The disease has been described in all parts of the world and is equally frequent in all races and in both sexes. Heredity is self-evident in only a minority of cases—50 percent in some series and as little as 14 percent in the series of Bundag and Evans (cited by Brett). The disease is determined by two autosomal dominant genes (see below), but it has been estimated as 1 in 20,000 to 300,000. The disease is inherited in an autosomal dominant fashion but with variable penetrance. The abnormal gene may be in one of two sites—the long arm of chromosome 9, designated as TSC1 (hamartin), or in the short arm of chromosome 16, TSC2 (tuberin), which is common. A wide variety of mutations have been described and both alleles must be affected for expression of the disease (“loss of heterozygosity”). Approximately 15 percent of sporadic cases show no identifiable mutation and tend to have milder manifestations, perhaps on the basis of mosaicism. Hamartin and tuberin function as tumor suppressor proteins and interact to suppress cell growth. This may, in part, explain the proclivity to develop various growths and hamartomas. The cerebral lesions and two of the three associated skin lesions of tuberous sclerosis are of this type. Several hypotheses relating to neuronal migration or to excessive secretion of growth factors have been proposed to link the inactivation of these genes with the pathogenesis of the characteristic lesions. Much of the work in understanding the function of these two proteins and their role in tumor formation has been performed in Drosophila and are summarized in the extensive review by Crino and colleagues.
The disease involves many organs in addition to the skin and brain and it may assume a diversity of forms, the least severe of which (i.e., the forme fruste) is difficult to diagnose; hence, one cannot be precise about its incidence. Tuberous sclerosis accounts for about 0.66 percent of the developmentally delayed in institutions and 0.32 percent of epileptics. The medical literature contains a number of reports of patients whose cognitive functioning is preserved and who have never had convulsions.
The cellular elements within the nodular cerebral lesions (called tubers; see below) are abnormal in number, size, and orientation. The tumor-like growths in different organs may include cells of more than one type (e.g., fibroblasts, cardiac myoblasts, angioblasts, glioblasts, and neuroblasts), and their number is locally excessive. Something appears to have gone awry with the proliferative process during embryologic development, yet it is kept under control, in the sense that only rarely do the growths undergo malignant transformation. Highly specialized cells within the lesions may attain giant size; neurons 3 to 4 times normal size may be observed in the cerebral scleroses. These facts emphasize the potentially blastomatous character of the process.
Surgically resected tubers show activation of a cell-size control pathway (mammalian target of rapamycin [mTOR]); this is in keeping with the effects of TSC mutations on this cascade and probably explains the giant neurons, as reviewed by Kwiatkowski and Manning.
The disease may be evident at the time of birth (the diagnosis has been made by CT or MRI in neonates), but more often the infant is judged at first to be normal. In approximately 75 percent of cases, attention is drawn to the disease initially by the occurrence of focal or generalized seizures or by slowed psychomotor development. As with any condition that leads to developmental delay, the first suspicion is raised by delay in reaching normal maturational milestones. Whatever the initial symptom, the convulsive disorder and developmental delay become more prominent within 2 to 3 years. The facial cutaneous abnormality, adenoma sebaceum, appears later in childhood, usually between the fourth and tenth years, and is progressive thereafter.