Two new cases of acute promyelocytic leukemia following mitoxantrone treatment in patients with multiple sclerosis.
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Adult↗
Biomedical subjects
E Cocco
Publications and source records attributed to E Cocco.
Dementia, pyramidal system involvement, and leukoencephalopathy with a presenilin 1 mutation.
The authors describe four members of a family with a novel P284S presenilin 1 mutation presenting a clinical phenotype characterized by early-onset dementia, paratetraparesis, dysarthria, dysphagia, and marked involvement of brain white matter. The distinctive clinical and MRI findings in the family studied extend the phenotypic spectrum of dementia associated with mutation of the PS1 gene.
Adult↗
A novel Cx32 mutation causes X-linked Charcot-Marie-Tooth disease with brainstem involvement and brain magnetic resonance spectroscopy abnormalities.
The objective of this study was to study genetic and phenotypic features of a family with X-linked Charcot-Marie-Tooth consisting of a healthy father, affected mother, two affected sons and one healthy one. A detailed electrophysiological and neuroimaging study, along with sequencing of the Cx32 gene, was performed in all family members. A novel Cx32 123 G>C mutation, determining an aminoacid variation (Glu41Asp), was found in the mother and the affected sons. An alteration in brainstem evoked potentials was found in the mother and one affected son. The affected son, who underwent magnetic resonance imaging, showed symmetrical hyperintensities in paratrigonal white matter, not found in his heterozygous mother, while both subjects exhibited alterations in brain metabolite ratios derived from localised proton-magnetic resonance spectroscopy. These data extend previous findings about central nervous system involvement in Cx32 mutated subjects and further support a functional role of the protein expression in oligodendrocytes.
Adolescent↗
Interaction of loci within the HLA region influences multiple sclerosis course in the Sardinian population.
We examined the influence of alleles at the HLA loci, previously found to be associated with multiple sclerosis (MS) in Sardinia, on the clinical course of the disease in 835 relapsing (R) and 100 primary progressive (PP) patients. Multivariate analysis was carried out on predisposing 0301 or non-associated DPB1 alleles, susceptible or non-associated DRB1-DQB1 haplotypes, both predisposing and non-predisposing, and negatively and non-negatively associated D6S1683 alleles, taking interaction between them into account. Intra-patient analysis showed that the presence of the susceptible or protective D6S1683 allele interacting with predisposing DP 0301 modulated risk of PP disease. These findings suggest that a locus telomeric to HLA class I exerts an effect on alleles at the DPB1 locus in modulating disease course.
Adolescent↗
Vagal nerve stimulation effects on cerebellar tremor in multiple sclerosis.
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Adult↗
Multiple Sclerosis Severity Score: using disability and disease duration to rate disease severity.
BACKGROUND: There is no consensus method for determining progression of disability in patients with multiple sclerosis (MS) when each patient has had only a single assessment in the course of the disease. METHODS: Using data from two large longitudinal databases, the authors tested whether cross-sectional disability assessments are representative of disease severity as a whole. An algorithm, the Multiple Sclerosis Severity Score (MSSS), which relates scores on the Expanded Disability Status Scale (EDSS) to the distribution of disability in patients with comparable disease durations, was devised and then applied to a collection of 9,892 patients from 11 countries to create the Global MSSS. In order to compare different methods of detecting such effects the authors simulated the effects of a genetic factor on disability. RESULTS: Cross-sectional EDSS measurements made after the first year were representative of overall disease severity. The MSSS was more powerful than the other methods the authors tested for detecting different rates of disease progression. CONCLUSION: The Multiple Sclerosis Severity Score (MSSS) is a powerful method for comparing disease progression using single assessment data. The Global MSSS can be used as a reference table for future disability comparisons. While useful for comparing groups of patients, disease fluctuation precludes its use as a predictor of future disability in an individual.
Adult↗
HLA-DR,DQ and APOE genotypes and gender influence in Sardinian primary progressive MS.
The authors examined the influence of APOE and human leukocyte antigen-DRB1-DQB1 polymorphisms on the course of multiple sclerosis in 871 patients, 773 with relapsing and 98 with primary progressive disease, and 348 control subjects. The risk of the primary progressive course was increased (odds ratio = 6.81, p = 0.002) in women carrying the APOE4 but not the DRB1-DQB1 predisposing genotype, suggesting in this subgroup of patients a reciprocal influence between these genes and gender in modulating clinical variability of the disease.
Apolipoprotein E4↗
Intense immunosuppression followed by autologous stem cell transplantation in severe multiple sclerosis.
Aggressive forms of multiple sclerosis (MS) represent a limited group of demyelinating diseases that rapidly progress to severe disability. Currently available therapies are poorly effective against these clinical entities. Recently, it has been demonstrated that intense immunosuppression followed by autologous haematopoietic stem cell transplantation (AHSCT) can affect the clinical course of individuals with severe MS and completely abrogate the inflammatory activity detected by MRI. We report the result of the Italian phase 2 GITMO study, a multicentre study in which 21 MS patients, who were rapidly deteriorating and not responding to the usual therapeutic strategies, were treated with this procedure. The clinical effect of the treatment is long lasting, with a striking abrogation of inflammation detected by MRI findings. These results support a role for intense immunosuppression followed by ASCT as treatment in rapidly evolving MS cases unresponsive to conventional therapies.
Adult↗
The IVS1 +319 t>a of SOD1 gene is not an ALS causing mutation.
Amyotrophic lateral sclerosis (ALS) is caused by mutations in the gene for Cu/Zn superoxide dismutase (SOD1) in 10% of familial and sporadic cases. During the SOD1 analysis of 9 FALS and 121 SALS, in only one sporadic case we found the exonic mutation N19S; in 15 SALS patients we found a 319t>a variation in IVS1 sequence, at 108 bp upstream from exon 2. This variation has an unusually high frequency of 11% and is always in linkage disequilibrium with a described polymorphism in IVS3, +34a>c. The 319t>a variation is classified in two different public databases, HGMD and The ALS Online Database, as a splicing mutation and not as a polymorphism. The unusually high frequency of this mutation in our patients prompted us to determinate its frequency in 130 age- and gender- matched healthy controls and in 54 patients with Alzheimer's disease. We found again linkage disequilibrium with the polymorphism in intron 3, and the frequency of 11% and 7.8%, respectively. These results strongly support the idea that the IVS1 +319 t>a alone is not an ALS causing mutation, and that special care must be taken in the interpretation of data from mutations databases for correct genetic counselling.
Aged↗
Bias in parental transmission of the HLA-DR3 allele in Sardinian multiple sclerosis.
The authors analyzed the female: male (F:M) ratio according to the HLA-DRB1-DQB1 genotype in a cohort of multiple sclerosis (MS) patients from Sardinia, where the disease is associated with DR3 and DR4. In the whole cohort of 1,097 patients, F:M ratio was 2.24; however, it was 2.88 in DR3/DR3 and 2.52 in DR3/DRX (X#DR3 and DR4) individuals. Parental transmission of DR3 and DR4, assessed in a set of 565 case-parent triads, showed evidence of paternal inheritance of DR3 in affected women, thus explaining the excess of females in the DR3 category.
Alleles↗
The prevalence of pain in multiple sclerosis: a multicenter cross-sectional study.
In a multicenter cross-sectional study, the authors assessed pain in patients with multiple sclerosis (MS) using a symptom-oriented approach. Out of 2,077 questionnaires, we used 1,672 for data analysis. Pain and frequencies included trigeminal neuralgia 2%, Lhermitte's sign 9%, dysesthetic pain 18.1%, back pain 16.4%, and painful tonic spasms 11%. Comparison between different groups showed significant differences for age, Expanded Disability Status Scale, disease duration, and disease course, but not for sex. This study underlines the relevance of pain in the clinical history of MS.
Adolescent↗
Anticipation of age at onset in multiple sclerosis: a Sardinian cohort study.
BACKGROUND: To assess the temporal trend in multiple sclerosis (MS) onset during the last 50 years in Sardinia, Italy. METHODS: The authors used a cohort study to assess age at onset in 1,513 MS patients at the MS clinic in Cagliari, all born and living in Sardinia. They also assessed age at onset in 41 pairs of familial patients from two generations and 78 pairs of affected sibs. Each familial couple was paired with three couples of sporadic patients born in the same year as the familial ones. The time interval between the first symptoms and diagnosis was analyzed in first and second-diagnosed patients from both familial and control couples. RESULTS: Mean age at onset progressively decreased from the most remote to the most recent decade of birth (log-rank test 778.27, p < 0.0001), being 41 years in the former decade and 22 years in the latter. A genetic influence was ruled out, because the younger member of familial patients coming from two generations had onset 14.0 years earlier than the older one (p < 0.0001), as in the paired control couples (11.6 years, p < 0.0001). Moreover, mean onset in younger sibs was 3.4 years earlier than in older ones (p = 0.01), similar to that of control couples (4.1 years, p < 0.0001). CONCLUSION: Age at onset decreases progressively from older to younger generations in Sardinian MS patients. Nongenetic but recent widespread environmental changes might contribute to shortening of the preclinical phase-overt disease interval.
Adolescent↗
Genetic factors and the founder effect explain familial MS in Sardinia.
OBJECTIVE: To estimate the presence of familial aggregation and determine the contribution of genetic factors to familial clustering of MS in patients coming from Sardinia, a Mediterranean island considered a genetically homogeneous, isolated area having high disease incidence and prevalence. METHODS: Recurrence risk in siblings of 901 Sardinian patients and factors influencing risk (patient and sibling sex, patient age at onset, sibling birth cohort, and presence of affected relatives other than siblings) were examined. The presence of distant familial relationships among patients was evaluated by tracing the extended pedigrees of all patients with MS born in one Sardinian village. RESULTS: Twenty-three brothers and 36 sisters of the 2,971 siblings were affected with MS. Recurrence risk was greater in siblings of index patients with onset age less than 30 years (p < 0.01, increased risk 2.33 times) and having a relative with MS other than a sibling or parent (p < 0.01, increased risk 2.90 times). Pedigree analysis of patients from the village of L. showed that all 11 patients descended from 3 pairs of ancestors, whereas no cases occurred in the remaining 2,346 inhabitants. In descendants from the 3 couples, MS prevalence was dramatically greater than the regional average and 1.5 times greater than that observed in siblings of affected cases. CONCLUSIONS: Data from this study indicate that MS familial aggregation in Sardinians is influenced by genetic factors and that founder effect and the isolation of Sardinia can be considered causes of the enrichment of "etiologic" MS genes.
Adult↗
Dissection of the HLA association with multiple sclerosis in the founder isolated population of Sardinia.
Several studies have indicated that multiple sclerosis (MS) is associated and linked to the major histocompatibility complex (MHC)/human leukocyte antigen (HLA) region of chromosome 6p21.3, but the exact location and nature of the primarily associated locus within the HLA complex is still controversial and largely presumptive. By linkage disequilibrium mapping, we have systematically investigated this chromosome region in the founder population of Sardinia to determine the relative associations of the various loci with MS. An overall 11.4 Mb region, which encompasses the whole HLA complex, was scanned with 19 microsatellite markers and with single nucleotide polymorphisms within 12 functional candidate genes and assessed for MS association using the extended transmission disequilibrium test (ETDT). A peak of association represented by the three adjacent DRB1, -DQA1 and -DQB1 loci was detected in the class II region. Two additional less significant areas of association were detected, respectively, in the centromeric side of the class II region at the DPB1 locus and, telomeric of the classically defined class I loci, at the D6S1683 microsatellite. Conditional ETDT analysis indicated that these regions of association could be independent of each other. Within the main peak of association, DRB1 and DQB1 contribute to the disease association independently of each other whereas DQA1 had no detectable primary genetic effects. We evaluated the haplotype distribution at the region showing the strongest association and found five DQB1-DRB1 haplotypes positively associated with MS in Sardinia. These consistently included all the haplotypes previously found associated with MS in the various human populations, thus supporting a primary effect of the products of these loci in MS. Overall these results are consistent with a multilocus model of the MHC encoded susceptibility to MS.
Adolescent↗
ICAM-1 gene is not associated with multiple sclerosis in sardinian patients.
An increased amount of the intercellular adhesion molecule (ICAM) 1 molecule has been found in the blood of actively relapsing multiple sclerosis (MS) patients, but is unclear whether this enhanced expression is partially causative of the MS process, or whether it is merely an epiphenomenon of the inflammatory-immunological reaction. Using the transmission disequilibrium test (TDT), we studied exon 4 and exon 6 polymorphism of the ICAM-1 gene from 157 families with both parents, one affected and one healthy sib coming from Sardinia, an Italian island having a high incidence and prevalence of MS. TDT did not show variation in the expected 50:50 frequency in transmission in either healthy or affected sibs, using phenotypic or genotypic analysis. Moreover, independence from the predisposing HLA-DRB1-DQA1-DQB1 haplotype was confirmed by TDT analysis performed on patients stratified according to the presence or absence of the HLA-DRB1, DQA1, DQB1 Sardinian predisposing haplotypes. Our data suggest that the increased expression of the ICAM-1 molecule observed in both blood and periplaque microvessels may be considered a consequence of the inflammatory process rather than the result of a genetic variation.
Adult↗
Age at onset in multiple sclerosis.
Age at onset of multiple sclerosis (MS) can vary from childhood to adult life. Many reports have been carried out over the years concerning the role of age at onset in determining the disease outcome. In a sporadic MS population of 1463 patients with homogeneous clinical and demographic features, derived from three Italian neurological centres (Bari, Cagliari and Sassari), we analysed the relative weights of current age and age at onset on disease severity according to the expanded disability status scale (EDSS) score, by fixing the disease duration. The results of present study demonstrate that clinical disability in MS is influenced by the patient's age (p < 0.01) and not by the age at onset. Therefore, these data do not confirm the hypothesis that an early age at onset should be considered a favourable prognostic factor of the disease outcome.
Adolescent↗
Is multiple sclerosis severity a genetically influenced trait?
Multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system of unknown pathogenesis, is a complex disease with a multifactorial etiology determined by both genetic and environmental factors. The pathological entity MS has a wide phenotype, and also the severity of the disease is widely variable. Clinical heterogeneity of the disease might arise from different genotype-phenotype interactions. Results of recent studies and theories about the modifying role of different genes in the course and the severity of MS are here discussed.
Apolipoproteins E↗
The contribution of HLA to multiple sclerosis susceptibility in Sardinian affected sibling pairs.
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HLA Antigens↗