ANT1, Twinkle, POLG, and TP. New genes open our eyes to ophthalmoplegia. Hirano M, DiMauro S. Neurology 2001;57:2163–2165

Abstract

Chronic progressive external ophthalmoplegia (CPEO) is the combination of ptosis and limited ocular motility that occurs in a variety of diseases, including congenital myasthenic syndromes, congenital myopathies, oculopharyngeal muscular dystrophy, and the primary mitochondrial disorders. Among the mitochondrial disorders with CPEO, PEO may be isolated or associated with a wide variety of ocular (pigmentary retinopathy, cataracts), neurologic (myopathy, peripheral neuropathy, sensorineural hearing loss), and systemic (diabetes mellitus, cardiac conduction defects and myopathy, other endocrine disorders, short stature) manifestations. Muscle biopsies typically reveal the common features of ragged red fibers and partial cytochrome c oxidase deficiency. Because both the nuclear and mitochondrial genomes code for proteins essential to normal mitochondrial function, abnormalities of either genome can produce a mitochondrial disorder with CPEO as its major manifestation. Disorders in which the primary genetic abnormality is found within the nuclear chromosomes will be inherited in a Mendelian fashion, while those secondary to point mutations in the mitochondrial DNA will be inherited maternally. Other mitochondrial disorders associated with CPEO appear to be sporadic. Complicating the matter is that most of the CPEO disorders caused by nuclear gene defects have multiple deletions or depletion of the mitochondrial DNA, probably as a result of faulty nuclear-encoded proteins which have a role in mitochondrial DNA replication. These first two articles propose new mutations associated with CPEO, one a point mutation in the mitochondrial genome, and the other a point mutation in the nuclear genome. In the former, a muscle biopsy from a woman with CPEO, myopathy and exercise intolerance, revealed a heteroplasmic deletion of a single nucleotide (αDT5885) in the mitochondrial tRNA tyrosine gene (tRNATyr). In the latter, a heterozygous T293C mutation was found in the ANT1 gene (chromosome 4q34-35) in a Greek family with autosomal dominant CPEO. In the accompanying editorial, Hirano and DiMauro review what we know to date regarding the genetics of the mitochondrial disorders with CPEO. It remains unclear how these diverse genetic abnormalities produce CPEO. Once again, the mitochondrial diseases prove fascinating in their genotypic-phenotypic correlations, with multiple different genotypic abnormalities resulting in the same clinical phenotype of CPEO and, conversely, with the same gene abnormality causing varied clinical manifestations.—Nancy J. Newman