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Abstract Despite multiple sexual exposure to HIV-1 virus, some individuals remain HIV-1 seronegative (exposed seronegative, ESN). The mechanisms underlying this resistance remain still unclear, although a multifactorial pathogenesis can be hypothesised. Although several genetic factors have been related to HIV-1 resistance, the homozigosity for a mutation in CCR5 gene (the 32 bp deletion, i.e. CCR5-Delta32 allele) is presently considered the most relevant one. In the present study we analysed the genotype at CCR5 locus of 30 Italian ESN individuals (case group) who referred multiple unprotected heterosexual intercourse with HIV-1 seropositive partner(s), for at least two years. One hundred and twenty HIV-1 infected patients and 120 individuals representative of the general population were included as control groups. Twenty percent of ESN individuals had heterozygous CCR5-Delta 32 genotype, compared to 7.5% of HIV-1 seropositive and 10% of individuals from the general population, respectively. None of the analysed individuals had CCR5-Delta 32 homozygous genotype. Sequence analysis of the entire open reading frame of CCR5 was performed in all ESN subjects and no polymorphisms or mutations were identified. Moreover, we determined the distribution of C77G variant in CD45 gene, which has been previously related to HIV-1 infection susceptibility. The frequency of the C77G variant showed no significant difference between ESN subjects and the two control groups. In conclusion, our data show a significantly higher frequency of CCR5-Delta 32 heterozygous genotype (p = 0.04) among the Italian heterosexual ESN individuals compared to HIV-1 seropositive patients, suggesting a partial protective role of CCR5-Delta 32 heterozygosity in this cohort.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by homozygous mutations of the SMN1 gene. Based on clinical severity, three forms of SMA are recognized (type I-III). All patients have at least one (usually 2-4) copies of a highly homologous gene (SMN2) which produces insufficient levels of functional SMN protein, due to alternative splicing of exon7. Recently, evidence has been provided that SMN2 expression can be enhanced by different strategies. The availability of potential candidates to treat SMA has raised a number of issues, including the availability of data on the natural history of the disease, the reliability and sensitivity of outcome measures, the duration of the studies, and the number and clinical homogeneity of participating patients. Equally critical is the availability of reliable biomarkers. So far, different tools have been proposed as biomarkers in SMA, classifiable into two groups: instrumental (the Compound Motor Action Potential, the Motor Unit Number Estimation, and the Dual-energy X-ray absorptiometry) and molecular (SMN gene products dosage, either transcripts or protein). However, none of the biomarkers available so far can be considered the gold standard. Preclinical studies on SMA animal models and double-blind, placebo-controlled studies are crucial to evaluate the appropriateness of biomarkers, on the basis of correlations with clinical outcome. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by homozygous mutations of the SMN1 gene. Three forms of SMA are recognized (type I–III) on the basis of clinical severity. All patients have at least one or more (usually 2–4) copies of a highly homologous gene (SMN2), which produces insufficient levels of functional SMN protein, because of alternative splicing of exon 7. Recently, evidence has been provided that SMN2 expression can be enhanced by pharmacological treatment. However, no reliable biomarkers are available to test the molecular efficacy of the treatments. At present, the only potential biomarker is the dosage of SMN products in peripheral blood. However, the demonstration that SMN full-length (SMN-fl) transcript levels are reduced in leukocytes of patients compared with controls remains elusive (except for type I). We have developed a novel assay based on absolute real-time PCR, which allows the quantification of SMN1-fl/SMN2-fl transcripts. For the first time, we have shown that SMN-fl levels are reduced in leukocytes of type II–III patients compared with controls. We also found that transcript levels are related to clinical severity as in type III patients SMN2-fl levels are significantly higher compared with type II and directly correlated with functional ability in type II patients and with age of onset in type III patients. Moreover, in haploidentical siblings with discordant phenotype, the less severely affected individuals showed significantly higher transcript levels. Our study shows that SMN2-fl dosage in leukocytes can be considered a reliable biomarker and can provide the rationale for SMN dosage in clinical trials. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is caused by insufficient levels of survival motor neuron (SMN) protein. Recently, we found that sodium 4-phenylbutyrate (PB), a well-tolerated FDA approved drug, enhances SMN gene expression in vitro. We provide here the first evidence that oral administration of PB (triButyrate®) significantly increases SMN expression in leukocytes of SMA patients. This finding provides a strong rationale to further investigate the effects of PB as also supported by preliminary clinical data.European Journal of Human Genetics (2005) 13, 256-259. doi:10.1038/sj.ejhg.5201320 Published online 3 November 2004 [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 7 (SCA7) is an autosomal-dominant, late-onset, slowly progressive disorder, primarily characterized by gradual loss of motor coordination, resulting from dysfunction and degeneration of the cerebellum and its connecting pathways. The disease is caused by expansion of a CAG trinucleotide repeat within the SCA7 gene, which encodes a polyglutamine tract within a novel protein, termed ataxin-7. The expansion of polyglutamine-encoding CAG repeats in dissimilar genes underlies eight neurodegenerative conditions besides SCA7, including a number of dominant ataxias related to SCA7. Although elongated polyglutamine itself can initiate neuronal dysfunction and death, its toxicity is modulated by the context of the disease proteins, as evidenced by the differing clinical and pathological presentation of the various disorders. In this respect, it is exciting that SCA7 constitutes the only polyglutamine disorder, in which the photoreceptors of the retina are also severely affected, leading to retinal degeneration and blindness. Since the discovery of the SCA7 mutation, numerous studies attempted to pinpoint the molecular mechanisms underlying the unique features of SCA7, particularly the retinal involvement. Here we summarize the clinical, pathological, and genetic aspects of SCA7, and review the current understanding of the pathogenesis of this disorder.European Journal of Human Genetics (2004) 12, 2-15. doi:10.1038/sj.ejhg.5201108 Published online 22 October 2003 [ABSTRACT FROM AUTHOR]

Studies the role of the survival motor neuron (SMN) gene in the modulation of disease severity in spinal muscular atrophy patients. Genetic basis for the clinical variability in disease severity; Possibility that some SMN2 genes may be functionally different due to sequence variations or rearrangements.

The presence of the apolipoprotein E (APOE) epsilon4 allele is a definite risk factor for the onset of Alzheimer's disease (AD). Its presence seems to affect especially the memory in the early stage of the disease, but the effect on the progression of the disease and survival is still controversial. Some longitudinal studies could be influenced by variables other than APOE, such as the response to medical treatment, rehabilitation therapy and inclusion of patients at different stages of progression at baseline. Moreover, the inclusion in the same study sample of patients of different ages at onset of the disease (below 65 or above 80 years) appears arbitrary. In our study, we evaluated a population of newly diagnosed untreated AD patients at their first neuropsychological examination and with the onset of their first symptoms not longer than 3 years ago. In order to analyse the different effects of the APOE epsilon4 allele on the different ages at the onset of the disease, we split the study sample into two groups: (1) subjects under 65 years [early-onset AD (EOAD); n = 30] and subjects over 70 years [late-onset AD (LOAD); n = 41], excluding subjects with an age of onset between 66 and 69 years. Our results show that the APOE epsilon4 allele carriers are characterised by a different neuropsychological pattern at the disease onset; however, only in the EOAD group is this effect significant: in EOAD, the epsilon4 allele carriers obtained worse performances in learning, long-term verbal memory and general intelligence tasks. On the contrary, in LOAD patients, the pattern of cognitive impairment at the onset is not dependent on the possession of an epsilon4 allele in the genotype. Such data could suggest a careful control of the study sample concerning age at the onset of the disease since APOE could play a different role in EOAD and LOAD mainly due to the different pathogenic mechanism at the onset and evolution of AD., (Copyright 2004 S. Karger AG, Basel)

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease, characterized by degeneration of the anterior horn cells of the spinal cord. SMA presents with a highly variable phenotype ranging from very severe to mild (type I-III). No cure for SMA is available at present. All forms of SMA are caused by homozygous loss of the functional survival motor neuron (SMN1) gene. However, all patients have one or more copies of the SMN2 gene, nearly identical to SMN1. Both genes encode the SMN protein but the level produced by SMN2 is insufficient to protect from disease. Increasing SMN2 gene expression could be of considerable therapeutic importance. The aim of this study was to assess whether SMN2 gene expression can be increased by 4-phenylbutyrate (PBA). Fibroblast cell cultures from 16 SMA patients affected by different clinical severities were treated with PBA, and full-length SMN2 transcripts were measured by real-time PCR. In all cell cultures, except one, PBA treatment caused an increase in full-length SMN2 transcripts, ranging from 50 to 160% in type I and from 80 to 400% in type II and III cultures. PBA was found also effective in enhancing SMN protein levels and the number of SMN-containing nuclear structures (gems). These data show that SMN expression is considerably increased by PBA, and suggest that the compound, owing also to its favorable pharmacological properties, could be a good candidate for the treatment of SMA.