Learning disability and epilepsy in an epidemiological sample of individuals with tuberous sclerosis complex

BACKGROUND: Intellectual impairments are a recognized feature of tuberous sclerosis complex (TSC), but the frequency and degree of intellectual impairments has not been systematically studied in large epidemiological samples using standardized measures. As such, the form of the IQ distribution (uni- or bi-modal) has not been established and the relationship between IQ and other features (e.g. epilepsy history) is poorly delineated. To address these shortcomings, we assessed the intellectual abilities of a large epidemiological sample of individuals with TSC, drawn from the 'Wessex' area of SW England and compared them with the abilities of their unaffected siblings. METHOD: Standardized tests were used to estimate the abilities of 108 (56 males, 52 females, median age = 25, range = 4-75) individuals with TSC and 29 unaffected siblings (14 males, 15 females, median age = 18, range = 6-55). Seizure history was obtained from informants and medical records. RESULTS: Estimated IQ was bi-modally distributed: 55.5% had an IQ in the normal range; 14% had mild to severe impairments: and 30.5% had profound disability (IQ < 21). Forty-four per cent of the individuals with TSC had an IQ < 70. In the subset of normally intelligent individuals with TSC, IQ was normally distributed with a mean of 93.6. This mean was significantly lower than the mean IQ of unaffected siblings (IQ = 105.6). All individuals with learning disability had a history of seizures that usually commenced before 12 months of age and that often presented as infantile spasms. Multivariate analyses indicated that a history of seizures as well as a history of infantile spasms was predictive of the degree of intellectual impairment. CONCLUSIONS: Intellectual abilities were bi-modally distributed in a representative sample of individuals with TSC. The likelihood of impairment was associated with a history of seizures, particularly infantile spasms. The genetic and brain basis of these findings requires further investigation.     

Cytogenetic studies in tuberous sclerosis

A cytogenetic study was performed with cultures derived from peripheral blood, unaffected skin, and angiofibromas of four patients suffering from the sporadic form of tuberous sclerosis (TSC). Increased frequencies of unstable chromosomal anomalies were found in lymphocytes and in fibroblasts from unaffected skin of the patients. The slight increase of the overall rate of unstable anomalies observed in angiofibroma-derived cultures above that of lymphocytes and skin fibroblasts, respectively, could almost entirely be attributed to a higher frequency of dicentric chromosomes. Of the 17 facial angiofibromas from which a total of 20 cell cultures were established, nine showed a normal karyotype, while eight exhibited stable chromosomal rearrangements, among which 19 clonal types could be identified. Unbalanced forms of various translocations caused partial trisomies of the long arms of chromosomes 1, 3, 7, 10, and 15. There was no clustering of breakpoints to a particular chromosomal region, nor was one particular chromosome preferentially involved. Frequencies and kinds of rearrangements varied between cultures derived from different angiofibromas from the same patient and between different culture charges from the same tumor. Tetraploidy was not generally more abundant in the angiofibroma-derived cultures, but there were a few culture charges with exceedingly high rates of tetraploid cells. The occurrence of premature centromere disjunction (PCD), either affecting all chromosomes or only part of them in angiofibroma-derived cultures, first described in TSC by Scappaticci et al. could be confirmed.     

Non-penetrance in tuberous sclerosis.

Non-penetrance has not been reported in tuberous sclerosis when modern non-invasive investigations have been performed. We report a four generation family in which there was a subject with minimal expression and another with non-penetrance between a great grandfather and his great grandson. This situation highlights the need for full investigation of children of tuberous sclerosis patients before counselling a low recurrence risk for the disease.     

Deciduous teeth in tuberous sclerosis

Shed deciduous teeth from patients with tuberous sclerosis, cerebral palsy, Down syndrome, phenylketonuria and healthy persons were examined with a surface microscope. We found enamel pits in all 87 deciduous teeth from the 20 patients with tuberous sclerosis, but in none of the 253 deciduous teeth from 142 controls constituting patients with cerebral palsy, phenylketonuria and Down syndrome as well as healthy persons. Enamel pits always occurred in the facial surface of the central incisor, lateral incisor and canine, while the number of enamel pits in the other surfaces of the deciduous teeth varied from none to nine. Ground sections examined microscopically revealed an undisturbed pattern of incremental lines (Retzius striae) surrounding the pits. In five dental sacs from patients with tuberous sclerosis, microscopic examination showed that the inner surface of the operculum was remarkably more irregular than in control patients.     

Splenic involvement in tuberous sclerosis

Summary Three cases of tuberous sclerosis in neonates were found to have focal, frequently perivascular, collections of large cells with abundant eosinophilic cytoplasm. These cells resembled those found in brain lesions of tuberous sclerosis but did not stain for acidic protein. Ultrastructurally, they were characterized by many membrane bound cytoplasmic bodies, 90 to 270 nm in diameter, with amorphous contents. Filaments were not demonstrated. Their appearance is considered most consistent with histiocytic origin.Large cells with a histiocytic appearance and a superficial resemblance to those seen in the brain in tuberous sclerosis, but a different ultrastructure and reaction to GFAP staining, may be found in the spleen of neonates with this disease.     

Cyst-like cerebral lesions in tuberous sclerosis

Known brain manifestations of tuberous sclerosis (TSC) are cortical sclerotic tubera, giant cell astrocytomas, subependymal calcified nodules in the lateral walls of the lateral ventricles, and white matter heterotopias. In addition, small cyst-like lesions in the white matter have been described. We report on three TSC patients with hitherto undescribed large cyst-like cerebral lesions in subcortical and white matter locations. We emphasize that cystoid brain degeneration is a rare but typical cerebral manifestation of TSC and suggest that, in patients with such lesions, TSC should be taken into consideration.     

Pitted enamel hypoplasia in tuberous sclerosis

Thirty patients with tuberous sclerosis (from 29 different families) were examined for evidence of macroscopically visible pitted enamel hypoplasia. Of 23 patients with permanent teeth, 11 (48%) showed multiple enamel pits (mean 4.6 pits, range 3-9), but none were seen in six patients with deciduous teeth. Five of 563 controls (0.88%) had similar pitted enamel hypoplasia. Simple dental examination may be a useful adjunct in the assessment of patients with permanent teeth when a diagnosis of tuberous sclerosis is being considered, but is less likely to be helpful in the pre-school child.     

Pulmonary manifestations in tuberous sclerosis complex

Tuberous sclerosis complex has manifestations in many organ systems, including brain, heart, kidney, skin, and lung. The primary manifestations in the lung are lymphangioleiomyomatosis (LAM) and multifocal micronodular pneumocyte hyperplasia (MMPH). LAM affects almost exclusively women, and causes cystic lung destruction, pneumothorax, and chylous pleural effusions. LAM can lead to dyspnea, oxygen dependence, and respiratory failure, with more rapid disease progression during the premenopausal years. In contrast, MMPH affects men and women equally, causing small nodular pulmonary deposits of type II pneumocytes that rarely progress to symptomatic disease. Here, we review the clinical features and pathogenesis of LAM and MMPH.     

Reduced penetrance in tuberous sclerosis.

Two first cousins are reported with clinical evidence of tuberous sclerosis. The intervening brother and sister show no evidence of the disease on clinical and Wood's lamp examination, nor on CT scan.     

Variability of expression in tuberous sclerosis.

We present three families in whom a diagnosis of tuberous sclerosis is difficult to secure and we review published reports about similar cases. Tuberous sclerosis has been reported to affect as many as 1 in 9400 subjects in the population. The manifestations of this disease vary not only between but also within families. Currently no reliable method of prenatal diagnosis is available. For these reasons, subjects known to be at 50% risk should be assessed scrupulously to clarify their status. These cases illustrate the difficulties in the clinical diagnosis of tuberous sclerosis and further reinforce the need for a molecular method of determining whether an at risk subject has the disease.