Tuberous sclerosis complex

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By Hema R Murali MBBS and Narayana S Murali MD

Genetics. Tuberous sclerosis complex is an autosomal-dominant disorder caused by a genetic mutation in 1 of 2 different genes. Chromosomal bands 9q34.3 and 16p13.3 are the loci for the 2 genes; they are respectively called TSC1 (tuberous sclerosis complex 1) and TSC2 (tuberous sclerosis complex 2) (Fryer et al 1987; Kandt et al 1992). The 16p13.3 TSC2 gene, identified first, and its 5.5 kilo base TSC2 transcript encode a 200 KDa protein called tuberin. The 9q34.3 TSC1 gene, identified from a 900-kilobase region containing over 30 genes, and its 8.6 kilo base TSC1 transcript encode a 140 KDa protein called hamartin.

As of December 9, 2014, 683 unique allelic DNA variants of TSC1 and 1902 unique allelic variants of TSC2 have been reported. More information is available at |{WebSite:LOVD tuberous sclerosis database}{WebURL:}|.

There are differences in the phenotypic expressions of TSC1 and TSC 2 gene mutations. For instance, TSC2 mutations express a more severe phenotype – more severe renal involvement, mental retardation, more cerebral and facial lesions, less reproductive fitness (Jones 1999), and more pulmonary involvement. There does not appear to be a strict correlation between mutation and clinical phenotype. Mutation occurrence is more common in TSC2, accounting for approximately 75% to 80% of sporadic cases. About 80% of cases are caused by de novo mutation (Roach et al 1999). Tuberous sclerosis complex may be caused by germline mosaicism, with 2 different cell lines in the gametes inherited from the mother (Yates et al 1997). This could appear as sporadic disease in the general population. Several other deletional mutations affecting different parts of the TSC2 gene have been identified in unrelated patients (European Chromosome 16 Tuberous Sclerosis Consortium 1993).

In This Article

Historical note and nomenclature
Clinical manifestations
Clinical vignette
Pathogenesis and pathophysiology
Differential diagnosis
Diagnostic workup
Prognosis and complications
References cited