This is the second nationwide epidemiological study of LHON in Japan. In questionnaire surveys, high collection and sampling rates, as well as the avoidance of duplicate registrations, are the keys to increasing the reliability of the results.
The collection rate improved significantly in this survey (79.3%) compared to the previous survey (61.6%). The major reason for this increase was an increased awareness of and interest in this project, because this was the second survey. The next most important factor was a change in the facilities to which the questionnaires were sent. In the previous survey, all facilities accredited by the Japanese Ophthalmological Association and all facilities with at least one member of the Japanese Neuro-Ophthalmology Society were surveyed, a total of 1,397 facilities. This time, however, we reduced the number of facilities to which questionnaires were sent to 997. The questionnaire was sent to facilities accredited by the Japanese Ophthalmological Association, as in the previous survey, but the number of facilities affiliated with the Japanese Neuro-Ophthalmology Society was limited to those to which the council members belonged. This change was made because it was assumed that the council members of the Japanese Neuro-Ophthalmology Society would generally be more familiar with the diagnosis of LHON than the general membership, would be less likely to overlook or misdiagnose the condition, would be more likely to receive referrals of eligible candidates, and would be more likely to respond positively to the questionnaire.
In this study, the extraction rate was assumed to be 1 for the analysis. The extraction rate will be less than 1 if a patient with LHON is seen at a facility other than the one included in this study and is not referred to the study facility. If this actually happened and the true extraction rate was low, the number of new cases could have been underestimated. In practice, the number of new cases reported in the questionnaire was lower in this survey than in the previous survey. However, this decrease was not due to a decrease in the extraction rate, but rather due to a decrease in the number of cases of duplicate registration. In the previous survey, there were several reports of patients who had developed the disease before the target year, and duplicate reports of the same patient from several institutions by multiple members of the Japanese Neuro-Ophthalmology Society. The previous survey was the first national epidemiological survey on LHON, and the requirement that the target population was limited to new-onset patients in the past year may not have been fully understood by the surveyed institutions and researchers. In addition, the LHON accreditation criteria had only been established relatively recently, so the diagnosis may have been inaccurate in less experienced facilities. This time, the bias caused by duplicate registrations and inaccurately diagnosed cases was considered to be very low because, as mentioned above, the survey was limited to facilities with more experience and sufficient expertise, and because the understanding of the diagnostic criteria appears to have spread sufficiently, with the designation of LHON as an intractable disease. Since most LHON patients are school-aged to mature males, have subacute, binocular vision loss, and an uninsured mitochondrial genetic test is essential for diagnosis, it is highly likely that patients will visit a neuro-ophthalmologist, rather than being treated by general ophthalmologists, neurologists, or other institutions outside the scope of this study. Therefore, the extraction rate is expected to approximate to 1 with a fairly high probability. However, since the possibility of duplicate registrations cannot be completely ruled out, we may have overestimated the number of new-onset patients.
In the current survey, the age distribution and sex ratio were almost the same as in the previous survey. Compared to previous reports from other countries, the average age of onset was higher, and males accounted for a higher percentage of cases. As in the previous survey, this increase in the age of onset is thought to be due to the increasing average life expectancy of Japanese people and the declining birth rate. As the decline in the birthrate and the aging of the population accelerates, the age of onset of LHON in the Japanese population is likely to continue to rise. The reason for the greater susceptibility of males is unknown. Although the number of cases was small, the age of onset of LHON was higher in women than in men. It has been suggested that sex hormones may play a role in the development of LHON. 16 Estrogen is presumed to act as a protective factor for retinal ganglion cells and other nerve cells, 17 and may delay the onset of the disease in female mutation carriers until around menopause, when the amount of estrogen in the body decreases.
The other difference between this and the previous survey is the mtDNA mutation sites investigated. In the previous study, only the three primary mutations were included, but in this study, all mutations reported to be associated with LHON in the designation criteria, including rare mutations, were included. As a result, the present study reported the presence of patients with two mutations, np12811 T > C and np11696 G > A, which have been reported as rare mutations in LHON 9–11.
There are several limitations to this study. First, because it is a single-year questionnaire survey, it is affected by variations in patient population estimates due to differences in survey years. As noted above, the number of new cases was estimated to be lower than in the 2014 survey. Periodic epidemiological surveys and prospective all-patient registries should be conducted to obtain more accurate epidemiological trends.
Secondly, the number of patients in this study was calculated based on the assumption that the life expectancy of individuals with LHON is equivalent to that of healthy people. However, since there are reports of lower life expectancy in patients with LHON 18, the total number of patients calculated in this study may be an overestimate.
Third, as a method for estimating the total number of patients, we used the formula published by Godefrooij et al. to estimate the number of keratoconus patients in The Netherlands. As discussed by the authors, this method is only an estimation, producing a rough estimate of the prevalence, and it is still necessary to conduct a full patient registry to accurately determine the actual number.