Absence of Acanthocytosis in Huntington’s Disease-like 2: A Prospective Comparison with Huntington’s Disease

Background: Huntington’s Disease-like 2 (HDL2) is classified as a neuroacanthocytosis; however, this remains unverified. We aim to determine if acanthocytes are present in HDL2 and whether acanthocytes can differentiate HDL2 from Huntington’s disease (HD). Methods: We prospectively compared 13 HD and 12 HDL2 cases against 21 unaffected controls in Johannesburg. Blood smears were prepared using international standards and reviewed by at least two blinded reviewers. An acanthocytosis rate of greater than 1.2% in the dry smear or greater than 3.7% in the wet smear was designated a priori as the threshold for clinical significance based on previously established standards. Flow cytometry was performed on all but four of the cases. Red cell membrane protein analysis was performed on all participants. Results: There were 12 HDL2, 13 HD, and 21 controls enrolled. None of the HD or HDL2 participants had defined acanthocytosis or other morphological abnormalities. None of the HD or HDL2 cases had evidence of an abnormal band 3. Discussion: Acanthocytosis was not identified in either HDL2 or HD in our patient population. Our results, based on the first prospective study of acanthocytes in HDL2 or HD, suggest that screening for acanthocytes will not help establish the diagnosis of HD or HDL2, nor differentiate between the two disorders and raises the question if HDL2 should be placed within the neuroacanthocytosis syndromes

FXTAS is rare among Portuguese patients with movement disorders: FMR1 premutations may be associated with a wider spectrum of phenotypes

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by expansions of 55-200 CGG repeats in the 5'UTR of the FMR1 gene. These FMR1 premutation expansions have relatively high frequency in the general population. To estimate the frequency of FMR1 premutations among Portuguese males with non-familial, late-onset movement disorders of unknown etiology, we assessed CGG repeat size in males with disease onset after the age of 50 and negative or unknown family history for late-onset movement disorders, who were sent for SCA, HD, or PD genetic testing at a reference laboratory. The selected patients had a primary clinical diagnosis based on one of the following cardinal features of FXTAS: ataxia, tremor, or cognitive decline. A total of 86 subjects were genotyped for the CGG repeat in the FMR1 gene. We detected one patient with an expansion in the premutation range. The frequency of FMR1 premutations was 1.9% (1/54) in our group of patients with ataxia as the primary clinical feature, and 1.2% (1/86) in the larger movement disorders group. In the family of the FXTAS case, premutation-transmitting females presented a history of psychiatric symptoms, suggesting that, given the wide phenotypical expression of the premutation in females, neuropsychiatric surveillance is necessary. In conclusion, genetic testing for FXTAS should be made available to patients with adult-onset movement disorders to enable adequate genetic counseling to family members

Population stratification may bias analysis of PGC-1α as a modifier of age at Huntington disease motor onset

Huntington’s disease (HD) is an inherited neurodegenerative disorder characterized by motor, cognitive and behavioral disturbances, caused by the expansion of a CAG trinucleotide repeat in the HD gene. The CAG allele size is the major determinant of age at onset (AO) of motor symptoms, although the remaining variance in AO is highly heritable. The rs7665116 SNP in PPARGC1A, encoding the mitochondrial regulator PGC-1α, has been reported to be a significant modifier of AO in three European HD cohorts, perhaps due to affected cases from Italy. We attempted to replicate these findings in a large collection of (1,727) HD patient DNA samples of European origin. In the entire cohort, rs7665116 showed a significant effect in the dominant model (p value = 0.008) and the additive model (p value = 0.009). However, when examined by origin, cases of Southern European origin had an increased rs7665116 minor allele frequency (MAF), consistent with this being an ancestry-tagging SNP. The Southern European cases, despite similar mean CAG allele size, had a significantly older mean AO (p < 0.001), suggesting population-dependent phenotype stratification. When the generalized estimating equations models were adjusted for ancestry, the effect of the rs7665116 genotype on AO decreased dramatically. Our results do not support rs7665116 as a modifier of AO of motor symptoms, as we found evidence for a dramatic effect of phenotypic (AO) and genotypic (MAF) stratification among European cohorts that was not considered in previously reported association studies. A significantly older AO in Southern Europe may reflect population differences in genetic or environmental factors that warrant further investigation

Candidate glutamatergic and dopaminergic pathway gene variants do not influence Huntington’s disease motor onset

Huntington’s disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and behavioral disturbances. It is caused by the expansion of the HTT CAG repeat, which is the major determinant of age at onset (AO) of motor symptoms. Aberrant function of N-methyl-D-aspartate receptors and/or overexposure to dopamine has been suggested to cause significant neurotoxicity, contributing to HD pathogenesis. We used genetic association analysis in 1,628 HD patients to evaluate candidate polymorphisms in N-methyl-D-aspartate receptor subtype genes (GRIN2A rs4998386 and rs2650427, and GRIN2B rs1806201) and functional polymorphisms in genes in the dopamine pathway (DAT1 3′ UTR 40-bp variable number tandem repeat (VNTR), DRD4 exon 3 48-bp VNTR, DRD2 rs1800497, and COMT rs4608) as potential modifiers of the disease process. None of the seven polymorphisms tested was found to be associated with significant modification of motor AO, either in a dominant or additive model, after adjusting for ancestry. The results of this candidate-genetic study therefore do not provide strong evidence to support a modulatory role for these variations within glutamatergic and dopaminergic genes in the AO of HD motor manifestations

Keeping secrets from parents: Advantages and disadvantages of secrecy in adolescence.

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Determinants and impact of role-related time use allocation on self-reported health among married men and women: a cross-national comparative study

Background Research on the effects of marriage on health maintains that there is a gender-specific gradient, with men deriving far greater benefits than women. One reason provided for this difference is the disproportionate amount of time spent by women on housework and childcare. However, this hypothesis has yet to be explicitly tested for these role-related time use activities. This study provides empirical evidence on the association between role-related time use activities (i.e. housework, childcare and paid work) and self-reported health among married men and women. Methods Data from the Multinational Time Use Study (MTUS) on 32,881 men and 26,915 women from Germany, Italy, Spain, the UK and the US were analyzed. Seemingly unrelated regression (SUR) models and multivariable logistic regression were used to estimate the association between role-related time use activities and self-reported health among married men and women. Results The findings showed that education, occupation and number of children under 18 years old in the household were the most consistent predictors of time allocation among married men and women. Significant gender differences were also found in time allocation, with women sacrificing paid working time or reducing time devoted to housework for childcare. Men, in contrast, were less likely to reduce paid working hours to increase time spent on childcare, but instead reduced time allocation to housework. Allocating more time to paid work and childcare was associated with good health, whereas time spent on housework was associated with poor health, especially among women. Conclusions Time allocation to role-related activities have differential associations on health, and the effects vary by gender and across countries. To reduce the gender health gap among married men and women, public policies need to take social and gender roles into account

A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease

Objective: To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD. Methods: We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach. Results: An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was generally safe and well-tolerated throughout the study. Conclusions: These data do not justify use of CoQ as a treatment to slow functional decline in HD

As cold as a fish? Relationships between the Dark Triad personality traits and affective experience during the day: A day reconstruction study

The Dark Triad of personality is a cluster of three socially aversive personality traits: Machiavellianism, narcissism and psychopathy. These traits are associated with a selfish, aggressive and exploitative interpersonal strategy. The objective of the current study was to establish relationships between the Dark Triad traits (and their dimensions) and momentary affect. Machiavellianism, grandiose narcissism, vulnerable narcissism and the dimensions of the Triarchic model of psychopathy (namely, boldness, meanness and disinhibition) were examined. We used the Day Reconstruction Method, which is based on reconstructing affective states experienced during the previous day. The final sample consisted of 270 university students providing affective ratings of 3047 diary episodes. Analyses using multilevel modelling showed that only boldness had a positive association with positive affective states and affect balance, and a negative association with negative affective states. Grandiose narcissism and its sub-dimensions had no relationship with momentary affect. The other dark traits were related to negative momentary affect and/or inversely related to positive momentary affect and affect balance. As a whole, our results empirically demonstrated distinctiveness of the Dark Triad traits in their relationship to everyday affective states. These findings are not congruent with the notion that people with the Dark Triad traits, who have a dispositional tendency to manipulate and exploit others, are generally cold and invulnerable to negative feelings. The associations between the Dark Triad and momentary affect were discussed in the contexts of evolutionary and positive psychology, in relation to the role and adaptive value of positive and negative emotions experienced by individuals higher in Machiavellianism, narcissism and psychopathy