Diversity of mitochondrial disorders : what child neurologists should know

Abstract

  Mitochondrial disorders cause various organ abnormalities. Consequently, the clinical presentation and disease concept are highly variable, making it difficult to diagnose. Because mitochondrial disorders are caused by abnormal respiratory chain enzyme complexes, biochemical diagnosis by examining respiratory chain enzyme activity and quantitatively or qualitatively evaluating protein complexes is important. However, genetic diagnosis is critical for determining treatment according to etiology and genetic counseling. Unfortunately, genetic diagnosis is not easy because of the following reasons : mitochondrial and nuclear DNAs are involved in the biogenesis of mitochondrial respiratory chain complexes, the pathogenicity of novel mitochondrial DNA mutations is difficult to evaluate, and causative genes cannot be identified even though nuclear DNA abnormality is suspected. Regarding the diagnosis of mitochondrial DNA mutations, it is important to pay attention to heteroplasmy, where the mutation rate varies depending on organ involvement. Nuclear DNA abnormalities are also observed in respiratory chain complexes and other factors involved in biogenesis, including respiratory chain assemblies. Although there are many types of etiologies of mitochondrial disorders, increasing numbers of causative genes have recently been discovered using next-generation sequencing, and patient diagnosis is progressing. In order to make the use of these genetic analyses, first of all, careful physical examination with an understanding of diverse clinical symptoms and types of mitochondrial diseases as well as a record of exhaustive medical history is required. Mitochondrial abnormalities should also be accurately diagnosed by comprehensive special examinations, such as biochemical and pathological evaluations, followed by appropriate clinical tests. The future treatments that correspond to individual and patient-specific disease etiologies require an accurate diagnosis and understanding of the disease mechanisms.