The mutations m.5628T>C and m.8348A>G in single muscle fibers of a patient with chronic progressive external ophthalmoplegia

2012 ◽  
Vol 320 (1-2) ◽  
pp. 131-135 ◽  
Author(s):  
Juliana Gamba ◽  
Beatriz Hitomi Kiyomoto ◽  
Acary Souza Bulle de Oliveira ◽  
Alberto Alain Gabbai ◽  
Beny Schmidt ◽  
...  
Author(s):  
Agnes Wong

To understand how eye muscles move the eyeball, it is necessary to understand the geometry of the eye and the functions of the muscles. The eyeball rotates about three axes: horizontal, vertical, and torsional. These axes intersect at the center of the eyeball. Eye rotations are achieved by coordinated contraction and relaxation of six extraocular muscles—four rectus and two oblique—attached to each eye. The action of the muscles on the globe is determined by the point of rotation of the globe, as well as the origin and insertion of each muscle. Recent evidence suggests that the muscles also exert their effects on the globe via the extraocular muscle pulleys. Considering that we make at least 100,000 saccades alone each day, it is not surprising that many extraocular muscles are very resistant to fatigue. Extraocular muscles are also different from other skeletal muscles in many respects. For example, eye muscle fibers are richly innervated, and each motoneuron innervates only 10–20 muscle fibers, the smallest motor unit known in the body. Extraocular muscles also have more mitochondria and a higher metabolic rate than other skeletal muscles. Thus, extraocular muscles are one of the fastest contracting muscles. This property allows animals to shift gaze swiftly, so that they can avoid approaching predators or detect prey in the vicinity. The unique immunologic and physiologic properties of extraocular muscles may also explain why they are more susceptible to certain disease processes, such as Grave’s disease and chronic progressive external ophthalmoplegia, but more resistant to others such as Duchenne’s dystrophy, which mainly affects skeletal muscles in the rest of the body. The eyeball rotates about three axes: x-axis (naso-occipital or roll axis), y-axis (earthhorizontal or pitch axis), and z-axis (earth-vertical or yaw axis). Ductions refer to monocular movements of each eye. They include abduction, adduction, elevation (sursumduction), depression (deorsumduction), incycloduction or incyclotorsion, and excycloduction or excyclotorsion (see table on opposite page). Versions refer to binocular conjugate movements of both eyes, such that the visual axes of the eyes move in the same direction. They include dextroversion, levoversion, elevation (sursumversion), depression (deorsumversion), dextrocycloversion, and levocycloversion (see table).


2016 ◽  
Vol 263 (7) ◽  
pp. 1449-1451 ◽  
Author(s):  
Lorenzo Gaetani ◽  
Andrea Mignarri ◽  
Maria Di Gregorio ◽  
Paola Sarchielli ◽  
Alessandro Malandrini ◽  
...  

2008 ◽  
Vol 28 (2) ◽  
pp. 89-96 ◽  
Author(s):  
Cornelia Kornblum ◽  
Gábor Zsurka ◽  
Rudolf J. Wiesner ◽  
Rolf Schröder ◽  
Wolfram S. Kunz

CPEO (chronic progressive external ophthalmoplegia) is a common mitochondrial disease phenotype in adults which is due to mtDNA (mitochondrial DNA) point mutations in a subset of patients. Attributing pathogenicity to novel tRNA mtDNA mutations still poses a challenge, particularly when several mtDNA sequence variants are present. In the present study we report a CPEO patient for whom sequencing of the mitochondrial genome revealed three novel tRNA mtDNA mutations: G5835A, del4315A, T1658C in tRNATyr, tRNAIle and tRNAVal genes. In skeletal muscle, the tRNAVal and tRNAIle mutations were homoplasmic, whereas the tRNATyr mutation was heteroplasmic. To address the pathogenic relevance, we performed two types of functional tests: (i) single skeletal muscle fibre analysis comparing G5835A mutation loads and biochemical phenotypes of corresponding fibres, and (ii) Northern-blot analyses of mitochondrial tRNATyr, tRNAIle and tRNAVal. We demonstrated that both the G5835A tRNATyr and del4315A tRNAIle mutation have serious functional consequences. Single-fibre analyses displayed a high threshold of the tRNATyr mutation load for biochemical phenotypic expression at the single-cell level, indicating a rather mild pathogenic effect. In contrast, skeletal muscle tissue showed a severe decrease in respiratory-chain activities, a reduced overall COX (cytochrome c oxidase) staining intensity and abundant COX-negative fibres. Northern-blot analyses showed a dramatic reduction of tRNATyr and tRNAIle levels in muscle, with impaired charging of tRNAIle, whereas tRNAVal levels were only slightly decreased, with amino-acylation unaffected. Our findings suggest that the heteroplasmic tRNATyr and homoplasmic tRNAIle mutation act together, resulting in a concerted effect on the biochemical and histological phenotype. Thus homoplasmic mutations may influence the functional consequences of pathogenic heteroplasmic mtDNA mutations.


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