Breathing in Duchenne muscular dystrophy: translation to therapy.

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease caused by a deficiency in dystrophin - a structural protein which stabilises muscle during contraction. Dystrophin deficiency adversely affects the respiratory system leading to sleep-disordered breathing, hypoventilation, and weakness of the expiratory and inspiratory musculature, which culminate in severe respiratory dysfunction. Muscle degeneration-associated respiratory impairment in neuromuscular disease is a result of disruptions at multiple sites of the respiratory control network, including sensory and motor pathways. As a result of this pathology, respiratory failure is a leading cause of premature death in DMD patients. Currently available treatments for DMD respiratory insufficiency attenuate respiratory symptoms without completely reversing the underlying pathophysiology. This underscores the need to develop curative therapies to improve quality of life and longevity of DMD patients. This review summarises research findings on the pathophysiology of respiratory insufficiencies in DMD disease in humans and animal models, the clinical interventions available to ameliorate symptoms, and gene-based therapeutic strategies uncovered by preclinical animal studies.

Genetic variation in toll like receptors 2, 7, 9 and interleukin-6 is associated with cytomegalovirus infection in late pregnancy.

BACKGROUND: Maternal cytomegalovirus (CMV) infection and/or reactivation in pregnancy is associated with a myriad of adverse infant outcomes. However, the role of host genetic polymorphisms in modulating maternal CMV status is inconclusive. This study investigated the possible association of single nucleotide polymorphisms in toll-like receptor (TLR) and cytokine genes with maternal plasma CMV DNA status in black Zimbabweans. METHODS: In a cross-sectional study, 110 women in late gestation who included 36 CMV infected cases and 74 CMV uninfected, age and HIV status matched controls were enrolled. Twenty single nucleotide polymorphisms in 10 genes which code for proteins involved in immunity against CMV were genotyped using Iplex GOLD SNP genotyping protocol on the Agena MassARRAY® system. Statistical analyses were performed using Stata SE and the 'Genetics' and 'SNPassoc' packages of the statistical package R. RESULTS: The TLR7 rs179008A > T (p < 0.001) polymorphism was associated while the TLR9 rs352139T > C (p = 0.049) polymorphism was on the borderline for association with CMV positive (CMV+) status. In contrast, the interleukin (IL)-6 rs10499563T > C (p < 0.001) and TLR2 rs1816702C > T (p = 0.001) polymorphisms were associated with CMV negative (CMV-) status. Furthermore, allele frequencies of SNPs in TLR2, TLR4, TLR9, TLR7, IL-6, IL-10, IL-28B, IL-1A and interferon AR1 (IFNAR1) genes are being reported here for the first time in a Zimbabwean population. The allele frequencies in the Zimbabwean population are generally comparable to other African populations but different when compared to European and Asian populations. CONCLUSIONS: Toll-like receptor and interleukin genetic polymorphisms influence CMV status in late gestation among black Zimbabweans. This is attributable to possible modulation of immune responses to CMV reactivation in a population previously exposed to CMV infection.

The Value of Pharmacogenetics to Reduce Drug-Related Toxicity in Cancer Patients.

Many anticancer drugs cause adverse drug reactions (ADRs) that negatively impact safety and reduce quality of life. The typical narrow therapeutic range and exposure-response relationships described for anticancer drugs make precision dosing critical to ensure safe and effective drug exposure. Germline mutations in pharmacogenes contribute to inter-patient variability in pharmacokinetics and pharmacodynamics of anticancer drugs. Patients carrying reduced-activity or loss-of-function alleles are at increased risk for ADRs. Pretreatment genotyping offers a proactive approach to identify these high-risk patients, administer an individualized dose, and minimize the risk of ADRs. In the field of oncology, the most well-studied gene-drug pairs for which pharmacogenetic dosing recommendations have been published to improve safety are DPYD-fluoropyrimidines, TPMT/NUDT15-thiopurines, and UGT1A1-irinotecan. Despite the presence of these guidelines, the scientific evidence showing the benefits of pharmacogenetic testing (e.g., improved safety and cost-effectiveness) and the development of efficient multi-gene genotyping panels, routine pretreatment testing for these gene-drug pairs has not been implemented widely in the clinic. Important considerations required for widespread clinical implementation include pharmacogenetic education of physicians, availability or allocation of institutional resources to build an efficient clinical infrastructure, international standardization of guidelines, uniform adoption of guidelines by regulatory agencies leading to genotyping requirements in drug labels, and development of cohesive reimbursement policies for pretreatment genotyping. Without clinical implementation, the potential of pharmacogenetics to improve patient safety remains unfulfilled.

Neuro-respiratory pathology in spinocerebellar ataxia.

The spinocerebellar ataxias (SCA) are a heterogeneous group of neurodegenerative disorders with an autosomal dominant inheritance. Symptoms include poor coordination and balance, peripheral neuropathy, impaired vision, incontinence, respiratory insufficiency, dysphagia, and dysarthria. Although many patients with SCA have respiratory-related complications, the exact mechanism and extent of this pathology remain unclear. This review aims to provide an update on the recent clinical and preclinical scientific findings on neuropathology causing respiratory insufficiency in SCA.