Mitochondrial Disorders Affecting the Nervous System

R.H. Haas, MB, BChir; Z. Zolkipli, MB, ChB


Semin Neurol. 2014;34(3):321-340. 

In This Article

CNS and Neuromuscular Disease

Mitochondrial diseases are typically multiorgan system disorders, but the CNS, muscle, and autonomic and peripheral nerves are frequently involved. Neurologic presentations are the most common manifestations of mitochondrial disease. The high energy requirement of nervous tissue is the likely explanation for its frequent involvement. The common distribution of brain lesions also follows a pattern of high energy need and vulnerability to oxidative injury. Phenotypes vary widely with common molecular defects often identified initially and later expanded as our knowledge base enlarges. Alpers syndrome was the earliest described mitochondrial brain disease (degeneration of the cerebral gray matter in infancy)[12] with a rapid fluctuating neurodegenerative course with basal ganglia and cortical lesions often producing occipitally predominant epilepsia partialis continua. Later, hepatic degeneration was described.[13] The first biochemical defect identified was complex IV deficiency,[14] and later Naviaux et al identified mitochondrial polymerase γ (PolG1) deficiency as the usual underlying molecular defect resulting in mtDNA depletion.[15] Subsequently, the Twinkle helicase[16] and FARS2 encoding the mitochondrial phenylalanyl-tRNA synthetase[17] have also been recognized as rare causes of the Alpers phenotype.

Leigh syndrome is the most common pediatric manifestation of genetic mitochondrial disease. This neurodegenerative disease can be viewed as the final common pathway for energy failure in the young brain with clinical manifestations that may include failure to thrive, global developmental delay, ataxia, dystonia, seizures, eye movement abnormalities, and central respiratory failure. Recently, several reviews have described the progressive longitudinal course.[18,19] Other neurologic phenotypes to be discussed in detail (all with a variety of genetic causes) include neuropathy ataxia and retinitis pigmentosa (NARP), Kearns-Sayre syndrome, mitochondrial encephalomyopathy with ragged red fibers and stroke-like episodes (MELAS), myoclonic epilepsy with ragged red fibers (MERRF), mitochondrial neurogastrointestinal encephalopathy (MNGIE), Alpers syndrome, and Leber hereditary optic neuropathy (LHON).