Mitochondrial neurological diseases: a clinician's perspective.

CMYK 305 Mitochondrial neurological disorders remain esoteric but fascinating to the clinician. Aspects of their biology illuminate the complexities of their clinical manifestations. The hallmark multiple organ dysfunction is traceable to failure of mitochondria, the ubiquitous organelles of energy generation. High energy cell populations that are post-mitotic and nondividing at birth, are especially vulnerable as exemplified by the brain, retina, optic nerves, organ of Corti, skeletal and cardiac muscle, cardiac conduction system, renal tubular cells, endocrine and pancreatic exocrine glands. The accumulation of mutant mitochondria in vulnerable tissues may cause progressive worsening organ function. Similar mitochondrial segregation may increase abnormal cells in some tissues and decrease in others, shifting clinical dysfuction, say from bone marrow failure to myopathy. Cytoplasmic maternal inheritance is another distinctive feature: mitochondrial gene mutations are transmitted exclusively by the mother through the cytoplasm of the egg, to offsprings of both sexes. As the mutant mitochondria multiply and segregate randomly into different cell lines in the dividing egg, they reach different organs randomly accounting for diversity and variablity of the phenotype among patients with the same mutation (mitotic heteroplasmy). Some of the best defined syndromes due to mitochondrial gene defects are: Leber’s hereditary optic neuropathy (LHON); Kearns –Sayre syndrome (KSS) of chronic progressive external ophthalmoplegia, retinitis pigmentosa, sensoryneural deafness and cardiac conduction disturbances; chronic progressive external ophthalmoplegia (CPEO); the syndrome of mitochondrial encephalomyopathy , lactic acidosis and stroke-like episodes (MELAS); myoclonic epilepsy with ragged red fibers (MERRF); neuropathy with ataxia and retinitis pigmentosa (NARP/Leigh’s) and the recently identified LHON with dystonia and sporadic focal dystonia. A paradigm shift occurred when the nuclear genome was found to regulate most of the mitochondrial biology including assembly, replication and maintainance and autosomally transEditorial