1 - Genetics Department, Hospital Dona Estefânia, Centro Hospitalar Universitário Lisboa Central, Lisbon, Portugal
2 - Pediatrics Department, Hospital Dona Estefânia, Centro Hospitalar Universitário Lisboa Central, Lisboa, Portugal
3 - Reference Centre of Inherited Metabolic Diseases, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
4 - Pediatric Intensive Care Unit, Pediatrics Department, Hospital Dona Estefânia, Centro Hospitalar Universitário Lisboa Central, Lisboa, Portugal
5 - Neonatal Intensive Care Unit, Pediatrics Department, Hospital Dona Estefânia, Centro Hospitalar Universitário Lisboa Central, Lisboa, Portugal
6 - Pneumology Unit, Pediatrics Department, Hospital Dona Estefânia, Centro Hospitalar Universitário Lisboa Central, Lisboa, Portugal
7 - Pediatric Cardiology Department, Hospital Santa Marta, Centro Hospitalar Universitário Lisboa Central Lisboa, Portugal
8 - CGPP – Centro de Genética Preditiva e Preventiva, IBMC – Instituto de Biologia Molecular e Celular, i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
9 - Child Neurology Unit, Pediatrics Department, Hospital Dona Estefânia, Centro Hospitalar Universitário Lisboa Central, Lisboa, Portugal
- SSIEM Annual Symposium Genetics meets environment, reunião internacional, sob a forma de poster
Background:VARS2 gene encodes a mitochondrial valyl-tRNA synthetase responsible for mitochondrial proteinsynthesis. Biallelic pathogenic variants in VARS2 can lead to failure of mitochondrial mRNA translation resulting in an extremely rare form of encephalocardiomyopathy (Combined Oxidative PhosphorylationDeficiency 20 - COXPD20).
Case Study / Methods:Case StudyResults: A full term male neonate presented with hypotonia and progressive respiratory distress, requiring mechanical ventilation. Additional findings included increased creatine kinase and hyperlactacidemia. Attempts of extubation were unsuccessful due to respiratory insufficiency and recurrence ofhyperlactacidemia. Extensive inconclusive investigation was performed. At D27, a therapeutic trial with acetylcholinesterase (AChE) inhibitors was initiated to assess the diagnostic hypothesis of congenital myasthenic syndrome, with improvement in respiratory autonomy. At D52, already with noinvasive ventilation, the patient presented with sudden hemodynamic compromise due to cardiac tamponade and hypertrophic cardiomyopathy, successfully treated with pericardiocentesis and diuretic therapy. Urgent exome sequencing identified two variants in VARS2, a pathogenic variantc.1100C>T (p.(Thr367Ile)) and a likely pathogenic c.1258G>A (p.(Ala420Thr)). Parental segregation studies confirmed the diagnosis of COXPD20. At D77, AChE inhibitor was suspended and supportive antioxidant therapies were introduced. He was discharged at 3 months on continuous non-invasive ventilation (NIV). At 6 months of age follow up he has adequate growth, achieved head control, regression of cardiomyopathy, mild hyperlactacidemia and NIV during sleep.
Conclusion / Discussion: This phenotype shows many overlapping features with previously described COXPD20 cases, but also an unexpected evolution. Although both variants have been previously reported, this is the first case harbouring both in compound heterozygosity. Further understanding of genotype-phenotype correlations is needed.
Palavras Chave: VARS2 gene, encephalocardiomyopathy, defect of oxidative phosporylation, hypotonia, respiratory distress