Subclinical carriers and conversions in Leber hereditary optic neuropathy: a prospective psychophysical study.
OBJECTIVE
The authors previously presented the results of their 2001 field investigation to rural Brazil to investigate a 336-member pedigree of Leber hereditary optic neuropathy (LHON). The present work describes the yearly field investigations 2001 to 2005, utilizing a variety of highly sophisticated psychophysical and electrophysiologic procedures, in asymptomatic LHON carriers, some of whom converted to affected status.


METHODS
Careful, repeated examinations of 75 carriers of homoplasmic 11778 LHON mtDNA J-haplogroup mutants were performed as part of the field investigation of this pedigree. All subjects underwent a detailed neuro-ophthalmologic investigation, including formal visual fields (Humphrey; HVF) and fundus photography. In addition, many subjects underwent rigorous psychophysical examination, including Cambridge Research Systems color vision and contrast sensitivity testing, OCT, GDx, and multifocal visual evoked response (mfVER) and multifocal electroretinogram (mfERG). Two patients followed as nonsymptomatic LHON carriers converted to affected status.


RESULTS
Many LHON carriers did, in fact, show subclinical or occult abnormalities. Focal edema was often seen involving the arcuate nerve fiber bundles, and this corresponded with areas of relative paracentral or arcuate scotomas on HVF testing. Compared to controls, LHON carriers had significant losses in color vision affecting mostly the red-green system and reduction in spatial but not temporal contrast sensitivity. The mfVER and mfERG data showed that most carriers had depressed central responses and abnormal interocular asymmetries.


CONCLUSIONS
In this very large pedigree of 11778 LHON, the carriers frequently showed manifestations of optic nerve impairments. Their occult disease reflected low-grade compromise that waxed and waned. In two cases, these changes led to a crescendo of dramatic impairments that characterize conversion to affected status.
Sadun
Alfredo A
AA
Keck-USC School of Medicine/Doheny Eye Institute, Los Angeles, California, USA.
Salomao
Solange R
SR
Berezovsky
Adriana
A
Sadun
Federico
F
Denegri
Anna Maria
AM
Quiros
Peter A
PA
Chicani
Filipe
F
Ventura
Dora
D
Barboni
Piero
P
Sherman
Jerome
J
Sutter
Erich
E
Belfort
Rubens
R
Carelli
Valerio
V
D000293:Adolescent; D000328:Adult; D001938:Brazil; D002353:Carrier State; D002648:Child; D003119:Color Perception Tests; D015350:Contrast Sensitivity; D004272:DNA, Mitochondrial / Q000235:genetics; D004596:Electroretinography; D005074:Evoked Potentials, Visual; D005260:Female; D006801:Humans; D008297:Male; D029242:Optic Atrophy, Hereditary, Leber / Q000175:diagnosis* / Q000235:genetics; D009898:Optic Disk / Q000473:pathology; D009900:Optic Nerve / Q000473:pathology*; D010375:Pedigree; D017354:Point Mutation; D011446:Prospective Studies; D012424:Rural Population; D013351:Subcommissural Organ; D014786:Vision Disorders / Q000175:diagnosis*
D004272:DNA, Mitochondrial