Cause
LHON is a mitochondrial disease. It is usually caused by one of several pathogenic genetic mutations in the mitochondria. Those who have a mitochondrial LHON mutation without vision loss are referred to as “carriers” or “unaffected carriers.” In some individuals who carry an LHON mutation, the optic nerves suddenly begin to swell then atrophy. This causes a disruption in the signals between the eyes and the brain, leading to vision loss. Those who have central vision loss due to LHON are referred to as “affected.”
The most common LHON mutation among those affected is the 11778 (ND4) mutation, causing over 65% of all LHON cases. Most of the remaining LHON cases are caused by the 14484 (ND6) and 3460 (ND1) mutations. Several very rare mitochondrial mutations cause most of the other cases.
Recently, some nuclear mutations that impact the mitochondria have been associated with LHON vision loss. DNAJC30 is the most common of the nuclear mutations causing LHON.
While a genetic variant is the root cause of LHON symptoms, not all who carry an LHON mutation become symptomatic. This “incomplete penetrance” indicates that additional factors have an impact on whether or not an individual with an LHON mutation develops symptoms. Genetic factors such as heteroplasmy of the LHON mutation, as well as nuclear variants such as haplotype, are believed to play a role. Exposure to various environmental factors are also believed to impact the likelihood of an unaffected carrier becoming affected.
