Mitochondrial diseases are characterized by considerable clinical variability and are most often caused by mutations in mtDNA. Because of the phenotypic variability, epidemiological studies of the frequency of these disorders have been difficult to perform. We studied the prevalence of the mtDNA mutation at nucleotide 3243 in an adult population of 245,201 individuals. This mutation is the most common molecular etiology of MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes), one of the clinical entities among the mitochondrial disorders. Patients with diabetes mellitus, sensorineural hearing impairment, epilepsy, occipital brain infarct, ophthalmoplegia, cerebral white-matter disease, basal-ganglia calcifications, hypertrophic cardiomyopathy, or ataxia were ascertained on the basis of defined clinical criteria and family-history data. A total of 615 patients were identified, and 480 samples were examined for the mutation. The mutation was found in 11 pedigrees, and its frequency was calculated to be >=16. 3/100,000 in the adult population (95% confidence interval 11.3-21. 4/100,000). The mutation had arisen in the population at least nine times, as determined by mtDNA haplotyping. Clinical evaluation of the probands revealed a syndrome that most frequently consisted of hearing impairment, cognitive decline, and short stature. The high prevalence of the common MELAS mutation in the adult population suggests that mitochondrial disorders constitute one of the largest diagnostic categories of neurogenetic diseases.

Significant changes in the severity of disease, sensorineural hearing impairment, left ventricular hypertrophy, and quantitative EEG were seen in adult patients with 3243A>G during the 3-year follow-up.

The relationship between the phenotype and the genotype is complex in diseases caused by mutations in mitochondrial DNA (mtDNA). The 3243A-->G mutation in mtDNA frequently leads to sensorineural hearing impairment (HI), a phenotype that can be assessed in severity by audiometry; hence, consecutive audiograms can give an estimate of the rate of HI progression. We examined the audiological phenotype of 38 patients (14 men, 24 women; mean age: 45+/-14 years) who possessed the 3243A-->G mutation and who belonged to a population-based cohort ascertained in the province of Northern Ostrobothnia, Finland. The subjects took part in an otorhinolaryngologic examination, including audiometry. Factors modulating the severity of HI were analyzed, and the rate of HI progression was calculated. The better ear hearing level (BEHL) at frequencies 0.5, 1, 2, and 4 kHz (BEHL0.5-4kHz) was greater than 20 dB suggesting HI in 28 patients (74%). A good correlation (r=0.428, P=0.009) was found between BEHL0.5-4kHz and the degree of the mutant heteroplasmy. BEHL0.5-4kHz was worse in men than in women, and women outnumbered men among patients with normal hearing or mild HI. In addition, 181 consecutive audiograms were reviewed from 24 patients with HI. The rate of HI progression was calculated to be 2.9 dB/year in men and 1.5 dB/year in women, being clearly faster than the rates that have been observed in the corresponding age group in the general population. A high degree of mutant heteroplasmy, male gender, and age were found to increase the severity of HI. Phenotypic difference by gender may thus be a more universal phenomenon in mitochondrial diseases, not only being associated with Leber's hereditary optic neuropathy. This study provides the first estimate of the rate of disease progression among patients with the 3243A-->G mutation.

The cross-sectional population sample studied here was randomly selected from the population register of northern Finland. The subjects comprised 10 different age groups between 2 and 75 years of age. Pure tone averages over the frequencies of both 0.5, 1 and 2 kHz and 0.5, 1, 2 and 4 kHz - i.e. better ear hearing levels (BEHL) of BEHL0.5-2kH and BEHL0.5-4kHz - were calculated. The prevalence of various grades of hearing impairment was investigated among the 3518 people who participated in audiometric measurements. Two different classifications were used to grade the hearing impairment. According to the World Health Organization (WHO) classification (1991), 94.3% of the subjects had normal hearing, whereas 3.8% had mild hearing impairment, 1.3% had moderate impairment, 0.4% severe impairment and 0.1% profound impairment. When the more recent EU definition (1996) was used, 85.3% of the subjects had normal hearing. Mild impairment was found in 11.5% of the subjects, moderate impairment in 2.8%, severe impairment in 0.3%, and profound in 0.1%. The difference between the two definitions mentioned above (resulting in different prevalence figures of hearing impairments) is clear. The WHO classification reveals the need for rehabilitation and can thus be used as a basis of resource allocation, whereas the EU proposal reveals even the mildest hearing impairments and hence better illustrates the real prevalence of impairment. The need for the current and future audiological services may be estimated from the prevalence rates of hearing impairments. The proportion of the Finnish elderly - the people most frequently using health services - is expected to increase from today's 15% to 23% within the next 20 years. The same phenomenon is to be expected in other Western societies.

Several point mutations in mitochondrial DNA (mtDNA) have been shown to cause sensorineural hearing impairment (SNHI), but the frequency of these mutations among patients is not known. We identified 117 patients with possible matrilineal SNHI from population-based registers and found the 3243A > G mutation to be present in 4.3% and 1555A > G in 2.6%, while 7445T > C, 7472insC and 8344A > G were absent. Patients with 3243A > G and 1555A > G were clinically distinct. The prevalence of 1555A > G in the general adult population was estimated to be at least 4.7/100000, but these and previous data suggest that the figure may vary between populations. Screening for mtDNA mutations is worthwhile in connection with the diagnosis of SNHI.

The frequency of large-scale mitochondrial DNA deletions is similar among populations, suggesting that there is a constant rate of new deletions.

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