Congenital-onset MLASA2 from a novel

IntroductionMLASA (myopathy, lactic acidosis and sideroblastic anemia) is a rare, autosomal recessive mitochondrial disorder. Symptom onset typically occurs in childhood and differs considerably in disease severity. Congenital-onset disease is uncommon.MethodsWhole genome sequencing was performed which identified two heterozygous, rare YARS2 (NM_001040436.3) variants in trans, one of which was novel. The diagnosis was confirmed with muscle biopsy and mitochondrial enzyme activity testing. To compare the clinical phenotype of our patient to those previously described in the literature, we reviewed all YARS2-related cases in literature to identify age of symptom onset and associated clinical features.ResultsThe maternally-inherited variant, c.948G > T, p.(Arg316Ser), was previously reported with MLASA; the paternally-inherited variant, c.917T > C, p.(Phe306Ser) has not been previously reported. Muscle biopsy showed non-specific changes, that can be seen with mitochondrial dysfunction. Mitochondrial enzyme activity testing on frozen muscle tissue confirmed reduced complex I, III and IV activities.DiscussionIn our case report we describe a patient with MLASA, caused by compound heterozygous variants in YARS2. Our child with congenital-onset disease remains stable at 23 months old. Her stable course differs from two other children with congenital-onset disease who died in the first few days to months after birth. Mitochondrial enzyme activity testing is important to establish pathogenicity of novel variants in patients with this rare and clinically heterogeneous disease.