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Background: Blood biomarkers, that may improve the management of the pre−manifest phase of Huntington's disease (PRE−HD), are actively searched. We investigated telomere length (TL) and DNA damage signatures (DDS) as potential predictive biomarkers in peripheral blood mononuclear cells (PBMC) of PRE−HD and HD patients. Methods: We analysed the DNA isolated from fresh PBMC of 58 HD and 23 PRE−HD subjects with similar CAG expansion in the huntingtin (HTT) gene (44·20±2·85, 43·55±2·70; mean±SD) and 44 healthy controls (HC). We measured the TL by qPCR and double−strand DNA breaks by flow cytometric analysis of phosphorylated γ−H2AX (pγ−H2AX). Findings: PBMC from PRE−HD and HD groups showed shorter telomeres (p

Background:The primary aim of the present study was to determine the survival rates and identify predictors of disease duration in a cohort of Huntington's disease (HD) patients from Southern Italy.Methods:All medical records of HD patients followed between 1977 and 2008 at the Department of Neurological Sciences of Federico II University in Naples were retrospectively reviewed and 135 patients were enrolled in the analysis. At the time of data collection, 41 patients were deceased (19 males and 22 females) with a mean ± SD age at death of 56.6 ± 14.9 years (range 18-83).Results:The median survival time was 20 years (95% CI: 18.3-21.7). Cox regression analysis showed that the number of CAG in the expanded allele (HR 1.09 for 1 point triplet increase, p=0.002) and age of onset (HR 1.05 for 1 point year increase, p=0.022) were independent and significant predictors of lower survival rates.Conclusions:We believe that these findings are important for a better understanding of the natural history of the disease and may be relevant in designing future therapeutic trials.

CADASIL is a hereditary systemic vasculopathy which affects mainly small cerebral arteries and is caused by mutations in the Notch3 gene. Misfolding of Notch3 is linked to endoplasmic reticulum stress and increased reactive oxygen species, which may result in dysfunction of endothelial cells, inflammation and ischemia. Oxidative stress and inflammation may induce a rapid telomere shortening in peripheral blood leukocytes (PBLs). The aim of this study was to assess the telomere length in PBLs from 29 patients with a genetic diagnosis of CADASIL by using a modified quantitative real-time polymerase chain reaction based assay. PBL telomere length was significantly shorter in CADASIL patients (T/S ratio = 0.17, 95% CI, 0.14–0.20) than in the controls (T/S ratio = 0.31, 95% CI, 0.27–0.35, t-test p

OBJECTIVE—We explore the relationship among BMI, habitual diet, and the Pro12Ala polymorphism in the peroxisome proliferator–activated receptor (PPAR)γ2. RESEARCH DESIGN AND METHODS—The Pro12Ala variant was characterized in 343 unrelated type 2 diabetic patients who were consecutively seen at the outpatient clinic of a health district of the province of Naples. Anthropometric and laboratory parameters were measured; habitual diet was assessed by a validated semiquantitative food frequency questionnaire. RESULTS—The overall frequency of Ala12 was 12% (n = 42). BMI was significantly higher in Ala carriers than non-Ala carriers, whereas total daily energy intake or macronutrient composition of the diet were similar in the two groups. For further analysis, participants were stratified according to genotype and sex-specific quartiles of energy intake. BMI increased in both genotype groups with increasing energy intake (P < 0.03). BMI was similar in Ala carriers and non-Ala carriers (30.0 vs. 30.1 kg/m2, P > 0.10) in the lower quartile of energy intake but significantly higher in Ala carriers in the upper quartile (36.0 vs. 32.1 kg/m2, P < 0.001). Average daily energy intake and diet composition were comparable within each quartile for carriers or noncarriers of the Ala allele. Relative to the noncarriers, Ala carriers had a significantly lower energy intake per kilogram body weight, thus suggesting that the Ala allele is associated with a higher food efficiency. The confounding role of medications, glucose control, and physical exercise was ruled out. CONCLUSIONS—This study provides evidence of a differential susceptibility to fat accumulation, and, hence, weight gain, in response to habitual high energy intake for Ala carriers compared with Pro/Pro homozygotes.

Degeneration of substantia nigra has been described in spinocerebellar ataxia type 2 (SCA2). In this study, dopamine transporter (DAT) density with [123 I]FP-CIT SPECT was studied in six SCA2 patients with no parkinsonian signs, six Parkinson's disease (PD) patients, and six controls. Marked striatal DAT loss was found in both SCA2 and PD patients. However, a more severe reduction in the caudate and a higher putamen to caudate ratio distinguished SCA2 from PD patients, suggesting a more uniform nigrostriatal impairment in SCA2. Striatal DAT density of SCA2 patients correlated with the severity of cerebellar ataxia.

Objective: To perform a clinical and molecular study of a large autosomal dominant family with a complex neurologic syndrome that comprises early-onset dementia, extrapyramidal and cerebellar features, and epilepsy. Background: Early-onset forms of dementia often are caused by genetic factors. Mutations of three different genes— amyloid precursor protein ( APP ), presenilin 1 ( PS-1 ), presenilin 2 ( PS-2 )—have been found in early-onset autosomal dominant forms of AD, of the human microtubule associated-protein tau gene ( MAPT ) in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), of the BRI gene in familial British dementia, of the PI12 gene in familial encephalopathy with neuroserpin inclusion bodies. Linkage to chromosome 3 has been found in familial nonspecific dementia (FND) and linkage to chromosome 20 has been found in Huntington disease (HD)-like neurodegenerative disease. Dementia may be a feature of other neurodegenerative diseases such as HD, dentatorubro-pallidoluysian atrophy (DRPLA), diseases caused by mutations of the prion protein gene ( PRNP ), spinocerebellar ataxias (SCA), and familial parkinsonism. Methods: A southern Italian family with autosomal dominant dementia-plus was observed. The family includes 57 individuals in 5 generations (14 affected, 7 personally observed). The authors performed linkage analysis to APP, PS-1, PS-2, FTDP-17, BRI, PI12, FND, HD-like, SCA4, SCA5, SCA10, SCA11, SCA13, PARK1, PARK2, PARK3 loci; direct mutation analysis of HD, DRPLA, SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, and PRNP genes; and sequencing of the PRNP open reading frame. Results: Linkage to the examined loci was excluded. All of the direct mutation analyses were negative excluding mutations in the examined genes. Conclusions: This family has a peculiar phenotype and molecular analyses excluded genes known to cause hereditary dementias.

Two hundred and forty-eight patients from 116 Italian families with dominant ataxia were studied for CAG expansion within SCA1, 2, 3, 6, 7 (spinocerebellar ataxia) and DRPLA (dentatorubropallidoluysian atrophy) genes. Fifty-six percent of the families originated from Southern, 19% from Central and 25% from Northern Italy. SCA2 was the commonest mutation, accounting for 47% of the families, followed by SCA1 (24%), SCA6 (2%), SCA7 (2%) and DRPLA (1%). No SCA3 family was found. Twenty-four percent of the families carried a still unidentified mutation. When occurrence of mutations was evaluated according to the geographic origin, SCA1 was the commonest in Northern (72%), whereas SCA2 was prevalent (63%) in Southern Italy. The number of CAG repeats in SCA1 normal alleles was higher in Northern than in Central-Southern Italy.

The authors describe an Italian family with autosomal dominant ataxia, dementia, psychiatric and extrapyramidal features, epilepsy, mild sensorimotor axonal neuropathy, and MRI findings of cerebral and cerebellar atrophy. A child had a distinctive presentation with onset at 3 years, growth retardation, fast progression, and early death. Molecular analysis demonstrated an expanded CAG/CAA repeat in the TBP gene (SCA-17). The repeat size was 66 triplets in the child and 53 in all the other patients.

Autonomic nervous system dysfunction is part of the spinocerebellar ataxia (SCA) clinical picture, but few data are available on this topic. The present study is aimed to report a detailed investigation of autonomic nervous system in patients with molecular diagnosis of SCA type 2, one of the most frequent forms and the commonest in Italy. Nine patients with a mild to moderate form of SCA2 underwent a questionnaire about dysautonomic symptoms and a complete cardiovascular neurophysiologic evaluation of both sympathetic and parasympathetic system, comprising head-up tilt, standing, isometric hand grip, cold pressure, mental arithmetic, Valsalva manoeuvre, deep breathing, and hyperventilation tests. An echocardiographic study and Holter-ECG recording were also performed. All patients complained dysautonomic problems regarding urinary tract, cardiovascular system, or gastrointestinal dysfunction. The neurophysiologic study showed both sympathetic and parasympathetic involvement, with highly variable degree and pattern of dysautonomia. The present study results show that the autonomic dysfunction is common in SCA2 representing a significant component of the complex picture of the disease. We found a wide spectrum of cardiovascular autonomic abnormalities, without a typical pattern of dysfunction and without correlation with clinical variables.

Cerebellar vermis aplasia (ACV, OMIM 117360) is a rare malformation of the cerebellum, with only few familial patients reported so far. Main clinical features of this rare disorder include floppiness and delayed milestones in early infancy, preceding mild cerebellar ataxia, non-progressive clinical course, normal or slightly delayed intelligence, and occasional nystagmus. Neuroimaging reveals selective involvement of the cerebellum, which is prominent in the vermis. Because of the large preponderance of female patients, X-linked dominant transmission was suggested by [Fenichel and Phillips (1989); Arch Neurol 46:582-583], and subsequent reports only concern female patients. Only one family with male-to-male transmission presenting with a generalized atrophy of the cerebellum rather than a more localized vermis aplasia has been reported so far. We report on a family in which father and son are affected by a mild form of ACV, thus confirming an autosomal mode of inheritance of the disease. Our patients showed a progressive improvement of their motor abilities, neurological examination of the father being actually normal except for a mild mental retardation. We also evaluated the potential role of two candidate genes, EN2 and ZIC1, responsible for abnormal cerebellar development in murine knock-out models. However, molecular analysis failed to reveal any causative mutation in the coding sequence of the two genes in our patients. The understanding of the genetic basis of autosomal dominant ACV would allow a better classification of isolate cerebellar malformations and might permit to understand cell differentiation and migration in the developing central nervous system.

The objective was to determine the progression of nervous system involvement in spinocerebellar ataxia type 1 (SCA1). Three presymptomatic members of an Italian SCA1 family underwent molecular analysis and showed the SCA1 mutation. They were defined as "at risk/mutated" individuals. A clinical and electrophysiologic 7-9 year follow-up was performed. The Inherited Ataxia Progression Scale was used for clinical staging. Sensory and motor conduction velocities, somatosensory evoked potentials and transcranial magnetic stimulation were performed at least three times in each subject. Clinical examination showed the early corticospinal pathway involvement. Electrophysiologic investigations confirmed that at the asymptomatic stage only magnetic motor cortex stimulation was abnormal and rapidly worsened with time. Somatosensory pathway studies showed a later involvement and a light sensory-motor neuropathy was the last electrophysiologic abnormality to be recognised. These data confirm that SCA1 phenotype is characterised by early and prevalent pyramidal tract involvement and that peripheral neuropathy is a late and moderate complication.

Two brothers presented with late-onset cerebellar ataxia and severe dysphonia. Brain MRI showed vermian and hemispheric cerebellar atrophy. Laringofiberscopy revealed laryngeal abductor paralysis in both patients. Neurophysiologic studies showed a pure motor neuropathy. The combined findings and the molecular analysis suggest a new familial disorder. Inheritance is most likely autosomal recessive, but X-linked transmission is also possible.

Autosomal dominant cerebellar ataxia type I is the most common form of dominant ataxia. A genetic heterogeneity has been identified with five different loci (SCA1, 2, 3, 4, and 6). A pathological expansion of a CAG sequence has been identified in SCA1, 2, 3, and 6. We performed molecular analysis in 51 families with autosomal dominant cerebellar ataxia type I, mainly originating from southern Italy and Sicily. Thirty families carry an expanded CAG sequence within SCA2 gene. The mean number of repeats was 39.9 +/- 3.3 in 85 expanded alleles, with a range of 34-52. The number of triplets was inversely correlated with age at onset and explained 76% of the variance. The best fit was obtained with an exponential relationship between variables. Expanded alleles were unstable when transmitted from parents to offspring. Expansions were more common than contractions, accounting for 59% of the total meioses and for 80% of the father-child transmissions. The mean intergenerational variation was 1.9 repeats (range -3 to +15) with higher values for male transmissions. Bulbar and autonomic signs were related to disease duration, pyramidal signs to CAG size, cerebellar features and peripheral neuropathy to both. Among the remaining 21 families, three carried the SCA1 and one the SCA6 mutation. This study suggests that SCA2 is the prevalent mutation in southern Italy.

We assessed neuropsychological performances of 22 patients affected by Autosomal Dominant Cerebellar Ataxia type 1. All subjects completed a comprehensive battery of standardized tests requiring a verbal response, without time constraints. In order to verify the hypothesis that disease severity is the major factor in determining the cognitive status in this syndrome, patients were divided into three groups according to the severity of the clinical picture, as evaluated by the Inherited Ataxias Progression Scale (IAPS). Statistical analysis of the three groups' raw scores showed a significant decrement in patients with more severe clinical pictures on verbal short-term memory tasks. A similar trend, but not significant, was seen for general intelligence tests and verbal learning tasks. The decrement of verbal short-term memory could be related to motor speech problems. On the other hand, the decline of cognitive abilities over the course of the Autosomal Dominant Cerebellar Ataxia type 1 was not homogeneous enough to ensure statistically reliable trends. Therefore, this cross-sectional study suggests that the progression of the disease is a necessary factor in determining cognitive decline, but it is not sufficient. Other disease-related factors (age at onset, genotypic variety) could play a critical role: among these, the size of the expanded CAG repeats is significantly related to a decline of verbal intelligence and short-term memory in SCA2 patients.

We studied 83 patients from 36 Italian families with autosomal dominant cerebellar ataxia type I. Mean onset age ± SD was 34.2 ± 12.8 years with a mean anticipation of 12.8 ± 15.1 in 52 parent-offspring pairs. Onset age anticipation occurred predominantly through paternal transmission. Mean age at death was at 56.5 ± 15.5 years. The most common associated features were supranuclear ophthalmoplegia, corticospinal signs, peripheral neuropathy and cognitive impairment. Cerebellar atrophy was constant at MRI and usually associated with shrinkage of the pons and degeneration of the pontine transverse fibres. Direct mutation analysis in 29 families showed two families with SCA1 and none with Machado-Joseph/SCA3 mutation. We performed linkage analysis in the ten largest families. Two of them showed linkage to SCA2 locus and none to SCA4 and SCA5 loci. SCA2 patients showed higher occurrence of peripheral neuropathy and slow saccades, rarer corticospinal signs and a milder course of the disease in comparison with SCA1 patients.

We have analysed the CAG repeat in the Huntington disease (HD) gene in sperm and blood from 20 unrelated HD patients. Although the CAG repeat displayed significant mosaicism in sperm from all individuals, there were marked differences in the degree of repeat instability. Individuals who had either inherited or transmitted an expanded CAG repeat displayed the highest levels of repeat mosaicism, whereas individuals who had inherited or transmitted a contracted repeat had very limited CAG mosaicism in sperm. A strong association between intergenerational change in CAG allele size and the level of sperm repeat mosaicism was determined (P = 0.019). In contrast, neither blood CAG size nor repeat mosaicism in blood, were significantly associated with intergenerational CAG changes. These data suggest the presence of a cis-acting factor, separate from CAG size, that strongly influences the intergenerational behaviour of the CAG repeat. Additional studies are needed to determine whether analysis of CAG mosaicism in sperm is useful for assessing an individual's risk for transmitting large expansions or contractions to his offspring.

Background and aims The precise knowledge of the natural history of Huntington9s disease (HD) and the impact of variables that may modify the rate of survival are essential for counselling of patients and design of future therapeutic trials. Failure to use survival analyses methodology in previous studies may have produced serious bias in estimates of the survival rates in the disease. The aim of the present study was to examine the determinants of survival in HD. Methods We retrospectively reviewed 309 medical records of all HD patients and at risk subjects between 1977 and 2008 followed at the Department of Neurological Sciences of ‘Federico II’ University in Naples. Inclusion criteria were manifest signs and symptoms and positive molecular testing for HD (CAG triplet number >35). Demographic and clinical data were collected at the first evaluation and at follow-up although the last day we examined the patient in 2008. Results A total of 135 patients were included in the study. The remaining 174 subjects were excluded for the following reasons: gene test missing (n=84), lack of traceability (n=71), premanifest state (n=16) and refusal to participate in the study (n=3). At the time of data collection, 94 patients were still living and 41 patients were deceased (19 males and 22 females) with an average death age of 56.55 years±14.94 (mean±SD, range 18–83). Mean follow-up time after diagnosis was 145 months (range 12–552). Higher survival probabilities were registered in patients with CAG repeat length ≤47 (n=101, 75% of the cohort; p=0.015) and with onset ≤41 (n=74, 55% of the cohort; p=0.046). The individual contribution of each covariate was assessed using a Cox analysis and the final model was generated considering only the significant ones. Conclusions Survival time was longer in patients with a triplet repeat size of the mutant allele ≤47 and with onset of the disease ≤41 years of age. No significant impact either of the size of the wild-type allele or its interaction with the expanded allele was found in the survival rates. Larger studies using the appropriate statistical tool are necessary to better understand the disease duration determinants in HD.