamycin (mTOR), a major regulator of protein translation and cell growth. In mammalian cells, Tsc similarly couples signaling from growth factor receptors to the activity of mTOR (Fig), whereas nutrients (amino acids and glucose) signal to mTOR independently of the Tsc proteins.9-11 Fig. The tuberous sclerosis complex (TSC) couples signaling from growth factor receptors to mammalian target of rapamycin (mTOR), thereby regulating cell growth, proliferation, and metabolism. PI3 = phosphatidylinositol-3; PIP2 = phosphatidylinositol-4,5-biphosphate; PIP3 = phosphatidylinositol-3,4,5-trisphosphate. Growth factor receptors act in part to activate phosphatidylinositol-3 (PI3) kinase, generating phosphatidylinositol-3,4,5-trisphosphate (PIP3). Phosphatidylinositol-3,4,5-trisphosphate couples phosphatidylinositol-3 kinase to Akt, a serine-threonine kinase, which, in turn, phosphorylates Tsc2, downregulating its GTPase (GAP) activity. Tsc2 is bound to Tsc1 in cells, where Tsc1 stabilizes the complex, by blocking ubiquitination and proteolysis of Tsc2.12-14 Tsc1/2 drives the small GTPase Rheb into an inactive GDP-bound state, leading to activation of mTOR. A number of mTOR-independent functions have also been ascribed to Tsc, including modification of the cytoskeleton, regulation of other small G proteins, and interaction with D-type cyclins.15-18 Although loss of the retained allele of Tsc1 or Tsc2 contributes to the generation of subependymal giant cell tumors in TSC,19 similar loss of heterozygosity appears not to occur in cortical tubers.20 A recent study suggests that haploinsufficiency may contribute to the neuropathology and clinical manifestations of Tsc, because rodents haploinsufficient for Tsc1 or Tsc2 had large neuronal cell bodies in the hippocampus, enlargement and decreased densities of dendritic spines, and altered properties at glutamatergic synapses.21 Whether similar pathology occurs in human Tsc currently is unknown. Inhibitors of mTOR are now available clinically, and they have been shown (in a recent issue of Annals) to cause regression of subependymal giant cell tumors in Tsc.22 Although such agents may be of value in treating severely affected patients with Tsc, major questions remain unanswered. It will be critical to decipher mTOR-dependent and -independent contributions to the clinical spectrum of this disorder and to address the role of inhibitors of mTOR in the treatment of intractable epilepsy observed in many Tsc patients. A more vexing problem is whether chronic pharmacological inhibition of mTOR will limit the cognitive and behavioral abnormalities in TSC. The dosage and scheduling of such therapy is of particular importance, because complete inhibition of mTOR is likely to have profound effects on normal growth and development in children with TSC. With these questions in mind, it is of critical importance to identify patients at risk for severe manifestations of Tsc1, to start thinking about therapy for the group of children most disabled by this disease. Mutational analysis in patients with TSC suggests that a wide degree of phenotypic variation can be seen with a particular genotype.23 Mutations in TSC1 appear to be associated with a milder phenotype, and these patients may have lower rates of mental retardation, autistic disorder, severe facial angiofibroma, seizures (including infantile spasms), renal disease, and retinal hamartomas.24-28 In this issue of Annals, Jansen and colleagues29 perform genotype–phenotype correlations in a large French-Canadian kindred with TSC, and in 15 other families that have mutations at the same codon. They describe functional studies on three different amino acid substitutions at codon 905 and draw associations to phenotype. The French-Canadian kindred have a R905Q substitution in Tsc2. The phenotype in this pedigree was mild, with intrafamilial variability ranging from isolated hypomelanotic macules to phenotypes including subependymal giant cell tumors, epilepsy, mild cognitive impairment, and renal angiomyolipoma. Three other families and six sporadic patients with the same mutation were studied. Their phenotype was again found to be mild, with only a minority of patients showing cognitive impairment or severe epilepsy. For comparison, 10 families with the R905W mutation and 1 family with the R905G mutation had cortical tubers, subependymal nodules, or subependymal giant cell tumors. Seizures were prominent and included infantile spasms and Lennox–Gastaut syndrome. Skin lesions were more severe. Cognitive impairment occurred commonly and was more extreme. Angiomyolipomas, rhabdomyomas, and retinal hamartomas also occurred more frequently. In functional studies, all three substitutions were found to disrupt the ability of tuberin to antagonize signaling through mTOR. The R905Q substitution affected tuberin function to a lesser degree than the R905G and R905W substitutions. This finding is consistent with the milder phenotype observed in patients with the R905Q substitution. These results broaden our understanding of the genotype–phenotype relationship in TSC. First, patients with familial mutations in TSC2 mutations tend to be mildly affected.24-28 Second, the lack of strict correlation between genotype and phenotype suggests that other genes modify the severity of this disorder. Third, the effect of a particular mutation on tuberin function can be measured biochemically and may help to predict the severity of disease. These findings represent a start in identifying patients at risk for the most severe manifestations of this disorder, so that these patients can be entered into clinical trials to determine whether inhibitors of mTOR can be both safe and effective in the group of patients most impacted by TSC. This research was supported by the NIH (National Cancer Institute, R01CA 102321, W.A.W.; National Institute of Neurological Disorders and Stroke, R21NS5Z161, W.A.W.); The Brain Tumor Society; The Goldhirsh, Pediatric Brain Tumor, Sandler Family, and Waxman Foundations; Clinical Scientist Awards in Translational Research from the Burroughs Wellcome Fund, and Thrasher Funds; and a UC-Genentech Discovery Grant (bio-05-10501).

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