Glioblastoma multiforme in a child with tuberous sclerosis complex.

Tuberous Sclerosis Complex (TSC) is characterized by the presence of benign tumors in the brain, kidneys, heart, eyes, lungs, and skin. The typical brain lesions are cortical tubers, subependimal nodules and subependymal giant-cell astrocytomas. The occurrence of malignant astrocytomas such as glioblastoma is rare. We report on a child with a clinical diagnosis of TSC and a rapidly evolving glioblastoma multiforme. Genetic analysis identified a de novo mutation in TSC2. Molecular characterization of the tumor was performed and discussed, as well as a review of the literature where cases of TSC and glioblastoma multiforme are described. Although the co-occurrence of TSC and glioblastoma multiforme seems to be rare, this possible association should be kept in mind, and proper clinical and radiological follow up should be recommended in these patients.

Interstitial 6q microdeletion syndrome and epilepsy: a new patient and review of the literature.

Interstitial deletions of the long arm of chromosome 6 represent a rare genomic disorder. Variable phenotypes has been reported in patients carrying this deletion, including facial dysmorphisms, intellectual disability/developmental delay, growth retardation and hypotonia, upper limb and cardiac malformations, and Prader-Willi (PWS)-like features. We describe a new patient with an interstitial 6q deletion of 11.58 Mb detected by CGH-Array, who showed facial dysmorphic features, small hands and feet, and severe dorsal scoliosis. Ataxic gait and frequent hand stereotypies were also noted. She started having seizures at 14 years, characterized by loss of consciousness, clonic jerks of the limbs, roaring breathing, fixed gaze, and generalized hypotonia. In the course of the disease she experienced cluster of seizures requiring intensive treatment. The electroencephalographic recording showed slowing of the background activity and bilateral paroxysmal activity over the posterior regions. Review of the literature done to pinpoint the epileptological features of the syndrome identified heterogeneous descriptions of the electro-clinical picture in patients with interstitial 6q deletions. Genotype-phenotype correlations of this syndrome have been lacking until recently, when patients can be characterized with microarray-based comparative genomic hybridization. Description of additional patients with interstitial 6q deletions will help to delineate candidate genes associated with particular phenotypes.

Long-term outcome of epilepsy with onset in the first three years of life: Findings from a large cohort of patients.

BACKGROUND: To describe the clinical features of patients with seizure onset within the first three years of life, and to evaluate risk factors for long-term prognosis. METHODS: We selected 266 patients among 3096 individuals consecutively observed at a single Epilepsy Center between 1992 and 2012, and retrospectively analyzed their clinical, EEG, neuro-radiological and genetic characteristics. RESULTS: Mean ages at epilepsy onset and at follow-up were 14.9 months and 29.3 years, respectively. Mean follow-up period 8.2 years. We identified a recognizable etiology in 147 individuals (55.2%), while 76 (28.6%) were classified as unknown cause and 43 (16.2%) as genetic, according to the ILAE criteria. Thirty-four patients (27.9%) had a confirmed genetic diagnosis and 12 (9.8%) had a metabolic diagnosis. Febrile seizures (p = 0.008), positive family history (p = 0.049), drug resistance (p = 0.048), moderate (p = 0.04) and severe intellectual disability (p = 0.005) were significantly more frequent in patients with seizure onset 0-12 months than in those with onset 13-36 months. Multiple regression analysis demonstrated a link between early age of epilepsy onset and intellectual disability (p = 0.008). No further variables were significantly associated with age at epilepsy onset (for etiology p = 0.095, for drug resistance p = 0.646, and for neuro-radiological findings p = 0.087). CONCLUSION: Our study demonstrated worse outcome in symptomatic epilepsies in a large and representative sample. We also confirmed that the earlier age at seizure onset, the poorest the epilepsy outcome.

Blood oxidative stress and metallothionein expression in Rett syndrome: Probing for markers.

OBJECTIVES: Oxidative stress seems to be involved in Rett syndrome (RTT). The aim of this study was to assess the antioxidant status in RTT children with MECP2 gene mutations with respect to healthy controls, and to explore novel blood antioxidant markers for RTT severity. METHODS: In erythrocytes from RTT females aged 2-14 years (n = 27) and age-matched controls (n = 27), we measured the levels of malonaldehyde and the activity of two antioxidant enzymes, Cu/Zn-superoxide dismutase and catalase, by spectrophotometric assays. In leukocytes, the expression of metallothioneins, the main non-enzymatic antioxidants, was assessed by real-time RT-PCR. In nine selected RTT children, methylome analysis was also performed. RESULTS: Blood of RTT patients showed increased lipid peroxidation and a dysregulated pattern of MT expression, while enzymatic activities did not change significantly with respect to controls. Moreover, we observed no epigenetic dysregulation in CpG-enriched promoter regions of the analysed genes but significant hypomethylation in the random loci. CONCLUSIONS: As the haematic level of MT-1A directly correlates with the phenotype severity, this metallothionein can represent a marker for RTT severity. Moreover, the attempt to link the level of blood oxidative stress with MECP2 mutation and specific clinical features led us to draw some interesting conclusions.

Autism spectrum disorder in tuberous sclerosis complex: searching for risk markers.

BACKGROUND: Neuropsychiatric disorders are present in up to 90% of patients with Tuberous Sclerosis Complex (TSC), and represent an important issue for families. Autism Spectrum Disorder (ASD) is the most common neurobehavioral disease, affecting up to 61% of patients. The aims of this study were: 1) to assess the prevalence of ASD in a TSC population; 2) to describe the severity of ASD; 3) to identify potential risk factors associated with the development of ASD in TSC patients. METHODS: We selected 42 individuals over age 4 years with a definite diagnosis of TSC and followed at a TSC clinic in Northern Italy. We collected and reported clinical and genetic data, as well as cognitive level, for each of them. We administered the Social Communication Questionnaire (SCQ) as a reliable screening tool for ASD, and performed comparisons between the average scores and each clinical and genetic feature. RESULTS: Seventeen out of 42 patients (40.5%) had a score at the SCQ suggestive of ASD (≥15 points). When calculated for each cognitive level category, the average SCQ score tended to be progressively higher in patients with a worse cognitive level, and the number of pathological SCQ scores increased with worsening of intellectual disability. With respect to ASD severity, the scores were equally distributed, indicating that the degree of ASD in TSC patients may have a large variability. By comparing the average SCQ scores with the clinical features, we found statistically significant correlations with epilepsy, seizure onset before age one year, spasms, mutations in TSC2, cognitive level, sleep disorders, and other psychiatric problems, but not with seizure frequency, tubers localization and gender. CONCLUSIONS: Our study showed a prevalence of ASD of 40.5%, confirming the higher risk for this disorder in patients with TSC. However, the severity seems to have a notable variability in TSC patients. Risk factors for ASD are epilepsy, infantile spams, and mutations in TSC2.