Luca Pradotto

MDM2 overexpression is associated with short survival in adults with medulloblastoma.

In adult medulloblastoma, postoperative radiotherapy is significantly effective in prolonging time to recurrence and survival time; however, the response of individual cases to radiotherapy, that is the total survival, is different. Apoptosis is an important cellular response to radiation. It can be hypothesized that the individual radiosensitivity of medulloblastomas depends on the individual capability to undergo apoptosis. p53 protein is involved in the apoptotic response to ionizing radiation; loss of function of p53 can be the consequence not only of TP53 mutations, but also of amplification and/or overexpression of the MDM2 gene. We have analyzed cerebellar medulloblastomas from 51 adults (>16 years of age) for MDM2 gene amplification (by differential polymerase chain reaction assay), TP53 gene mutation (by polymerase chain reaction single-strand conformation polymorphism analysis of exons 5-8), and immunohistochemical expression of p53 (clone DO1) and MDM2 (clone IF2). The results have been evaluated in relation to age, tumor location, classic or desmoplastic type, MIB-1 labeling index, and total survival. No tumor had MDM2 amplification. Ten tumors had MDM2 positive tumor cells. One case had a mutated TP53 gene; 16/51 cases had intense p53 immunostaining. Only 2 MDM2 protein-positive tumors were also p53-positive. Both subgroups of MDM2 - and p53-positive tumors had a significantly shorter postoperative survival. In conclusion, the overexpression of MDM2 protein and the accumulation of wild-type p53 are unrelated in adult medulloblastoma; they may result in a reduced apoptotic response after radiotherapy and contribute to a shortened survival. Also, MDM2 amplification and TP53 gene mutation are rare events in medulloblastomas of adults.

Molecular genetic changes in a series of neuroepithelial tumors of childhood.

Amplification of the EGFR, mdm2, CDK4 and PDGFR A genes has been widely demonstrated in adult malignant gliomas, almost exclusively glioblastomas. To determine the role of these mutational events in pediatric astrocytic gliomas we investigated the presence of EGFR, mdm2, CDK4 and PDGFR A gene amplification in 38 childhood brain tumor biopsies, including 24 low-grade astrocytomas and 14 malignant tumors. We used differential PCR assay on DNA extracted either from paraffin embedded or frozen tissues. EGFR gene amplification was detected in 4 out of 14 malignant tumors; no low-grade astrocytoma showed amplification. Tumors with EGFR gene amplification were negative for the presence of p53 mutations, as observed in a previous study. One glioblastoma showed PDGFR A amplification, while no amplifications were observed for mdm2 and CDK4 genes.These data are in line with those obtained from studies on gliomas of adults and suggest the existence of two different subsets of malignant gliomas also in pediatric brain tumors: one carrying EGFR gene amplification, the other showing p53 mutations.

A new NOTCH3 mutation presenting as primary intracerebral haemorrhage

Primary intracerebral haemorrhages (PICH) are defined as haemorrhages within the brain parenchyma in the absence of readily identifiable causes. CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a hereditary vascular disease and its mainly clinical manifestations are early-onset infarcts. Spontaneous lobar haematomas are a rare occurrence. We report a very unusual presentation of CADASIL in a 65 year-old man carrying a new NOTCH3 mutation. The clinical onset of the disease was related to an intracerebral haematoma following colon surgery and causing a delirium. In brief, our report suggests that CADASIL must be considered in patient with PICH.

An Italian family with Ala-47 transthyretin mutation associated with cardiomyopathy and polyneuropathy

We describe two Italian first cousins with familial amyloidotic polyneuropathy associated with transthyretin variant consisting of the substitution of alanine for glycine at codon 47 (TTR Ala-47), from a family with a history of cardiac failure. The 40-year-old patient presented with autonomic dysfunction and the 44-year-old cousin with congestive heart failure. Both developed sensorimotor and autonomic polyneuropathy. Since a similar clinical picture has been described in another Italian family, the cardiac involvement must be regarded as a salient and early feature of the TTR Ala-47 mutation.

Episodic ataxia and SCA6 within the same family due to the D302N CACNA1A gene mutation

Several dominant mutations of CACNA1A gene were associated with at least three different allelic disorders: spino-cerebellar ataxia type 6 (SCA6), episodic ataxia type 2 (EA2), and familial hemiplegic migraine-1 (FHM1). It is generally thought that loss-of-function mutations are associated with EA2, gain-of-function missense mutations with FHM1, and abnormal CAG expansions with SCA6. But, overlapping features, atypical symptoms and co-occurrence of distinct phenotypes within the same family were reported. We describe a four generation family showing different phenotypes ranging from EA2 to SCA6 and carrying the p.D302N CACNA1A gene mutation. In our family the phenotypes maintained separate and gender differences corresponding to different phenotypes were observed.

Most recent common ancestor of TTR Val30Met mutation in Italian population and its potential role in genotype-phenotype correlation

Abstract Introduction: Transthyretin (TTR)-related amyloidosis is characterized by autosomal transmission of amyloidogenic mutated TTR. Val30Met is one of the most common amyloidogenic TTR mutations, showing a worldwide distribution with phenotypic heterogeneity among human populations. Multiple founder mutations for Val30Met foci have been hypothesized and the different origins may explain the phenotypic variability. The aim of our study is to determine the origin of Italian Val30Met and to analyze the genetic relationship of other Val30Met foci. Methods: We analyzed the origin of Italian Val30Met through 11 microsatellite markers around the TTR gene in 29 patients and 34 healthy controls. Results: Our genetic analysis showed an estimated age of origin of 34–36 generations ago for the Italian Val30Met. Comparing Italian Val30Met haplotypes with those from Sweden and Portugal highlights relevant differences that seem to be consistent with an independent origin of Italian Val30Met mutation. This genetic evidence agrees with the disease phenotypic variation in these populations. Discussion and conclusions: Italian Val30Met mutation should have originated before the Portuguese and Swedish Val30Met ones (which arose through independent mutational events). This indicates a genetic diversity in the surrounding regions of three different Val30Met mutations, supporting the hypothesis that TTR non-coding regions may contribute to phenotypic heterogeneity.

Non-coding variants contribute to the clinical heterogeneity of TTR amyloidosis

Coding mutations in TTR gene cause a rare hereditary form of systemic amyloidosis, which has a complex genotype–phenotype correlation. We investigated the role of non-coding variants in regulating TTR gene expression and consequently amyloidosis symptoms. We evaluated the genotype–phenotype correlation considering the clinical information of 129 Italian patients with TTR amyloidosis. Then, we conducted a re-sequencing of TTR gene to investigate how non-coding variants affect TTR expression and, consequently, phenotypic presentation in carriers of amyloidogenic mutations. Polygenic scores for genetically determined TTR expression were constructed using data from our re-sequencing analysis and the GTEx (Genotype-Tissue Expression) project. We confirmed a strong phenotypic heterogeneity across coding mutations causing TTR amyloidosis. Considering the effects of non-coding variants on TTR expression, we identified three patient clusters with specific expression patterns associated with certain phenotypic presentations, including late onset, autonomic neurological involvement, and gastrointestinal symptoms. This study provides novel data regarding the role of non-coding variation and the gene expression profiles in patients affected by TTR amyloidosis, also putting forth an approach that could be used to investigate the mechanisms at the basis of the genotype–phenotype correlation of the disease.

Recurrent transient global amnesia as presenting symptoms of CADASIL

Despite transient global amnesia is considered unusual in Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and causal relation is still unclear, this report suggests to consider CADASIL in those patients with recurrent transient global amnesia, especially when MRI shows multifocal hyperintensities affecting the cerebral white matter or when it is followed by cognitive decline.

Population diversity of the genetically determined TTR expression in human tissues and its implications in TTR amyloidosis

BackgroundTransthyretin (TTR) amyloidosis is a hereditary disease with a complex genotype-phenotype correlation. We conducted a literature survey to define the clinical landscape of TTR amyloidosis across populations worldwide. Then, we investigated whether the genetically determined TTR expression differs among human populations, contributing to the differences observed in patients. Polygenic scores for genetically determined TTR expression in 14 clinically relevant tissues were constructed using data from the GTEx (Genotype-Tissue Expression) project and tested in the samples from the 1,000 Genomes Project.ResultsWe observed differences among the ancestral groups and, to a lesser extent, among the investigated populations within the ancestry groups. Scandinavian populations differed in their genetically determined TTR expression of skeletal muscle tissue with respect to Southern Europeans (p = 6.79*10−6). This is in line with epidemiological data related to Swedish and Portuguese TTR Val30Met endemic areas. Familial amyloidotic cardiomyopathy (TTR deposits occur primarily in heart tissues) presents clinical variability among human populations, a finding that agrees with the among-ancestry diversity of genetically determined TTR expression in heart tissues (i.e., Atrial Appendage p = 4.55*10−28; Left Ventricle p = 6.54*10−35).ConclusionsGenetically determined TTR expression varied across human populations. This might contribute to the genotype-phenotype correlation of TTR amyloidosis.

Electrogastrographyc activity in Parkinson's disease patients with and without motor fluctuations

Gastroenteric dysfunctions are very common in Parkinsons disease, but their relationship with dopaminergic response and motor fluctuations is still unclear. Electrogastrography is a noninvasive method for measuring gastric myoelectrical activity.