Myopathy with Lactic Acidosis and Sideroblastic Anemia Caused By a Novel PUS1mutation

Mutations in the mitochondrial aminoacyl tRNA synthetases (ARSs) are associated with various clinical phenotypes, including myopathy, lactic acidosis, and sideroblastic anemia (MLASA), which is a rare autosomal recessive disorder. Due to oxidative phosphorylation disorder and abnormal iron metabolism in the skeletal muscle and erythroid bone marrow lines, patients show progressive muscle weakness, exercise intolerance, lactic acidosis, siderocyte anemia, and growth retardation, etc. Herein, we report a case of MLASA caused by a novel homozygous missense mutation (c.597G>T p.R199S) in the pseudouridine synthase 1 ( PUS1) gene, causing the loss of protein function. The patient's parents had a consanguineous marriage, with a grandmother in common. All mutations were heterozygous without disease. While the patient was homozygous for the mutation and developed symptoms of anemia, no specific treatment exists for this genetic disease. Deferrization therapy can reduce iron overload, which leads to reduced heme synthesis in such patients but cannot treat the disease. Consanguineous marriage often causes autosomal recessive genetic diseases and prohibiting it can reduce the incidence of these diseases.

The present patient's condition was caused by a mutation in nuclear PUS1, which manifested as SA, hyperlactatemia, iron overload, and muscle damage. PUS1 mutations can be missense, nonsense, or frameshift. We identified a novel missense mutation type in PUS1 in this patient, located on chromosome 12, c.597G>T (p.R199S), which is a homozygous mutation. This was confirmed by the PUS1 analysis revealing homozygosity for the novel mutation. Both the parents and grandmothers were heterozygous for the mutation, but none of them had a clinical manifestation. Combining the patient's family history, medical history, laboratory examination, and genetic characteristics of the disease, the mutation was identified as a pathogenic variant, and the clinical manifestations and genetic findings of the patient expanded the genotype-phenotype spectrum of MLASA.

The possibility of MLASA should be suspected in cases of progressive muscle weakness, growth retardation, exercise intolerance in childhood, SA, and lactic acidosis before or after puberty. With the recognition of MLASA and the advent of NGS, identifying patients with PUS1 mutations characterizing incomplete MLASA syndrome became easier, thus further expanding the phenotypic and genotypic heterogeneities of these mitochondrial disorders. Targeting NGS may also significantly improve the prenatal and preimplantation genetic diagnosis of MLASA, providing better genetic counseling for parents. Genetic diseases lack effective treatment measures, and the curative effect is unsatisfactory. Therefore, prevention is more important. Prevention strategies include avoiding consanguineous marriage, genetic counseling, genetic testing for carriers, and a prenatal diagnosis.