Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations

Background: Heterozygous mutations in OPA1 are a common cause of autosomal dominant optic atrophy, sometimes associated with extra-ocular manifestations. Few cases harboring compound heterozygous OPA1 mutations have been described manifesting complex neurodegenerative disorders in addition to optic atrophy. Results: We report here three patients: one boy showing an early-onset mitochondrial disorder with hypotonia, ataxia and neuropathy that was severely progressive, leading to early death because of multiorgan failure; two unrelated sporadic girls manifesting a spastic ataxic syndrome associated with peripheral neuropathy and, only in one, optic atrophy. Using a targeted resequencing of 132 genes associated with mitochondrial disorders, in two probands we found compound heterozygous mutations in OPA1: in the first a 5 nucleotide deletion, causing a frameshift and insertion of a premature stop codon (p.Ser64Asnfs*7), and a missense change (p.Ile437Met), which has recently been reported to have clinical impact; in the second, a novel missense change (p.Val988Phe) co-occurred with the p.Ile437Met substitution. In the third patient a homozygous mutation, c.1180G > A (p.Ala394Thr) in OPA1 was detected by a trio-based whole exome sequencing approach. One of the patients presented also variants in mitochondrial DNA that may have contributed to the peculiar phenotype. The deleterious effect of the identified missense changes was experimentally validated in yeast model. OPA1 level was reduced in available patients\u2019 biological samples, and a clearly fragmented mitochondrial network was observed in patients\u2019 fibroblasts. Conclusions: This report provides evidence that bi-allelic OPA1 mutations may lead to complex and severe multi-system recessive mitochondrial disorders, where optic atrophy might not represent the main feature

Reduction in the levels of CoQ biosynthetic proteins is related to an increase in lifespan without evidence of hepatic mitohormesis

Mitohormesis is an adaptive response induced by a mild mitochondrial stress that promotes longevity and metabolic health in different organisms. This mechanism has been proposed as the cause of the increase in the survival in Coq7+/− (Mclk1+/−) mice, which show hepatic reduction of COQ7, early mitochondrial dysfunction and increased oxidative stress. Our study shows that the lack of COQ9 in Coq9Q95X mice triggers the reduction of COQ7, COQ6 and COQ5, which results in an increase in life expectancy. However, our results reveal that the hepatic CoQ levels are not decreased and, therefore, neither mitochondrial dysfunction or increased oxidative stress are observed in liver of Coq9Q95X mice. These data point out the tissue specific differences in CoQ biosynthesis. Moreover, our results suggest that the effect of reduced levels of COQ7 on the increased survival in Coq9Q95X mice may be due to mitochondrial mechanisms in non-liver tissues or to other unknown mechanisms.This work was supported by grants from Ministerio de Economía Competitividad, Spain, and the ERDF (Grant Number SAF2015-65786-R), from the Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía (grant number P10-CTS-6133) and from the University of Granada (grant reference “UNETE”, UCE-PP2017-06). AHG is a “FPU fellow” from the Ministerio de Educación Cultura y Deporte, Spain. MLS was a predoctoral fellow from the Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía. LCL was supported by the “Ramón y Cajal” National Programme, Ministerio de Economía y Competitividad, Spain (RYC-2011-07643)

A multi-element psychosocial intervention for early psychosis (GET UP PIANO TRIAL) conducted in a catchment area of 10 million inhabitants: study protocol for a pragmatic cluster randomized controlled trial

Multi-element interventions for first-episode psychosis (FEP) are promising, but have mostly been conducted in non-epidemiologically representative samples, thereby raising the risk of underestimating the complexities involved in treating FEP in 'real-world' services

Use of the mini-mental state examination in research on the elderly in Brazil: a systematic review

The Mini-Mental State Examination (MMSE) is the most widely used cognitive screening test around the world. In Brazil, different MMSE versions and many cut-off points have been used. A systematic review of papers indexed in Scielo was conducted in order to analyze use of the MMSE in Brazilian empirical studies with elderly people. To search for these texts, the complete name of the instrument and its abbreviation were used. A growth trend in the scientific production during the 1998 to 2013 period was observed. Eleven versions of the MMSE were identified and the Bertolucci et al. version was the most cited. Over half of the studies used schooling as the criteria to establish cut-off points. The studies were predominantly conducted using samples recruited from large cities in the Southeastern region and in the community. Despite the growing trend of research with the elderly using the MMSE, the psychometric properties of this scale of measurement have been the subject of little investigation. Despite the widespread use of the MMSE in Brazil, there is a lack of standardization and evidence of validity for this this scale of measurement.O Mini Exame do Estado Mental (MEEM) é o teste de rastreio cognitivo mais utilizado no mundo. No Brasil, diferentes versões e pontos de corte do MEEM têm sido usados. Para analisar seu uso em estudos empíricos brasileiros com idosos, efetuou-se uma revisão sistemática de artigos indexados na SciELO. Foram utilizados o nome completo do instrumento e sua abreviação para recuperar os textos. Observou-se uma tendência de crescimento da produção científica analisada, no período de 1998 a 2013. Foram mencionadas 11 versões do MEEM, destacando-se a de Bertolucci et al. Mais da metade das investigações fizeram uso da escolaridade como critério para estabelecer pontos de corte. Os estudos têm sido realizados predominantemente com amostras recrutadas em grandes cidades da região Sudeste e na comunidade. Não obstante a tendência de crescimento de pesquisas com idosos que utilizam o MEEM, as propriedades psicométricas dessa medida têm sido pouco investigadas. Apesar da ampla utilização do MEEM no Brasil, faltam padronização e evidências de validade para essa medida