Epidemiology of A3243G, the Mutation for Mitochondrial Encephalomyopathy, Lactic Acidosis, and Strokelike Episodes: Prevalence of the Mutation in an Adult Population

Abstract

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.

Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease

“…These current results for mtDNA mutations are similar to that reported previously in adult patients with mitochondrial disease in the North East of England a decade earlier and as such act as comparative data 3. Although the frequency of mtDNA mutations remain stable in our patient cohort, the point prevalence for the m.3243A>G mutation remains significantly lower than the frequency reported by Majamaa et al21 The reasons for this remain unclear. However, given that the point prevalence figures remain stable in the intervening decade in this English cohort, the genetic background and population structure may play a more significant role than study design in creating variability in prevalence rates than originally purported 3.…”

Extensive and rapid screening for major mitochondrial DNA point mutations in patients with hereditary hearing loss

“…A population-based study of the m.3243A4G mutation revealed the mutation in 7.4% of patients with maternally inherited HL in northern Finland. 38 In this study, this mutation was demonstrated to have a prevalence of 2.4% in the cases of Japanese hereditary HL, and this frequency is very close to that previously reported in Japan. 39 This screening system detected the m.8348A4G mutation in the MT-TK gene in a 6-year-old boy (patient TMD 408) with SNHL ( Figure 2a).…”

In situ genotyping individual DNA molecules by target-primed rolling-circle amplification of padlock probes

“…4c). Only wild-type signals were seen in the sample we investigated, which is expected considering the low frequency of the mutation in the general population 24 .…”