Asymptomatic Carriers of Leber's Hereditary Optic Neuropathy Have Elevated Serum Neuron Specific Enolase

Abstract

Purpose: : To assess the neuronal physiology of asymptomatic carriers of Leber’s Hereditary Optic Neuropathy (LHON) using a serum assay of neuron specific enolase (NSE). It is hypothesized that NSE levels will be elevated in asymptomatic carriers and that affected (end-stage) cases would have normal serum NSE levels.

Methods: : Serum was obtained from 75 members of a Brazilian pedigree with LHON identified by homoplasmic 11778 mitochondrial DNA (mtDNA). Based on genetic pedigree, 46/75 were ‘carriers’ with homoplasmic 11778 mtDNA but no visual symptoms. 15/75 were ‘affected’, characterized by homoplasmic 11778 mtDNA and blindness. 14/75 were non-family, ‘off pedigree’ controls. Enzyme linked immunosorbent assay (ELISA) specific for the γ-subunit of NSE was performed to quantify serum NSE concentrations.

Results: : ‘Carriers’ had elevated NSE levels (27.17 ug/L + 39.82), as compared to ‘off pedigree’ (6.20 ug/L + 2.35; P = .047) and ‘affected’ (5.89 + 4.15; P = 0.046) controls. Within the ‘carrier’ group there was a clustering of 32/46 (70%) subjects with NSE levels in the normal range (below 17 ug/L, mean = 5.9 + 4.2 ug/L). The remaining results were higher, ranging from 24 ug/L to 147 ug/L (mean = 75.8 + 42.3 ug/L). There was a 12-fold difference in serum NSE levels of those carriers in the normal range and those with elevated levels (P=0.0001). 9/14 (64%) of the high range individuals were male. NSE levels were 7-fold higher in male (40.65 + 51.21 ug/L) than in female carriers (5.85 + 22.27 ug/L; p=0.034).

Conclusions: : Serum NSE levels are significantly elevated in carriers of 11778 LHON. Carriers have NSE levels 4-fold greater than ‘off-pedigree’ and ‘affected’ controls. Normal NSE levels in the ‘affected’ group may be due to profound depletion of RGC neurons. The very high NSE levels in a subgroup of ‘carriers’ suggest that these individuals are experiencing significant RGC neuronal stress that may put them at even greater risk of becoming ‘affected’. Furthermore, males may be at higher risk than similarly predisposed females.

Keywords: visual impairment: neuro-ophthalmological disease • nerve fiber layer • mitochondria