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Background: Congenital myasthenic syndromes (CMSs) and primary mitochondrial myopathies (PMMs) can present with ptosis, external ophthalmoplegia, and limb weakness. Methods: Our method involved the description of three cases of CMS that were initially characterized as probable PMM. Results: All patients were male and presented with ptosis and/or external ophthalmoplegia at birth, with proximal muscle weakness and fatigue on physical exertion. After normal repetitive nerve stimulation (RNS) studies performed on facial muscles, a muscle biopsy (at a median age of 9) was performed to rule out congenital myopathies. In all three cases, the biopsy findings (COX-negative fibers or respiratory chain defects) pointed to PMM. They were referred to our neuromuscular unit in adulthood to establish a genetic diagnosis. However, at this time, fatigability was evident in the physical exams and RNS in the spinal accessory nerve showed a decremental response in all cases. Targeted genetic studies revealed pathogenic variants in the MUSK, DOK7, and RAPSN genes. The median diagnostic delay was 29 years. Treatment resulted in functional improvement in all cases. Conclusions: Early identification of CMS is essential as medical treatment can provide clear benefits. Its diagnosis can be challenging due to phenotypic overlap with other debilitating disorders. Thus, a high index of suspicion is necessary to guide the diagnostic strategy. [ABSTRACT FROM AUTHOR]

We report the case of two members of the same family with a novel mitochondrial DNA (mtDNA) gene variant in the MT-ND5 gene associated with MELAS syndrome and discuss limitations of genetics studies. The m.13045A > G mutation was detected at very low load in the daughter's urine cells (5%) and at different levels in the skeletal muscle of both mother (50%) and daughter (84%), being absent in blood, hair and saliva. Our findings suggest that non-invasive genetic assessment in urine cells may not be a sensitive diagnostic method neither a good predictor of disease development in relatives of some families with mtDNA-associated MELAS, particularly if involving MT-ND5 gene. [ABSTRACT FROM AUTHOR]

Purpose: Several researchers have suggested that the rs243865 (16q13-q21) polymorphism in the promoter region of the metalloproteinase-2 (MMP-2) gene could be associated with an increased risk of developing age-related macular degeneration (AMD). However, previous results remain inconclusive. To clarify this controversy, we conducted a meta-analysis of the relationship between rs243865 of MMP-2 and AMD. Methods: We included 6 independent case-control studies involving 1,682 AMD patients and 2,295 healthy subjects. The association between the rs243865 polymorphism and AMD was examined by the overall odds ratio (OR) with a 95% confidence interval (CI). We used a recessive genetic model analysis, sensitivity analysis, and assessment of bias in our meta-analysis. Results: Our results showed that there was no significant association between the variant T allele (p-value = 0.10, OR [95%CI] = 0.95 [0.82–1.10]) or the CT+TT genotype (p-value = 0.16, OR [95%CI] = 0.92 [0.76–1.12]) of rs243865 MMP-2 polymorphism and the presence of AMD. Conclusions: The rs243865 MMP-2 polymorphism was not associated with an increased risk of developing AMD. The MMP-2 (-1306 C>T) promoter variant is unlikely to have a major role in AMD risk susceptibility. [ABSTRACT FROM AUTHOR]

The presence of more than one non-severe pathogenic mutation in the same mitochondrial DNA (mtDNA) molecule is very rare. Moreover, it is unclear whether their co-occurrence results in an additive impact on mitochondrial function relative to single mutation effects. Here we describe the first example of a mtDNA molecule harboring three Leber's hereditary optic neuropathy (LHON)-associated mutations (m.11778G>A, m.14484T>C, m.11253T>C) and the analysis of its genetic, biochemical and molecular characterization in transmitochondrial cells (cybrids). Extensive characterization of cybrid cell lines harboring either the 3 mutations or the single classic m.11778G>A and m.14484T>C mutations revealed no differences in mitochondrial function, demonstrating the absence of a synergistic effect in this model system. These molecular results are in agreement with the ophthalmological characteristics found in the triple mutant patient, which were similar to those carrying single mtDNA LHON mutations. [ABSTRACT FROM AUTHOR]

Genetic background is an important determinant of the etiology of breast cancer and varies between subtle changes in risk caused by common genetic variants and high-risk susceptibility genes such as BRCA1 and BRCA2. We present an updated overview of the most important molecular and clinical features of the genes involved in breast cancer. We focus on the well-known BRCA1 and BRCA2 genes and on the management of patients in terms of risk assessment, screening, prevention, and emerging therapies based on BRCA molecular pathology. We also address other recently discovered susceptibility genes (eg, CHEK2, RAD51C, PALB2, and BRIP1) and other hereditary syndromes in which breast cancer frequently appears such as Li-Fraumeni Syndrome, Cowden Syndrome, Peutz Jeghers Syndrome, hereditary diffuse gastric cancer, and Lynch Syndrome. Finally, we briefly analyze the new concept of high-prevalence-low-penetrance genetic variants, which has arisen from genome-wide associated studies. [ABSTRACT FROM AUTHOR]

Mitochondrial haplogroups could influence individual susceptibility to mitochondrial DNA (mtDNA) damage, and human longevity, as indicated by previous studies with Caucasian (European) or Asian cohorts. Here, we compared the frequency of mtDNA haplogroups in a group of Spanish (Caucasian) centenarians ( n = 65, aged 100-108 years, 58 women, most from the central part of Spain) and a group of healthy young adults ( n = 138, 62 women, aged 20-40 years) of the same ethnic origin. We did not find significant differences between centenarians and the control group ( P > 0.2). Only two centenarians (both women) had the haplogroup J, which hampered comparison with the control group ( n = 15, five women). Our data confirm that the potential effects of mitochondrial haplogroups on human longevity might be population/geographic specific, with important differences between studies (notably, with regard to the previously reported potential benefit brought about by the haplogroup J) arising from the different living environment and ethnic background of the study cohorts. [ABSTRACT FROM AUTHOR]

Abstract: There is increasing evidence regarding the association between mitochondrial DNA (mtDNA) and aerobic capacity; however, whether mtDNA haplogroups are associated with the status of being an elite endurance athlete is more controversial. We compared the frequency distribution of mtDNA haplogroups among the following groups of Spanish (Caucasian) men: 102 elite endurance athletes (professional road cyclists, endurance runners), 51 elite power athletes (jumpers, throwers and sprinters), and 478 non-athletic controls. We observed a significant difference between endurance athletes and controls (Fisher exact test=17.89, P =0.015; Bonferroni''s significant threshold=0.017), yet not between power athletes and controls (Fisher exact test=47.99, P =0.381) or between endurance and power athletes (Fisher exact test=5.53, P =0.597). We observed that the V haplogroup was overrepresented in endurance athletes (15.7%) compared with controls (7.5%) (odds ratio: 2.284; 95% confidence interval: 1.237, 4.322). In conclusion, our findings overall support the idea that mtDNA variations could be among the numerous contributors to the status of being an elite endurance athlete, whereas no association was found with elite power athletic status. [Copyright &y& Elsevier]

Abstract: Genomic instability can be produced by ionising radiation, so-called radiation-induced genomic instability, and chemical mutagens. Radiation-induced genomic instability occurs in both germinal and somatic cells and also in the offspring of irradiated individuals, and it is characterised by genetic changes including chromosomal rearrangements. The majority of studies of trans-generational, radiation-induced genomic instability have been described in the male germ line, whereas the authors who have chosen the female as a model are scarce. The aim of this work is to find out the radiation-induced effects in the foetal offspring of X-ray-treated female rats and, at the same time, the possible impact of this radiation-induced genomic instability on the action of a chemical mutagen. In order to achieve both goals, the quantity and quality of chromosomal damage were analysed. In order to detect trans-generational genomic instability, a total of 4806 metaphases from foetal tissues from the foetal offspring of X-irradiated female rats (5Gy, acute dose) were analysed. The study''s results showed that there is radiation-induced genomic instability: the number of aberrant metaphases and the breaks per total metaphases studied increased and were found to be statistically significant (p ≤0.05), with regard to the control group. In order to identify how this trans-generational, radiation-induced chromosomal instability could influence the chromosomal behaviour of the offspring of irradiated rat females in front of a chemical agent (aphidicolin), a total of 2481 metaphases were studied. The observed results showed that there is an enhancement of the action of the chemical agent: chromosomal breaks per aberrant metaphases show significant differences (p ≤0.05) in the X-ray- and aphidicolin-treated group as regards the aphidicolin-treated group. In conclusion, our findings indicate that there is trans-generational, radiation-induced chromosomal instability in the foetal cells from X-ray-treated female rats and that this RIGI enhances the chromosomal damage caused by the chemical agent aphidicolin. [Copyright &y& Elsevier]

Abstract: The phenotypic manifestation of McArdle disease varies considerably from one individual to the next. The purpose of this study was to assess the possible association between the clinical severity of the disease, and each of the genotypes PYGM (R50X), ACE (I/D), AMPD1 (Q12X), PPARGC1A (G482S) and ACTN3 (R577X). We also assessed links between clinical disease severity and other potential phenotype modulators such as age or gender. McArdle disease was diagnosed in 99 patients of Spanish origin (60 male, 39 female; age range 8–81 years) by identifying the two mutant alleles of the PYGM gene. Disease severity was assessed using the grading scheme previously reported by Martinuzzi et al. [A. Martinuzzi, E. Sartori, M. Fanin, et al., Phenotype modulators in myophosphorylase deficiency, Ann. Neurol. 53 (2003) 497–502]. Significant correlation was observed (exact two-sided P <0.0001) between the number of D alleles of the ACE gene and the disease severity score. Rank-order correlation coefficients were 0.296 (95% CI: 0.169, 0.423) (Kendall''s τ) and 0.345 (95% CI: 0.204, 0.486) (Somer''s D). No significant relationships were detected between clinical severity and the remaining genotypes examined. Finally, disease severity was significantly worse in women with the disease. Our findings indicate that both ACE genotype and gender contribute to how McArdle disease manifests in an individual patient. The role of other candidate genes remains to be elucidated. [Copyright &y& Elsevier]

Congenital lactic acidosis (CLA) is a rare condition in most instances due to a range of inborn errors of metabolism that result in defective mitochondrial function. Even though the implementation of next generation sequencing has been rapid, the diagnosis rate for this highly heterogeneous allelic condition remains low. The present work reports our group's experience of using a clinical/biochemical analysis system in conjunction with genetic findings that facilitates the taking of timely clinical decisions with minimum need for invasive procedures. The system's workflow combines different metabolomics datasets and phenotypic information with the results of clinical exome sequencing and/or RNA analysis. The system's use detected genetic variants in 64% of a cohort of 39 CLA-patients; these variants, 14 of which were novel, were found in 19 different nuclear and two mitochondrial genes. For patients with variants of unknown significance, the genetic analysis was combined with functional genetic and/or bioenergetics analyses in an attempt to detect pathogenicity. Our results warranted subsequent testing of antisense therapy to rescue the abnormal splicing in cultures of fibroblasts from a patient with a defective GFM1 gene. The discussed system facilitates the diagnosis of CLA by avoiding the need to use invasive techniques and increase our knowledge of the causes of this condition. [ABSTRACT FROM AUTHOR]