Tuberous Sclerosis Complex (TSC). Sergei Kashirny , MD LSU Neurology February, 3, 2011. Case.
Sergei Kashirny, MD
February, 3, 2011
27 yo Asian female well-known in the clinic has been followed by neurology since infancy when she experienced infantile spasms. That condition was successfully treated with steriods and the patient remained seizure-free until age 10. At that age she had her first witnessed generalized tonic-clonic seizure. Her seizure became more frequent in the next 3 years and consist with CPS (complex partial seizure) and CPS with secondary generalization.
Except the presence of seizures she was the well developed child and had the average grades at school.
Clinically, TSC exhibits an autosomal dominant inheritance pattern, with a high spontaneous mutation rate. Two distinct genetic loci responsible for TSC have been identified: one on chromosome band 9q34 (also referred to as TSC1) and another on chromosome band 16p13 (TSC2).
The TSC2 gene was identified in 1993, and its protein product has been named tuberin. Tuberin has GTPase-activating properties and seems to function as a tumor suppressor. The highest levels of tuberin are found in adult human brain, heart, and kidney. Individual tubers are thought to arise developmentally when mutated neural progenitor cells in the subependymal germinal matrix give rise to abnormally migrating daughter cells that in turn produce tubers. The tubers may undergo cystic degeneration or calcification, or exhibit contrast enhancement on neuroimaging, but these features do not necessarily imply malignant transformation.
Hamartin, the TSC1 product, was identified in 1997 and may also function as a tumor suppressor. Hamartin and tuberin together form a tumor suppressor complex, which, through the GTPase activating function of tuberin.
Subsequent mutational analysis has shown TSC2 mutations to be present in 80-90% of affected individuals, while TSC1 mutations are present in 10-20%.
It is found a higher incidence of "mental handicap" in persons with TSC2 mutations than in those with TSC1 mutations.
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 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.
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.
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.
Prevalence - 1 case per 10,000 population.
TSC affects all races without a clear-cut predominance.
TSC affects both sexes equally.
TSC can present at any age.
TSC frequently presents with infantile spasm (generalized epilepsy occurring in infants).
Renal manifestations are the 2nd most common clinical feature.