Severe hepatopathy and neurological deterioration after start of valproate treatment in a 6-year-old child with mitochondrial tryptophanyl-tRNA synthetase deficiency

Background: The first subjects with deficiency of mitochondrial tryptophanyl-tRNA synthetase (WARS2) were reported in 2017. Their clinical characteristics can be subdivided into three phenotypes (neonatal phenotype, severe infantile onset phenotype, Parkinson-like phenotype). Results: Here, we report on a subject who presented with early developmental delay, motor weakness and intellectual disability and who was considered during several years as having a non-progressive encephalopathy. At the age of six years, she had an epileptic seizure which was treated with sodium valproate. In the months after treatment was started, she developed acute liver failure and severe progressive encephalopathy. Although valproate was discontinued, she died six months later. Spectrophotometric analysis of the oxidative phosphorylation complexes in liver revealed a deficient activity of complex III and low normal activities of the complexes I and IV. Activity staining in the BN-PAGE gel confirmed the low activities of complex I, III and IV and, in addition, showed the presence of a subcomplex of complex V. Histochemically, a mosaic pattern was seen in hepatocytes after cytochrome c oxidase staining. Using Whole Exome Sequencing two known pathogenic variants were detected in WARS2 (c. 797delC, p. Pro266ArgfsTer10/c. 938 A > T, p. Lys313Met). Conclusion: This is the first report of severe hepatopathy in a subject with WARS2 deficiency. The hepatopathy occurred soon after start of sodium valproate treatment. In the literature, valproate-induced hepatotoxicity was reported in the subjects with pathogenic mutations in POLG and TWNK. This case report illustrates that the course of the disease in the subjects with a mitochondrial defect can be non-progressive during several years. The subject reported here was first diagnosed as having cerebral palsy. Only after a mitochondriotoxic medication was started, the disease became progressive, and the diagnosis of a mitochondrial defect was made

Non-coding RNAs in the pathogenesis of COPD

A large part of the human genome is transcribed in non-coding RNAs, transcripts that do not code for protein, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). MiRNAs are short single-stranded RNA molecules that negatively regulate gene expression at the post-transcriptional level. They play an important regulatory role in many biological processes. Consequently, altered expression of these non-coding RNAs has been shown to lead to inflammation and disease. In contrast, lncRNAs, can both enhance or repress the expression of protein-coding genes. COPD is typically caused by tobacco smoking and leads to a progressive decline in lung function and a premature death. Exaggerated pulmonary inflammation is a hallmark feature in this disease, leading to obstructive bronchiolitis and emphysema. In this review, we discuss the miRNA expression patterns in lungs of patients with COPD and in mouse models and we highlight various miRNAs involved in COPD pathogenesis. In addition, we briefly discuss a specific lncRNA that is upregulated upon cigarette smoke exposure, providing a short introduction to this more recently discovered group of non-coding RNAs

Bone morphogenetic protein 6 (BMP-6) modulates lung function, pulmonary iron levels and cigarette smoke-induced inflammation

Chronic obstructive pulmonary disease (COPD) is associated with abnormal inflammatory responses and airway wall remodeling, leading to reduced lung function. An association between the bone morphogenetic protein (BMP-6) locus and forced vital capacity has been found in a genome-wide association study. However, the role of BMP-6 in the pathogenesis of COPD remains unknown. The pulmonary expression of BMP-6 was analyzed in patients with COPD and in cigarette smoke (CS)-exposed mice. We evaluated lung function and histology in BMP-6 KO mice at baseline. We exposed BMP-6 KO mice to CS for 4 weeks and measured pulmonary inflammation and iron levels. Pulmonary mRNA levels of BMP-6 were decreased in smokers with and without COPD and in CS-exposed mice. Importantly, BMP-6 expression was lowest in severe COPD. Accordingly, protein levels of BMP-6 were decreased in patients with COPD. Lung function measurements demonstrated a decreased compliance and total lung capacity in BMP-6 KO mice, whereas lung histology was normal. Furthermore, BMP-6 KO mice displayed elevated iron levels and an aggravated CS-induced inflammatory response. These results suggest that BMP-6 is important for normal lung function and that downregulation of BMP-6-as observed in patients with COPD-contributes to pulmonary inflammation after CS exposure