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This paper provides an overview of the different types of mitochondrial myopathies (MM), associated phenotypes, genotypes as well as a practical clinical approach towards disease diagnosis, surveillance, and management. nDNA-related MM are more common in pediatric-onset disease whilst mtDNA-related MMs are more frequent in adults. Genotype-phenotype correlation in MM is challenging due to clinical and genetic heterogeneity. The multisystemic nature of many MMs adds to the diagnostic challenge. Diagnostic approaches utilizing genetic sequencing with next generation sequencing approaches such as gene panel, exome and genome sequencing are available. This aids molecular diagnosis, heteroplasmy detection in MM patients and furthers knowledge of known mitochondrial genes. Precise disease diagnosis can end the diagnostic odyssey for patients, avoid unnecessary testing, provide prognosis, facilitate anticipatory management, and enable access to available therapies or clinical trials. Adjunctive tests such as functional and exercise testing could aid surveillance of MM patients. Management requires a multi-disciplinary approach, systemic screening for comorbidities, cofactor supplementation, avoidance of substances that inhibit the respiratory chain and exercise training. This update of the current understanding on MMs provides practical perspectives on current diagnostic and management approaches for this complex group of disorders. [Display omitted] [ABSTRACT FROM AUTHOR]

Highlights • Successful aging mediated the association between chronological age and telomere length. • Lower socioeconomic status was associated with larger age-related decreases in telomere length. • The cognitive functioning dimension of successful aging was uniquely related to telomere length. Abstract In a rapidly greying world, the notion that some individuals maintain successful aging trajectories, viz. high physical, cognitive, emotional, and social functioning in older age, is increasingly germane. Biomarkers of such successful aging are increasingly sought. Leukocyte telomere length (LTL), an emerging yardstick of cellular aging that is influenced by but distinct from chronological age, may also be associated to successful aging. Furthermore, given that socio-economic status (SES) influences successful aging trajectories, socioeconomic status may also moderate the association between chronological age and LTL. The goals of this study are to examine 1) whether successful aging is associated with LTL; 2) whether successful aging accounts for age-related LTL and 3) whether SES moderates the effect of age on LTL. Singaporean Chinese (n = 353) aged 65–80 completed a multidimensional assessment of successful aging and provided blood samples for LTL analysis. Results show that LTL negatively correlates with chronological age and positively correlates with successful aging. Successful aging mediates the association between chronological age and LTL. Moderated mediation analyses show that lower SES is associated with stronger negative associations of chronological age with successful aging and LTL. Moreover, the cognitive functioning dimension of successful aging is uniquely associated with LTL and its association with chronological age is moderated by SES. This study provides evidence that among older Singaporean Chinese with lower SES, declines in successful aging and in cognitive functioning are linked to age-related LTL shortening and hence to accelerated aging at the cellular level. [ABSTRACT FROM AUTHOR]

Much research has demonstrated the beneficial effects of mindfulness-based stress reduction (MBSR) on psychological and physical health, but it is not known whether MBSR may impact cellular aging in healthy populations. Further, little research has evaluated MBSR against an active control condition, which precludes strong conclusions regarding the unique effects of mindfulness on psychological functioning. The present study examined the effects of MBSR versus music therapy-based stress reduction (MTSR) on trait mindfulness, self-compassion, and several psychological health outcomes, as well as leukocyte telomere length (LTL). One hundred and fifty eight Singaporean Chinese adults were recruited and randomly assigned to an eight-week MBSR or MTSR course. Participants provided blood samples and completed a battery of self-report measures pre- and post-intervention. Analyses showed that participants in the MBSR condition demonstrated significantly greater improvements in depressive symptoms, trait mindfulness, and self-compassion compared to the control condition. Treatment condition did not predict changes in LTL, anxiety, stress, or happiness, though there was a trend for duration of home mindfulness practice to predict increases in LTL. Overall, the study demonstrated MBSR's unique effects in reducing depressive symptoms. Improvements in trait mindfulness and self-compassion correspond with theorized mechanisms of change underlying mindfulness training. The lack of intervention effect with regards to LTL suggests that a more intensive intervention may be required for mindfulness to exert noticeable impact on aging at the cellular level, or that the effect may only emerge over a longer term. [ABSTRACT FROM AUTHOR]

Background The SMN genes, SMN1 and SMN2 , are highly homologous genes which are related to the development or clinical severity of spinal muscular atrophy. Some alternative splicing patterns of the SMN genes have been well documented. In 2007, an SMN1 transcript with a full sequence of intron 3 was reported as the first intron-retained SMN transcript. Methods Intron-retained SMN transcripts in various cells and tissues were studied using reverse transcription (RT)-PCR. HeLa cells were used for subcellular localization of the transcripts and protein expression analysis with Western blotting. Results Two intron-retained SMN transcripts were detected, which contain full sequences of intron 2b or intron 3. These transcripts were produced from SMN1 and SMN2 , and ubiquitously expressed in human cells and tissues. Western blotting analysis showed no proteins derived from the intron-retained transcripts. Fractionation analysis showed that these intron-retained transcripts were localized mainly in the nucleus. Contrary to our expectation, the intron-retained transcript levels decreased during the treatment of cycloheximide, an inhibitor of nonsense-mediated decay (NMD), suggesting that they were not targets of NMD. Conclusion Intron 2b-retained SMN transcript and intron3-retained SMN transcript were ubiquitously expressed in human cells and tissues. The intron-retained transcripts were mainly localized in the nucleus and decreased through non-NMD pathway. [ABSTRACT FROM AUTHOR]

Why some individuals seek social engagement while others shy away has profound implications for normal and pathological human behavior. Evidence suggests that oxytocin (OT), the paramount human social hormone, and CD38 that governs OT release, contribute to individual differences in social skills from intense social involvement to extreme avoidance that characterize autism. To explore the neurochemical underpinnings of sociality, CD38 expression of peripheral blood leukocytes (PBL) was measured in Han Chinese undergraduates. First, CD38 mRNA levels were correlated with lower Autism Quotient (AQ), indicating enhanced social skills. AQ assesses the extent of autistic-like traits including the propensity and dexterity needed for successful social engagement in the general population. Second, three CD157 eQTL SNPs in the CD38/CD157 gene region were associated with CD38 expression. CD157 is a paralogue of CD38 and is contiguous with it on chromosome 4p15. Third, association was also observed between the CD157 eQTL SNPs, CD38 expression and AQ. In the full model, CD38 expression and CD157 eQTL SNPs altogether account for a substantial 14% of the variance in sociality. Fourth, functionality of CD157 eQTL SNPs was suggested by a significant association with plasma oxytocin immunoreactivity products. Fifth, the ecological validity of these findings was demonstrated with subjects with higher PBL CD38 expression having more friends, especially for males. Furthermore, CD157 sequence variation predicts scores on the Friendship questionnaire. To summarize, this study by uniquely leveraging various measures reveals salient elements contributing to nonkin sociality and friendship, revealing a likely pathway underpinning the transition from normality to psychopathology. [ABSTRACT FROM AUTHOR]

Abstract: The compactness of the Fugu rubripes (Fugu) genome has supported its use in comparative genome analysis. Nevertheless, as Fugu is distinct evolution-wise from humans, it is essential to determine the similarity between a Fugu gene and its human counterpart to confirm its potential for comparative genome analysis. We cloned and analyzed the Fugu survival motor neuron gene (fsmn) for similarities with human SMN gene (huSMN). The Fugu genome has a single fsmn that is 13.4 times smaller than huSMN. fsmn and huSMN are highly similar in their genome organization and tissue expression patterns. The functional domains of the Fugu smn and human SMN molecules are also highly conserved. In human MCF-7 cells, expression of fsmn protein resulted in the formation of “gems” in the cytoplasm and nucleus, similar to observations reported for huSMN protein. In these cells, fsmn RNA was also processed correctly and produced alternatively spliced transcripts like huSMN2. These findings indicate close structural and functional similarities between fsmn and huSMN, suggesting that regulation of the two genes may also be similar and supporting the use of fsmn in comparative genome studies for the identification of functional regulatory elements of huSMN. [Copyright &y& Elsevier]

Abstract: Desmin myopathy was identified in a Chinese man with complete heart block and mild proximal and distal limb weakness. A novel heterozygous missense S13F mutation of the desmin gene was found to be associated with the myopathy. Family members carrying the mutation showed a similar or milder phenotype. The mutation is located at a protein kinase-C phosphorylation site within a highly conserved nonapeptide sequence in the head domain of the desmin protein. Expression of the mutant desmin cDNA in cell lines induced large desmin accumulations associated with preservation of a filamentous network. [Copyright &y& Elsevier]

Frontal brain asymmetry has been linked to motivational processes in infants and adults, with left lateralization reflecting motivation to approach and right lateralization reflecting motivation to withdraw. We examined the hypothesis that variability in infants' social motivation may be linked to genetic variation in the oxytocin system. Eleven-month-old infants' brain responses and looking preferences to smiling and frowning individuals were assessed in conjunction with a polymorphism in CD38 (rs3796863) linked to autism spectrum disorder (ASD) and reduced oxytocin. Frontal brain asymmetry and looking preferences differed as a function of CD38 genotype. While non-risk A-allele carriers displayed left lateralization to smiling faces (approach) and a heightened looking preference for the individual who smiled, infants with the CC (ASD risk) genotype displayed withdrawal from smiling faces and a preference for the individual who frowned. Findings demonstrate that the oxytocin system is linked to brain and behavioral markers of social motivation in infancy. • Functional near-infrared spectroscopy (fNIRS)-derived frontal brain asymmetry was assessed in infants to explore neural motivation to social cues. • Person preference was assessed using eyetracking. • Genetic variability in the endogenous oxytocin system was assessed via a common single nucleotide polymorphism (SNP) on CD38. • Findings suggest that genetic variability of CD38 impacts infants' brain-derived and behavioral social motivation for particular partners. [ABSTRACT FROM AUTHOR]

The use of lipid-lowering statins has been associated with raised serum muscle enzymes and, occasionally, with rhabdomyolysis, especially in patients with pre-existing metabolic myopathies. The A3243G mutation is one of the most common mutations associated with mitochondrial disorders. A teenager harboring the A3243G mutation had the unusual association of hereditary glomerulopathy and recurrent episodes of raised creatine kinase levels with the use of lipid-lowering agents. Muscle biopsy showed both normal respiratory chain enzyme activities and normal coenzyme Q10 levels, although decreased muscle coenzyme Q10 concentration had been postulated to have a pathogenic role in statin-related myopathies. The close temporal relationship of statin administration and raised creatine kinase levels in this patient suggests caution in the use of statins in children and teenagers with mitochondrial myopathies. [Copyright &y& Elsevier]