What is the role of genetics in the pathogenesis of tuberous sclerosis complex (TSC)?

Updated: Aug 21, 2018
  • Author: David Neal Franz, MD; Chief Editor: Amy Kao, MD  more...
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The high incidence of sporadic TSC, coupled with a probable "second hit" phenomenon, seems a likely explanation for the marked phenotypic variability observed. The second hit hypothesis suggests that in addition to an inherited or sporadic autosomal mutation in one allele of either TSC 1 or TSC 2, clinical signs and/or symptoms manifest only after a further mutation or inactivating event in the second, unaffected allele (“second hit”). This allows considerable potential for diversity, not only among various deletions and mutations between 2 genetic loci, but also with regard to possible interactions between protein products of varying functionality arising from different mutations on each allele. Thereby adjacent tubers, angiomyolipomas, even facial angiofibromas can have different second hits and different genotypes within the same organ of the same patient.

Further complicating the high spontaneous mutation rate is the observation that parents of an affected child, who themselves show no sign of TSC, nonetheless have an increased risk (approximately 2% overall) of having additional affected children. This is thought to result from parental mosaicism for one of the TSC genes limited to cells of their germ line (ie, gonadal tissues). True failure of penetrance of the TSC genes is believed to be rare.

Recent research has identified phenotypic differences as they may relate to particular genotypes. Linkage studies initially suggested a roughly equal distribution of TSC1 and TSC2 mutations among affected individuals. However, subsequent mutational analysis has shown TSC2 mutations to be present in 80-90% of affected individuals, while TSC1 mutations are present in 10-20%. The TSC2 gene is contiguous with the gene producing polycystic kidney disease (PKD1). Individuals with features of both TSC and polycystic kidney disease (as opposed to simple renal cysts) likely have deletions spanning both genes.

Jones et al found a higher incidence of "mental handicap" in persons with TSC2 mutations than in those with TSC1 mutations. They identified mental handicap retrospectively in relatively broad terms: developmental quotient less than 70, inability to attend regular school without supplementary assistance, institutionalization, requiring assistance with daily activities, etc.

Dabora et al recently described genotypic and phenotypic features in 224 persons with TSC. [8] A TSC2 genetic abnormality was found to be associated consistently with more severe clinical disease regardless of organ system. Although prominent phenotypic variability was still the rule, patients with TSC2 abnormalities were more apt to have higher tuber counts, refractory seizures, autism, larger AML and/or cardiac rhabdomyomata, and more severe cutaneous lesions. This suggests that, while tuberin and hamartin have similar functions, tuberin plays a more critical role in regulation of cellular differentiation. While TSC2 mutations are more apt to be associated with severe clinical phenotypes, they predominate in all forms of the disease, mild and severe, familial and sporadic. Spontaneous mutations are also much more likely to reflect TSC2 disease. Suggestions that TSC1 disease is more likely familial than sporadic appear to be incorrect.

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