Abstracts

Tuberous sclerosis (TS) is an autosomal dominant disorder characterized by hamartomata in various organs, including the brain, 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.
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.
We demonstrated linkage to the TSC2 locus. 28/58 individuals had a missense mutation in exon 23 (2714G to A, 905R to Q). Epilepsy was diagnosed in 15/28 (54%) individuals with the mutation. In most patients, seizures were well controlled by medication and became milder or ceased spontaneously. Some patients only had seizures in childhood. In 24/28 (86%) we detected ash-leaf or confetti spots or idiopathic hypomelanosis alone or in association. No facial angiofibromas or periungual fibromas were found. Eye exams, performed in 11/28 (39%) patients, demonstrated cataract in two and glaucoma, minor intraretinal lesions, and possible retinal hamartoma in one individual each. Neuroimaging studies, available in 21/28 (75%) individuals, revealed sub-ependymal giant cell astrocytoma and sub-ependymal nodules in one patient each. 7 individuals displayed areas of hypersignal in the cerebral white matter. 1/14 individuals who underwent abdominal ultrasound had a renal angiomyolipoma. No rhabdomyoma was found by echocardiography. A structured psychiatric interview diagnosed learning disabilities (6/28), impulsive behavior (1/28), anxiety disorder (4/28), and alcohol-related disorder (1/28). Psychiatric disorders were milder in the younger generations.
This study expands the phenotypic spectrum in familial TSC2 and demonstrates extremely mild clinical features in many affected individuals, in particular a benign prognosis of epilepsy. 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).
[Supported by: National Epifellows Foundation]