The m.7510T>C mutation: Hearing impairment and a complex neurologic phenotype

Abstract

ObjectivesMutations in mitochondrial DNA cause a variety of clinical phenotypes ranging from a mild hearing impairment (HI) to severe encephalomyopathy. The MT‐TS1 gene is a hotspot for mutations causing HI. The m.7510T>C mutation in MT‐TS1 has been previously associated with non‐syndromic HI in four families from different ethnic backgrounds.Materials and MethodsWe describe the clinical, genetic, and histopathological findings in a Finnish family with the heteroplasmic m.7510T>C mutation in mitochondrial DNA.ResultsThe family proband presented with a progressive mitochondrial disease phenotype including migraine, epilepsy, mild ataxia, and cognitive impairment in addition to HI. One young adult presented with HI only. Other family members had a mild phenotype comprising ataxia and tremor in addition to HI. Mutation heteroplasmy was 90% in the blood of maternal grandmother and ≥99% in the muscle and blood of the three other family members. Muscle histology was consistent with mitochondrial myopathy in three family members. The mitochondrial haplogroup of the family was a different branch of the haplogroup H than in the previous reports of this mutation.ConclusionOur results suggest that, in addition to sensorineural HI, the m.7510T>C mutation is associated with a spectrum of mitochondrial disease clinical features including migraine, epilepsy, cognitive impairment, ataxia, and tremor, and with evidence of mitochondrial myopathy.

Syrian child carrying multiple pathogenic variants in MBOAT7 and MT-TS1 genes: a case report on neurodevelopmental phenotypes and mitochondrial inheritance

“…This finding is consistent with a diagnosis of MT-TS1 gene-associated mitochondrial disorders, which leads to a wide range of mitochondrial phenotypes in affected individuals, including sensorineural hearing loss (SHL), myopathy, cognitive deficit, cerebellar ataxia, and myoclonic epilepsy, as documented in prior literature 12 . However, in the absence of sensorineural hearing loss, the clinical presentation of the child is more clearly associated with the MBOAT7 mutation than with the other gene because clinical manifestations, severity, and age of onset vary according to the level of mutant heteroplasmy, making it difficult to predict the extent of the estimated mutations’ contribution 7 , 13 .…”

“…Mitochondrial inheritance is maternal inheritance, meaning the mother’s mutations are transmitted to all offspring, affecting the entire genome and this is called homoplasmic, or a specific percentage called heteroplasmy 4 – 6 . MT_TS1, the mitochondrial tRNA Ser(UCN) gene, is a hotspot for pathogenic mutations and causes a variable mitochondrial phenotype in patients, including non-syndromic sensorineural hearing loss (SHL) and syndromic phenotype (epilepsy, ataxia, cognitive impairment, myoclonus and SHL) 4 , 6 , 7 .…”

Mitochondrial tRNASer(UCN) mutations associated non-syndromic sensorineural hearing loss in Chinese families

“…Structurally, the 7510T > C mutation is located at the 5′ side of the acceptor stem of tRNA and disrupts the highly conserved secondary structure of tRNA Ser (UCN) , which may reduce the levels of mature tRNA Ser (UCN) and decrease the synthesis of mitochondrial proteins, causing mitochondrial dysfunction [ 19 ]. In the published reports, symptoms associated with the 7510T > C mutation mainly presented as isolated SNHL [ [16] , [17] , [18] , [19] ], whereas patients from one Finnish family have also presented with neurological symptoms in addition to SNHL [ 20 ].…”

Ancient mitochondrial DNA pathogenic variants putatively associated with mitochondrial disease

“…Review of the published cases suggests that there is interfamilial variability in the age of onset, accompanying symptoms, and haplogroup background [54]. The results of Kytövuori and colleagues (2017) suggest that in addition to sensorineural hearing impairment, the m.7510T>C mutation is associated with a spectrum of mitochondrial disease clinical features including migraine, epilepsy, cognitive impairment, ataxia, and tremor, and with evidence of mitochondrial myopathy [53].…”