SUMMARYPurpose: Prevalence and long-term outcome of epilepsy in tuberous sclerosis complex (TSC) is reported to be variable, and the reasons for this variability are still controversial. Methods: We reviewed the clinical characteristics of patients with TSC who were regularly followed since 2000 at the San Paolo Multidisciplinary Tuberous Sclerosis Centre in Milan, Italy. From patient charts we collected data about age at epilepsy onset, seizure frequency and seizure type, history of infantile spasms (IS), epileptic syndrome, evolution to refractory epilepsy or to seizure freedom and/or medication freedom, electroencephalography (EEG) features, magnetic resonance imaging (MRI) findings, cognitive outcome, and genetic background. Key Findings: Among the 160 subjects (120 adults and 40 children), 116 (72.5%) had epilepsy: 57 (35.6%) were seizure-free, and 59 (36.9%) had drug-resistant epilepsy. Most seizure-free patients had a focal epilepsy (89.5%), with 54.4% of them drug resistant for a period of their lives. Epilepsy onset in the first year of life with IS and/or focal seizures was characteristic of the drug-resistant group of patients, as well as cognitive impairment and TSC2 mutation (p < 0.05). A small group of patients (7 patients, 4.4%) experienced a seizure only once; all of them had normal cognition. Significance: Although epilepsy management can be challenging in TSC, more than one third of patients had their seizures controlled: through monotherapy in 56% and by polytherapy in 32%. Moreover, 12% of the patients became seizure-free and were off medication. Identifying predictive features of epilepsy and cognitive outcome can ensure better management for patients with TSC and delineate genotype-phenotype correlations.

Tuberous sclerosis complex (TSC) is a tumor suppressor gene disorder characterized by mutations in the TSC1 or TSC2 genes. These mutations lead to the development of benign tumors involving smooth muscle cells, causing life-threatening lymphangioleiomyomatosis. We isolated and characterized two types of cells bearing a mutation in TSC2 exon 18 from a renal angiomyolipoma of a TSC patient: one population of alpha-actin-positive smooth muscle-like cells with loss of heterozygosity for the TSC2 gene (A(+) cells) and another of nonloss of heterozygosity keratin 8/18-positive epithelial-like cells (R(+) cells). Unlike control aortic vascular smooth muscle cells, A(+) cells required epidermal growth factor (EGF) to grow and substituting EGF with insulin-like growth factor (IGF)-1 failed to increase the cell number; however, omission of EGF did not cause cell loss. The A(+) cells constantly released IGF-1 into the culture medium and constitutively showed a high degree of S6K phosphorylation even when grown in serum-free medium. Exposure to antibodies against EGF and IGF-1 receptors caused a rapid loss of A(+) cells: 50% by 5 days and 100% by 12 days. Signal transduction mediated by EGF and IGF-I receptors is therefore involved in A(+) cell survival. These results may offer a novel therapeutic perspective for the treatment of TSC complications and lymphangioleiomyomatosis.

We compared the genome distribution, chromosomal allocation, and organization of the major and minor satellite DNAs (satDNAs) in 11 species and subspecies of the genus Mus. Southern blot analysis of the major and minor satDNAs showed similar fragment profiles in all 11 species, with the exception of M. cervicolor and M. cookii for the major satDNAs and M. caroli, M. cervicolor, and M. cookii for the minor satDNAs, where these sequences could not be detected by the probes used. In situ hybridization of the major and minor satDNA probes revealed chromosome-specific allocations of these sequences with quantitative species-specific patterns. Fluorometric analysis of the organization of the satellite sequences suggested that in the M. domesticus genome satDNA sequences are clustered in tandem repeats that are longer than those present in other Mus genomes. When compared with the other Mus genomes so far studied, the domesticus genome shows the highest quantity of satDNA sequences with a long-range organization of satDNA sequences.

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We examined 28 cases of primary bone lymphomas (PBL; stage IE) and 26 cases of systemic lymphomas involving the bone (SBL; stage IIE to IV). Two histologic types were prevalent: Diffuse large B-cell lymphomas (DLBCL; 26 PBL and 21 SBL) and CD30+ anaplastic large cell lymphomas (ALCL; 1 PBL and 4 SBL). A mature B phenotype (CD45+, CD20+, CD79a+, CDw75+/-, CD10-/+) was established in the DLBCL group. Bcl-2 immunoreactivity was demonstrated in 13/37 cases (35%), and bcl-6 immunostaining was observed in 22/32 cases (69%). ALCL showed null/T phenotype (CD3-/+; CD43+/-; CD30+), with ALK-1 expression in 3/3 cases. With use of a FR3A primer, a monoclonal pattern was demonstrated by PCR analysis in 22/41 lymphomas (54%). Bcl-2 translocation was identified in 2/41 cases (5%). This study details the clinical and pathological characteristics of bone lymphomas. Our immunohistochemical and molecular data suggest that most of them are "de novo" DLBCL and support their follicle center origin.

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The advent of pharmacological therapies for lymphangioleiomyomatosis (LAM) has made early diagnosis important in women with tuberous sclerosis complex (TSC), although the lifelong cumulative radiation exposure caused by chest computer tomography (CT) should not be underestimated. We retrospectively investigated, in a cohort of TSC outpatients of San Paolo Hospital (Milan, Italy) 1) the role of pulmonary function tests (PFTs) for LAM diagnosis, 2) the association between LAM and other features of TSC (e.g. demography, extrapulmonary manifestations, genetic mutations, etc.), and 3) the characteristics of patients with multifocal micronodular pneumocyte hyperplasia (MMPH). Eighty-six women underwent chest CT scan; pulmonary involvement was found in 66 patients (77%; 49% LAM with or without MMPH, and 28% MMPH alone). LAM patients were older, with a higher rate of pneumothorax, presented more frequently with renal and hepatic angiomyolipomas, and tended to have a TSC2 mutation profile. PFTs, assessed in 64% of women unaffected by cognitive impairments, revealed a lower lung diffusion capacity in LAM patients. In multivariate analysis, age, but not PFTs, resulted independently associated with LAM diagnosis. Patients with MMPH alone did not show specific clinical, functional or genetic features. A mild respiratory impairment was most common in LAM-TSC patients: In conclusions, PFTs, even if indicated to assess impairment in lung function, are feasible in a limited number of patients, and are not significantly useful for LAM diagnosis in women with TSC.