Objective: To describe a rare cause of mitochondrial ataxia in an Indian Agarwal family, associated with cytochrome c oxidase deficiency due to point mutation in the MT-TS1 gene (m:7465A>AC).

Background: 7465A>AC (also known as 7472insC) point mutation in mitochondrial tRNA^Ser(UCN) gene has been described as one of the rare causes of cytochrome c oxidase deficiency. But only a handful of cases have been reported worldwide and that too mainly in the European population [1-5].

Method: We assessed the clinico-radiological profile of an Indian family, who attended the movement disorder clinic at Institute of Neurosciences Kolkata (I-NK).

Results: The index case, a 57-year-old male, presented with progressive bilateral sensorineural hearing loss since the age of 22 years followed by development of gait ataxia and dysarthria years later. Subsequently, he developed sensory neuropathy, muscle cramps, migraine attacks, mild cognitive decline and hypothyroidism. Eye examination was normal. Routine blood investigations were normal including serum lactate and pyruvate. MRI Brain showed diffuse cerebral and cerebellar atrophy.

His other 5 siblings showed identical clinical features. Endocrinological manifestations reported were hypothyroidism and diabetes.

Considering the Indian Agarwal lineage in which SCA12 is the most common hereditary ataxia, spinocerebellar ataxia panel was sent (SCA1,2,3,6,7,12), which was normal. Whole exome sequencing was normal as well. Finally, mitochondrial genome sequencing showed a pathogenic homoplasmic mutation in the MT-TS1 gene (m.7465A >AC) leading to cytochrome c oxidase deficiency in the patient.

Tracking back the lineage, it was found that his maternal grandmother also had imbalance and hearing loss. All of the subsequent generations showed typical maternal inheritance. Interestingly, the 4th generation of the family (age group in 30’s) showed only SNHL as the predominant manifestation without any neurological or endocrinological findings.

Conclusion: This is the first case study from India reporting 7465A>AC mitochondrial tRNA ^Ser(UCN) gene [MTTS1] mutation. It further adds to the evidence that it is a rare but important cause of mitochondrial ataxia manifesting as progressive sensorineural hearing loss, ataxia, migraine, sensory neuropathy, cognitive decline and endocrine abnormalities and can have intra-familial phenotypic heterogeneity as well.

MRI Brain showing diffuse cerebral atrophy

MRI brain showing cerebellar atrophy

References: 1. Tiranti V, Chariot P, Carella F, Toscano A, Soliveri P, Girlanda P, et al. Maternally inherited hearing loss, ataxia and myoclonus associated with a novel point mutation in mitochondrial tRNASer(UCN) gene. Hum Mol Genet. 1995;4(8):1421-7.
2. Jaksch M, Hofmann S, Kleinle S, Liechti-Gallati S, Pongratz DE, Müller-Höcker J, et al. A systematic mutation screen of 10 nuclear and 25 mitochondrial candidate genes in 21 patients with cytochrome c oxidase (COX) deficiency shows tRNA(Ser)(UCN) mutations in a subgroup with syndromal encephalopathy. J Med Genet. 1998;35(11):895-900.
3. Schuelke M, Bakker M, Stoltenburg G, Sperner J, von Moers A. Epilepsia partialis continua associated with a homoplasmic mitochondrial tRNA(Ser(UCN)) mutation. Ann Neurol. 1998;44(4):700-4.
4. Verhoeven K, Ensink RJ, Tiranti V, Huygen PL, Johnson DF, Schatteman I, et al. Hearing impairment and neurological dysfunction associated with a mutation in the mitochondrial tRNASer(UCN) gene. Eur J Hum Genet. 1999;7(1):45-51.
5. Fetoni V, Briem E, Carrara F, Mora M, Zeviani M. Monomelic Amyotrophy Associated with the 7472insC Mutation in the MtDNA tRNASer(UCN) Gene. Neuromuscul. Disord. 2004; 14:723–726.

« Back to 2024 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/phenotypic-variability-of-mitochondrial-trna-serucn-gene-mtts1-mutation-first-report-from-india/