Adaptive optics scanning laser ophthalmoscopy images in a family with the mitochondrial DNA T8993C mutation.
OBJECTIVE
This study was designed to assess the effect of mitochondrial DNA (mtDNA) mutation T8993C on cone structure in a family expressing neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) syndrome.


METHODS
Five family members were studied, using clinical examination, nerve conduction studies, perimetry, optical coherence tomography (OCT) measures of central retinal thickness, and electroretinography. High-resolution images of cone structure using adaptive optics scanning laser ophthalmoscopy (AOSLO) were obtained in four subjects with stable fixation. Cone spacing was compared to 18 age-similar normal subjects and converted to z-scores at each location where unambiguous cones were identified. Tissue levels of T8993C mutant heteroplasmy in blood and hair follicles were quantified using real-time allele-refractory mutations system (ARMS) quantitative polymerase chain reaction (qPCR).


RESULTS
Subjects expressing the T8993C mutation showed varying levels of disease severity. The subject with the lowest mutant load (42%-54%) showed no neurologic or retinal abnormalities. The remaining four subjects with over 77% mutant load all expressed severe neurologic and/or retinal abnormalities. AOSLO images revealed three patterns of cone spacing: pattern 1, normal; pattern 2, increased cone spacing within a contiguous cone mosaic; and pattern 3, patchy cone loss with increased cone spacing. Visual function was most severely affected in pattern 3.


CONCLUSIONS
High levels of T8993C mutant load were associated with severe neurologic or visual dysfunction, while lower levels caused no detectable abnormalities. Visual function was better in patients with a contiguous and regular cone mosaic. Patients expressing high levels of the mtDNA T8993C mutation show abnormal cone structure, suggesting normal mitochondrial DNA is necessary for normal waveguiding by cones.
Yoon
Michael K
MK
Department of Ophthalmology, University of California, San Francisco, California 94143-0730, USA.
Roorda
Austin
A
Zhang
Yuhua
Y
Nakanishi
Chiaki
C
Wong
Lee-Jun C
LJ
Zhang
Qing
Q
Gillum
Leslie
L
Green
Ari
A
Duncan
Jacque L
JL
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001259:Ataxia / Q000235:genetics / Q000473:pathology*; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D006801:Humans; D007834:Lasers; D008297:Male; D008875:Middle Aged; D018908:Muscle Weakness / Q000235:genetics / Q000473:pathology*; D009887:Ophthalmoscopy; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology*; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000473:pathology*; D013577:Syndrome; D041623:Tomography, Optical Coherence
D004272:DNA, Mitochondrial