Audio Profiles in Mitochondrial Deafness m.1555A>G and m.3243A>G Show Distinct Differences

Abstract

BackgroundHearing loss is one of the most common symptoms of mitochondrial disorders. However, audiological phenotypes associated with different molecular defects in mtDNA are not yet well characterized.Material/MethodsA large cohort of 1499 nonconsanguineous patients aged 5–40 years with hearing loss of unknown etiology was screened for mutations in mtDNA. For further analysis, patients harboring m.1555A>G and m.3243A>G were selected.Hearing status of the patients was assessed by pure tone audiometry. Patterns of audiograms (hearing threshold levels at each examined frequency) were statistically compared among the carriers of the m.1555A>G and the m.3243A>G mutations.ResultsWe identified 20 patients positive for m.1555A>G mutation and 16 patients positive for m.3243A>G change. The frequency of the above transitions was calculated in our cohort as 1.33% and 1.06%, respectively. Seventeen affected family members carrying the mutations were included into the study.Typical shape of the audiograms in patients with m.1555A>G mutation presented a ski-slope pattern, whereas the audiometric curves among the m.3243A>G individuals had a pantonal shape (a flat curve) with slight downward sloping at the higher frequencies. The differences were statistically significant.The onset of hearing loss was noted earlier among m.1555A>G than m.3243A>G patients (12.5 and 26 years, respectively). Aminoglycoside administration was declared in both groups in 11 and 4 cases respectively, and caused abrupt hearing deterioration in all cases.ConclusionsA pattern of audiogram in patients with mitochondrial deafness may suggest a localization of mtDNA mutation. The pathogenesis of the audiometric differences needs further study.

Application of next‑generation sequencing to identify mitochondrial mutations: Study on m.7511T>C in patients with hearing loss

“…A study aimed at detecting both, known as well as novel mtDNA variants related to HL, is important and may bring new insight into the pathogenesis of HL. The fact that common mtDNA mutations such as m.1555A>G and m.3243A>G were identified among Polish HL families with an unexpected high frequency (~1%) prompted us to further investigate other mtDNA mutations causing HL ( 10 , 11 ). The presence of these two mutations was checked in our patients prior to their inclusion into the study.…”

“…Its frequency of 0.12% is not significantly different from that of m.7445A>G (0.4%, 1/250 Polish nonsydromic HL patients) ( 45 ), which is considered a major HL causative mutation in the MT-TS1 gene. Two other common mtDNA mutations in Polish HL patients are m.1555A>G in MT-RNR1 detected at a frequency of 1.3% (20/1499) and m.3243A>G in MT-TL1 with a frequency of 1% (16/1499) ( 10 , 11 ). Based on the results, the total percentage of mitochondrial HL-related mutations in Polish patients can be estimated at almost 3%.…”

“…It is known that some mutations in the mtDNA (e.g., m.1555A>G) create an increased susceptibility to aminoglycosides, which results in ototoxicity and HL ( 10 , 46 ). Except for one patient ( Table I ), none of the other studied individuals were treated with aminoglycosides.…”

“…Conversely, isolated, congenital maternally inherited SNHL is as rare as 1% ( 6 ) but the prevalence of postlingual, maternally inherited HL has been estimated even up to 30% ( 7 – 9 ). The most common mtDNA mutations in the Polish HL patients are m.1555A>G in the MT-RNR1 gene and m.3243A>G in the MT-TL1 gene with the prevalence of approximately 1% for each of them ( 10 , 11 ). The vast majority of mtDNA mutations cause postlingual, bilateral and symmetrical HL, which may progress over time.…”

Tinnitus in patients with hearing loss due to mitochondrial DNA pathogenic variants

“…In Polish HL patients, the most commonly studied pathogenic variants of the mitochondrial DNA are m.1555A>G in the MT-RNR1 gene and m.3243A>G in MT-TL1 [20, 21]. The pathogenic variant m.1555A>G causes an irreversible alteration in the 12S rRNA conformation, generating errors in protein synthesis [22] while m.3243A>G leads to deficient aminoacylation of tRNA Leu(UUR) , resulting in a reduced rate of mitochondrial protein synthesis and respiration defects [23].…”