서울성모병원 신선영
Introduction
Leber’s Hereditary Optic Neruopathy
(LHON)
• Maternally inherited: over 90% of cases carry a mtDNA point mutation
affecting complex I at nps 11778/ ND4(Wallace et al. 1988), 3460/ND1,
and 14484/ND6
• Male prevalence
• Variable penetrance despite most LHON maternal lineage area
homoplasmic mutant
• Acute/subacute central vision loss (papillomacular bundle) in
young/adults
• Retinal ganglion cell death (tissue specificity)
Biochemical effects of LHON mutations
• Mutation affecting complex I genes of mitochondrial DNA
(mtDNA) : defective complex I function
• Loss of energetic efficiency, increased oxidative stress, propensity
to apoptotic cell death
• -> altered axonal transport of organelles & axoplasmic stasis with
swelling of axons
Idebenone
• stimulate net ATP formation & act as potent free
radical scanvenger
• Particular suited for bypassing the functional
impairment of mitochondrial complex I
• Mashima (2000) : 14 pt, Idebenone+Vit C, B2
– No sig difference with visual recovery
– seemed to speed the recovery
• Barnils (2007) : prevention of 2nd eye invol in 2 pt with
11778
– no beneficial effects
Discussion
• 24wk multicenter, double blind, randomized, placebo-controlled trial
• 85 pt. Idebenone 900mg/day
• the best recovery VA : not significant
• changes in VA of the best eye at baseline & changes in VA for both
eyes in each patient : significant different
• the largest Tx effect : m.11778G>A, m.3460G>A mutation
• safe, well tolerated
Limitation of this study
• The original plan
– To enrol patients in the acute phase of LHON soon after first
eye involvement
– Poor recruitment
• Instead, pt with LHON (13 – 65 YO, visual loss for up
to 5 years) were enrolled
– Optic atrophy
– 14484 mutation
– Short FU period
by Nancy J. Newman
• avoiding agents that may act as “mitochondrial stressors”
: no proven benefit
• one recent epidemiologic study :
- tobacco use, excessive alcohol intake
- cyanide containing products
- medications that may have mitochondrial toxicity & environmental
toxins
- avoid especially during the acute phase of visual loss
Antioxidant Agents
• CoeZ Q-10 : Mitochondria cofactor
– Shuttles electron from complex I & II to III
– Limitation : poor delivery crossing lipid membranes
to mitochondria
• Idebenone : CoeZ Q-10 derivatives
– higher delivery to mitochondria
– Higher efficiency for crossing BBB
– May have limited beneficial effects
• retrospectively review the largest cohort
: 44 treated pt vs. 59 untreated pt
• > 10 YO, < 1 y of onset of visual loss > 5y FU
• 11778 mutation pt : increased frequency of visual recovery
: significant asso with early administation
: apparent delay in visual loss in 2nd eye
: ultimately 2nd eye involved & not better visual fx
• EPI-743
– Experimental therapeutic agent
– In vitro activity ⅹ1000 times
– Life-threatening inherited respiratory chain
disease of the mitochondria
20세 남자
LHON
1주일전부터 한
눈의 시력 소실
Idebenone
O
24세 형
LHON
3년전부터 양눈
의 시력 소실
ⅹ
18세 여동생
LHON
증상없음
ⅹ
•Tobacco smoking & alcohol consumption
•Exposure to less common toxic agents : solvent vapors
•Head trauma
•Uncontrolled DM
•Pharmaceutical agents that interfere with mitochondrial
metabolism (ethambutol, antiretroviral drugs)