Tuberous sclerosis complex without tubers and subependymal nodules: a phenotype-genotype study

Area of Science:

• Genetics
• Neurology
• Developmental Biology

Background:

• Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in TSC1 or TSC2 genes.
• Typical TSC neuroanatomic features include tubers and subependymal nodules (SENs) in the brain, present in most patients.
• Approximately 15% of TSC patients do not have identifiable TSC1 or TSC2 mutations.

Purpose of the Study:

• To investigate the genotype-phenotype characteristics of TSC patients who lack typical brain lesions.
• To explore potential genetic explanations for TSC in individuals with atypical presentations.

Main Methods:

• Analysis of clinical features in 11 TSC patients without typical neuroanatomic lesions.
• Genetic mutational analysis of TSC1/TSC2 genes in ten of these patients.

Main Results:

• Ten out of eleven patients tested negative for TSC1/TSC2 mutations.
• These patients presented with lesions of presumed neural crest (NC) origin, including hypomelanotic macules, facial angiofibromas, cardiac rhabdomyomas, angiomyolipomas, and lymphangioleiomyomatosis.

Conclusions:

• The absence of typical brain lesions and negative genetic tests in some TSC patients may indicate a mosaic form of TSC.
• This mosaicism is hypothesized to result from an early embryonic mutation in TSC1 or TSC2 within a neural crest cell.
• This developmental mechanism could explain negative genetic testing results from peripheral leukocytes.