Mild Expression in Familial TSC2

BACKGROUND: TS is an autosomal dominant disorder characterized by hamartomata in various organs, including the brain, and caused by mutations in the TSC1 (9q34) or TSC2 (16p13) genes. The disease phenotype was found to be more severe in sporadic TSC2 patients (Dabora et al, 2001). Here we analyze the genotype/phenotype correlations in a large extended kinship presenting with seizures who were found to have exceptionally mild TSC2.


DESIGN/METHODS: Field trips were carried out to examine family members and collect blood samples. Available individuals underwent brain MRI, CT scans, abdominal ultrasound, echocardiogram, expert neurological, dermatological, ophthalmological, and psychiatric evaluations. The pedigree included 202 individuals directly related to the proband. 58 individuals in 3 generations were genotyped for markers linked to TSC1 and TSC2 loci. For linkage and mutation analysis, we defined the affected status by the coexistence of epilepsy and skin lesions.


RESULTS: Linkage was demonstrated to TSC2 on 16p13.3. 28/58 individuals had a missense mutation in exon 23 (2714G to A, 905R to Q).


Epilepsy was present in 15/28 (54%) individuals with the mutation. Mean age at seizure onset was 9 years. Eleven patients had only partial seizures, and 13 showed good response or complete remission upon treatment. Skin lesions, namely, ash-leaf or confetti spots were present in 24/28 (86%) patients. Renal ultrasound in 14/28 patients detected angiomyolipoma in 1 patient. Ocular examination in 11/28 patients detected cataract in 2 patients, and glaucoma, minor intraretinal lesions, and retinal hamartoma in 1 patient each. Psychiatric evaluation demonstrated learning disabilities in 6/28 (21%) patients and anxiety disorder in 4/28 (14%). Brain imaging in 21/28 patients revealed left frontal subependymal giant cell astrocytoma in 1/21 (5%), subependymal nodules in 2/21 (10%) and white matter hypersignal in 7/21 (33%) patients.


CONCLUSIONS: In this family, the TSC2 mutation is associated with a mild expression as demonstrated by the absence of severe skin lesions, cardiac, and renal tumors in affected individuals, as well as benign prognosis of epilepsy, and absence of severe mental retardation. This is in contrast to the more severe phenotype described in a large series of sporadic TSC2 cases, and may indicate co-segragation of a modifying gene(s).