Early-onset coenzyme Q10 deficiency associated with ataxia and respiratory chain dysfunction due to novel pathogenic COQ8A variants, including a large intragenic deletion.

Coenzyme Q10 (CoQ10) deficiency is a clinically and genetically heterogeneous subtype of mitochondrial disease. We report two girls with ataxia and mitochondrial respiratory chain deficiency who were shown to have primary CoQ10 deficiency. Muscle histochemistry displayed signs of mitochondrial dysfunction-ragged red fibers, mitochondrial paracrystalline inclusions, and lipid deposits while biochemical analyses revealed complex II+III respiratory chain deficiencies. MRI brain demonstrated cerebral and cerebellar atrophy. Targeted molecular analysis identified a homozygous c.1015G>A, p.(Ala339Thr) COQ8A variant in subject 1, while subject 2 was found to harbor a single heterozygous c.1029_1030delinsCA variant predicting a p.Gln343_Val344delinsHisMet amino acid substitution. Subsequent investigations identified a large-scale COQ8A deletion in trans to the c.1029_1030delinsCA allele. A skin biopsy facilitated cDNA studies that confirmed exon skipping in the fibroblast derived COQ8A mRNA transcript. This report expands the molecular genetic spectrum associated with COQ8A-related mitochondrial disease and highlights the importance of thorough investigation of candidate pathogenic variants to establish phase. Rapid diagnosis is of the utmost importance as patients may benefit from therapeutic CoQ10 supplementation.

LMNA-Related Muscular Dystrophy with Clinical Intrafamilial Variability.

The LMNA gene is associated to a huge broad of phenotypes, including congenital Emery-Dreifuss muscular dystrophy and late-onset LMNA-related muscular dystrophy. In these forms, muscle weakness, contractures, and cardiac impairment are common. In an autosomal dominant pedigree including 5 affected patients, NGS molecular analysis performed in 6 relatives identifies the heterozygous c.1129C>T p.Arg377Cys variant in the exon 6 of the LMNA gene in three of them. Clinical, laboratorial, imaging investigation of these affected patients showed a significant clinical variability: the father presented subclinical imaging muscular dystrophy masqueraded as radiculopathy. One of his sons presented cardiac arrhythmia, muscular weakness, elbow contractures, and intranuclear pseudoinclusions on muscle biopsy. A second son presented only decreased tendon reflexes. Two other brothers presenting myalgia and cramps were not carriers of the same mutation in the LMNA gene. Early diagnosis, considering these variable phenotype and genotype, is important for genetic counseling, as well as cardiac, and rehabilitation management.

Inibitory effects of linalool on fungal pathogenicity of clinical isolates of Microsporum canis and Microsporum gypseum.

In humans worldwide, Microsporum sp. is a frequent agent of dermatophytsosis. When considering the emergence of resistant fungi and the clinical relevance of dermatophytosis, terpene antifungal activity is of great interest. Linalool is a monoterpene alcohol with pharmacological properties. In this study, antifungal in vitro activity of linalool and ketoconazole (as a positive control) were evaluated against clinical isolates of M. canis and M. gypseum. The minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of each drug were determined by broth microdilution. The effects of the drugs (1/2MIC, MIC, 2xMIC) on radial mycelial growth, conidial production and germination were analysed. The effect on the fungal cell membrane (release of intracellular material) was also investigated. Linalool (MIC: 128 µg/mL) and ketoconazole (MIC: 64 µg/mL) were effective in inhibiting all dermatophytes studied. The MFC values of linalool ranged between 128 and 256 µg/mL, whereas ketoconazole showed MFC values of from 64 to 256 µg/mL. Linalool (at MIC and 2xMIC) and ketoconazole (at 1/2MIC, MIC, 2xMIC) inhibited mycelial growth (P < 0.05). The drugs (1/2MIC, MIC, 2xMIC) were also active on conidiogenesis and conidia germination, causing complete inhibition (P < 0.05). Linalool caused leakage of intracellular material. Our study supports the use of linalool as a potential antifungal agent against M. canis and M. gypseum.

HLA-G 3'UTR polymorphisms in high grade and invasive cervico-vaginal cancer.

Besides HPV infection, the progression to cervical cancer also depends on the host immune response. HLA-G molecules are involved in the inhibition of cell-mediated immune responses and may permit the development of an infection in the female cervical tract. The aim of this study was to explore the possible influence of the two HLA-G polymorphisms located on the 3'UTR on the susceptibility to cervical cancer and risk factors in Brazilian patients. Polymorphism analysis (14 bp In/Del and +3142C/G) was performed by PCR. A total of 105 cervical samples were tested, 50 without lesions and 55 with lesions; 22 with high grade (HSIL) and 33 with invasive cancer (ICC). The polymorphisms (∗)Del/Del was associated with a decreased risk of developing ICC in smokers and (∗)In and (∗)In/In were associated with an increased risk of HSIL and a higher risk of ICC in smokers. The genotype (∗)In/Del was associated with the increased risk of HSIL only among women with a family history of cancer. The haplotypes (∗)In/G and (∗)Del/G were associated with increased and decreased risk of HSIL and cervical cancer, respectively. In conclusion, the 3'UTR of HLA-G is associated with an increased risk of developing cervical cancer, especially in smokers.

Incidence of cervical intraepithelial neoplasia in a cohort of HIV-infected women.

OBJECTIVE: To assess cervical intraepithelial neoplasia (CIN) incidence in HIV-positive women and the risk factors for these lesions. METHODS: A retrospective and longitudinal cohort study was conducted from June 13, 1997, to December 18, 2009. At the first visit, the 348 participants had a normal cytologic finding but a negative Schiller test result, or an abnormal cytologic finding but no histologic diagnosis of CIN. Infection with HPV was detected by polymerase chain reaction. The main outcome measure was CIN incidence. RESULTS: During a mean follow-up of 40 months, 47 women (13.5%) developed CIN, for an incidence of 4.1 cases per 100 person-years of follow-up. The HPV prevalence was 68.1%, 42 women (89.4%) developed CIN 1, and no invasive cervical cancers were identified. On multivariate analysis, women younger than 19 years at first sexual intercourse (RR, 2.6; 95% CI, 1.24-5.35) and women who had never used antiretrovirals or used them only during pregnancy (RR, 2.3; 95% CI, 1.31-4.19) were at higher risk for CIN. CONCLUSION: The CIN incidence was low despite the high HPV prevalence. Being younger than 19 years at first sexual intercourse and not using antiretroviral medications were found to be the main risk factors for CIN.