In an Italian population of 275 unrelated men affected by adult-onset sporadic progressive cerebellar ataxia, the authors found six patients carrying an FMR1 gene premutation. Age at onset (range, 53 ...to 69 years) and clinical-neuropathologic findings were consistent with the fragile-X tremor ataxia syndrome (FXTAS), although tremor was not as common as previously described. FXTAS accounted for 4.2% of the cases diagnosed at >50 years, suggesting that it is a frequent genetic cause of late-onset sporadic ataxia.
Large TSC gene rearrangements are not rare findings in tuberous sclerosis. Interestingly, all deletions, duplications and inversions so far described involve TSC2, none being associated with TSC1. In ...order to shed light on the structural basis of the preferential DNA rearrangements in TSC2 over TSC1 and to assess, in an unselected patient population, the prevalence of large re-arrangements in both TSC loci, we screened 202 tuberous sclerosis patients consecutively referred at our center. Southern blot analysis on EcoRI+HindIII double-digested DNA identified 19 partial or full-length gene deletions: three involved TSC1 and sixteen TSC2. The breakpoint sequence of seven internal deletions, three in TSC1 and four in TSC2, allowed us to speculate on the mechanism favoring TSC2 unequal recombinations and to identify a deletion hot spot that lies in TSC1 and that may be relevant in the routine genetic testing of tuberous sclerosis. Briefly, three major features appear to distinguish TSC1 from TSC2 deletions: (1) deletion size: all TSC1 deletions are within the transcriptional unit, whereas 12 of the 16 TSC2 deletions have at least one external breakpoint; (2) location within the gene: all TSC1 deletions are confined to the 3'end of the gene (all three 5' breakpoints being located in intron 20) thus resulting in the same frameshift mutation following amino acid K875, whereas the TSC2 internal breakpoints appear to be scattered along the gene; (3) preference for recombinatorial sequences: six out of eight internal TSC2 breakpoints map within Alu repeats, whereas none of the three TSC1 deletions appear to be Alu-mediated. Indeed, in the latter gene, unique structural features (a purine-rich tract flanked by pyrimidine-rich segments) surrounding one of the two identified breakpoint cluster regions might play a role in promoting inappropriate recombinations.
Several diagnostic strategies have been applied to the detection of
FMR1 gene repeat expansions in fragile X syndrome. Here, we report a novel polymerase chain reaction-based strategy using the ...Expand Long Template PCR System (Roche Diagnostics, Mannheim, Germany) and the osmolyte betaine. Repeat expansions up to ∼330 CGGs in males and up to at least ∼160 CGGs in carrier women could be easily visualized on ethidium bromide agarose gels. We also demonstrated that fluorescence analysis of polymerase chain reaction products was a reliable tool to verify the presence of premutation and full mutation alleles both in males and in females. This technique, primarily designed to detect premutation alleles, can be used as a routine first screen for expanded
FMR1 alleles.
...patients II.1 and II.2 are among the mildest A-T variant phenotypes so far described. ...while the stabilisation of p53 following ionising radiation is delayed in A-T cells, the kinetics and ...magnitude of their response in NBS and A-TLD cells are essentially unaffected, 16- 20 suggesting that ATM/p53 is not the sole pathway involved in cerebellar degeneration. Since p53 loss is also critical to tumour development, retention of partial p53 phosphorylation could also explain the absence of lymphoid tumours in this variant.
Autosomal dominant cerebellar ataxias are a clinical and genetically heterogeneous group of progressive neurodegenerative diseases, at present associated with 22 loci (spinocerebellar ataxia SCA ...1-SCA8, SCA10-SCA19, SCA21, SCA22, fibroblast growth factor 14 FGF14-SCA, and dentatorubral-pallidoluysian atrophy DRPLA). The relevant gene has been identified in 12 cases (SCA1-3, SCA6-8, SCA10, SCA12, FGF14, and DRPLA), and in all but the recently identified SCA14, SCA17, PRKCG and FGF14 genes, the defect consists of the expansion of a short nucleotide repeat.
To investigate the relative prevalence of SCA1-3, SCA6-8, SCA10, SCA12, and SCA17 gene expansions in Italian families with hereditary ataxia, specifically to verify the occurrence of SCA10, SCA12, and SCA17 in Italy; and to analyze samples from probands with negative test results at the initial screening by means of the repeat expansion detection technique to identify CAG/CTG expansions in novel loci.Patients Two hundred twenty-five unrelated Italian index cases with hereditary ataxia, most (n = 183) of whom presented with a clear dominantly transmitted trait.
We found that SCA1 and SCA2 gene mutations accounted for most cases (21% and 24%, respectively). We found SCA3, SCA6, SCA7, SCA8, and SCA17 to be very rare (approximately 1% each), and no case of SCA10 or SCA12 was identified. Half of the index cases (113/225) were negative for expansions in the known SCA genes. Repeat expansion detection analysis performed on 111 of these cases showed a CAG/CTG repeat expansion of at least 50 triplets in 22 (20%). Twenty-one of 22 expansions could be attributed to length variation at 2 polymorphic loci (expanded repeat domain CAG/CTG 1 ERDA1 or CTG repeat on chromosome 18q21.1 CTG18.1). In 1 patient, the expansion was assigned to the DRPLA gene.
The distribution of SCA1-3 and SCA6-7 gene mutations is peculiar in Italy. We found a relatively high frequency of SCA1 and SCA2 gene expansions; SCA3, SCA6, and SCA7 mutations were rare, compared with other European countries. No SCA10 or SCA12 and only a few SCA8 (2/225) and SCA17 (2/225) families were detected. In patients negative for defects in known SCA genes, repeat expansion detection data strongly suggest that, at least in our population, CAG/CTG expansions in novel genes should be considered an unlikely cause of the SCA phenotype.
Existe abundante información e investigaciones sobre las desigualdades en salud en Barcelona, pero este tema no estuvo claramente priorizado en la agenda política. Con la llegada al gobierno de un ...partido de la nueva izquierda (Barcelona en Comú) en 2015 hubo un impulso importante de la agenda política para reducir las desigualdades, también las de salud. El objetivo de esta revisión es describir el avance realizado respecto a las desigualdades en salud en estos 4 años, sobre todo en los ámbitos donde ha participado la salud pública. Respecto a la evidencia y la comunicación sobre las desigualdades en salud, se presentan los avances en el Informe Anual de Salud de Barcelona y la creación del Observatorio de Salud, Desigualdades e Impactos de las Políticas Municipales. Las políticas que se presentan se refieren a diferentes estrategias municipales, el Plan de Salud, el impulso del programa Barcelona Salud en los Barrios y el Plan para el Abordaje de las Desigualdades en la Agència de Salut Pública de Barcelona. La conjunción de la voluntad política, la capacidad técnica y el impulso de la ciudadanía han facilitado un avance en la ciudad de Barcelona en las políticas para reducir las desigualdades sociales en salud.
There is a wealth of information and research on health inequalities in Barcelona, but this issue has not been clearly prioritised on the political agenda. The arrival in government of a new left-wing party (Barcelona en Comú) in 2015, gave an important boost to the political agenda to reduce inequalities and health inequalities. The aim of this review is to describe the progress made in relation to health inequalities in these four years and especially in the areas involving public health. With respect to evidence and communication on health inequalities, the progress made is presented in the Barcelona annual health report and the creation of the Observatory on Health, Inequalities and Impacts of Municipal Policies. The policies presented refer to different municipal strategies, the Health Plan, the promotion of the Barcelona Health in the Neighbourhoods programme and the Plan for Tackling Inequalities in the Barcelona Public Health Agency. The combination of political will, technical capacity and the drive of citizens have facilitated progress in the city of Barcelona in policies to reduce social inequalities in health.
PDF
