Increased Penetrance in Siblings of Affected Females in a Large Leber’s Hereditary Optic Neuropathy Pedigree From Brazil Is Not Reflected by the Frequency of Subclinical Abnormalities

Abstract

Abstract: : Purpose: To compare disease penetrance and frequency of subclinical abnormalities in siblings of affected females and non–affected female mutation carriers from the same large maternal lineage of a Brazilian family with Leber’s hereditary optic neuropathy (LHON). Methods: Since 2001 we have comprehensively evaluated and reexamined members of a very large LHON/11778 family from Brazil. We have identified subclinical abnormalities in non–affected mutation carriers along the maternal lineage by GDx and fundus direct examination and photographic documentation. GDx was judged abnormal when significant changes in the nerve fiber layer (NFL) thickness, or a significant asymmetry between eyes was evident. Fundus examination was judged abnormal when temporal pallor, temporal atrophy or the combination of NFL swelling and microangiopathy were observed. Results: Disease penetrance was significantly higher in siblings of affected females (group I, 46.5%) versus siblings of non–affected female mutation carriers (group II, 23.1%). The stratification by sex showed the remarkable prevalence in males (61.9%) compared to females (31.8%) from group I. The reduced penetrance in group II showed exclusively affected males (40.9%). When we studied the frequency of subclinical abnormalities as assessed by GDx only, fundus exam only, or the combination of both criteria we found no significant sex prevalence nor differences between group I and II. Approximately half of examined non–affected mutation carriers had subclinical abnormalities (46.6% in group I and 55.5% in group II), distributed in over 60% of males (66.6% in group I and 63.6% in group II) and over 40% of females (41.6% in group I and 50% in group II). Conclusions: The significance of subclinical abnormalities in LHON mutation carriers is under scrutiny. Our results could suggest that subclinical abnormalities may be induced by a nuclear modifying gene, but not necessarily evolve in clinical LHON. A further factor may be critical, for example the exposure to an environmental trigger, for which there is gender prevalence. The variability of penetrance in LHON proves to be a complex, multi–factorial and multi–step process.

Keywords: neuro-ophthalmology: optic nerve • genetics • mitochondria