Primary mitochondrial diseases

Primary mitochondrial diseases (PMDs) are a heterogeneous group of hereditary disorders characterized by an impairment of the mitochondrial respiratory chain. They are the most common group of genetic metabolic disorders, with a prevalence of 1 in 4,300 people. The presence of leukoencephalopathy is recognized as an important feature in many PMDs and can be a manifestation of mutations in both mitochondrial DNA (classic syndromes such as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; myoclonic epilepsy with ragged-red fibers [RRFs]; Leigh syndrome; and Kearns-Sayre syndrome) and nuclear DNA (mutations in maintenance genes such as POLG, MPV17, and TYMP; Leigh syndrome; and mitochondrial aminoacyl-tRNA synthetase disorders). In this chapter, PMDs associated with white matter involvement are outlined, including details of clinical presentations, brain MRI features, and elements of differential diagnoses. The current approach to the diagnosis of PMDs and management strategies are also discussed. A PMD diagnosis in a subject with leukoencephalopathy should be considered in the presence of specific brain MRI features (for example, cyst-like lesions, bilateral basal ganglia lesions, and involvement of both cerebral hemispheres and cerebellum), in addition to a complex neurologic or multisystem disorder. Establishing a genetic diagnosis is crucial to ensure appropriate genetic counseling, multidisciplinary team input, and eligibility for clinical trials.