Variable phenotypes in a family with mitochondrial encephalomyopathy harboring a 3291T &gt; C mutation in mitochondrial DNA

Sunami, Yoko; Sugaya, Kimio; Chihara, Norio; Goto, Yu‐ichi; Matsubara, Shiro

doi:10.1007/s10072-011-0719-9

Cited by 9 publications

(6 citation statements)

References 8 publications

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“…Non‐syndromic : In a family with non‐syndromic MID die to the m.3291T>C mtDNA mutation, three members had myoclonic epilepsy . Epilepsy was also a phenotypic feature in a family carrying the m.8363G>A mtDNA mutation .…”

Section: Onset Of Epilepsy In Midsmentioning

confidence: 99%

Mitochondrial epilepsy in pediatric and adult patients

Finsterer

Zarrouk‐Mahjoub

2013

Acta Neurol Scand

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Few data are available about the difference between epilepsy in pediatric mitochondrial disorders (MIDs) and adult MIDs. This review focuses on the differences between pediatric and adult mitochondrial epilepsy with regard to seizure type, seizure frequency, and underlying MID. A literature search via Pubmed using the keywords 'mitochondrial', 'epilepsy', 'seizures', 'adult', 'pediatric', and all MID acronyms, was carried out. Frequency of mitochondrial epilepsy strongly depends on the type of MID included and is higher in pediatric compared to adult patients. In pediatric patients, mitochondrial epilepsy is more frequent due to mutations in nDNA-located than mtDNA-located genes and vice versa in adults. In pediatric patients, mitochondrial epilepsy is associated with a syndromic phenotype in half of the patients and in adults more frequently with a non-syndromic phenotype. In pediatric patients, focal seizures are more frequent than generalized seizures and vice versa in adults. Electro-clinical syndromes are more frequent in pediatric MIDs compared to adult MIDs. Differences between pediatric and adult mitochondrial epilepsy concern the onset of epilepsy, frequency of epilepsy, seizure type, type of electro-clinical syndrome, frequency of syndromic versus non-syndromic MIDs, and the outcome. To optimize management of mitochondrial epilepsy, it is essential to differentiate between early and late-onset forms.

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Section: Onset Of Epilepsy In Midsmentioning

confidence: 99%

Mitochondrial epilepsy in pediatric and adult patients

Finsterer

Zarrouk‐Mahjoub

2013

Acta Neurol Scand

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“…RRFs and COX-negative fibers Valente et al [ 18 ] 12 NA Deafness, cognitive impairment NA NA Reduction complex I. RRFs Salsano et al [ 19 ] Puberty F Slowly progressive cognitive decline, behavioral disturbances, Wolff-Parkinson-White syndrome, hearing loss, weight loss, hyperkinesia (myoclonic jerks and tics), cerebellar symptoms and cortical and cerebellar atrophy 95% (muscle), 40% (blood) Elevated (serum), normal at re-evaluation (serum) Reduction complex I. RRFs and COX-negative fibers Variant absent in unaffected mother and sister (blood and urine). Schizophrenia and Wolff-Parkinson-White syndrome are reported for maternal aunts Sunami et al [ 10 ] 45 F Severe cerebellar ataxia, myopathy, mild ophthalmoparesis, hearing loss, and asymptomatic EEG abnormality 11% (peripheral leukocytes), 74% (muscle) Normal (sample not specified) RRFs, succinate dehydrogenase reactive vessels, COX-negative fibers Family of 5 affected individuals in 4 generations Sunami et al [ 10 ] NA F Hearing loss and glaucoma NA NA NA Family of 5 affected individuals in 4 generations Sunami et al [ 10 ] 14 F Palindromic rheumatism, recurrent migraine. Multiple small hyperintense areas in subcortical white matter of cerebrum on T2 MRI NA NA NA Family of 5 affected individuals in 4 generations Sunami et al [ 10 ] 36 F Photo-induced myoclonus, atrophy of cerebellum, absence of tendon reflexes, truncal ataxia, normal mental status 16% (peripheral leukocytes) NA NA Family of 5 affected individuals in 4 generations Sunami et al [ 10 ] 15 F Generalized seizures, myoclonic jerks, slight cognitive decline, absence of tendon reflexes 27% (peripheral leukocytes) ...…”

Section: Resultsmentioning

confidence: 99%

A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis

et al. 2021

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The genetic etiology of intellectual disability remains elusive in almost half of all affected individuals. Within the Solve-RD consortium, systematic re-analysis of whole exome sequencing (WES) data from unresolved cases with (syndromic) intellectual disability (n = 1,472 probands) was performed. This re-analysis included variant calling of mitochondrial DNA (mtDNA) variants, although mtDNA is not specifically targeted in WES. We identified a functionally relevant mtDNA variant in MT-TL1 (NC_012920.1:m.3291T > C; NC_012920.1:n.62T > C), at a heteroplasmy level of 22% in whole blood, in a 23-year-old male with severe intellectual disability, epilepsy, episodic headaches with emesis, spastic tetraparesis, brain abnormalities, and feeding difficulties. Targeted validation in blood and urine supported pathogenicity, with heteroplasmy levels of 23% and 58% in index, and 4% and 17% in mother, respectively. Interestingly, not all phenotypic features observed in the index have been previously linked to this MT-TL1 variant, suggesting either broadening of the m.3291T > C-associated phenotype, or presence of a co-occurring disorder. Hence, our case highlights the importance of underappreciated mtDNA variants identifiable from WES data, especially for cases with atypical mitochondrial phenotypes and their relatives in the maternal line.

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“…A heteroplasmic m.3291T>C variant in the MTTL1 gene has previously been reported on 4 separate occasions, in association with MELAS [2], isolated mild myopathy [5], dementia with hearing loss [6] and cerebellar ataxia with ophthalmoparesis, hearing loss and myopathy [7]. These reports provided strong evidence linking m.3291T>C to disease through genetic analysis and molecular investigations.…”

Section: Introductionmentioning

confidence: 74%

The m.3291T>C mt-tRNALeu(UUR) mutation is definitely pathogenic and causes multisystem mitochondrial disease

Yarham¹,

Blakely²,

Alston³

et al. 2013

Journal of the Neurological Sciences

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Mitochondrial tRNA point mutations are important causes of human disease, and have been associated with a diverse range of clinical phenotypes. Definitively proving the pathogenicity of any given mt-tRNA mutation requires combined molecular, genetic and functional studies. Subsequent evaluation of the mutation using a pathogenicity scoring system is often very helpful in concluding whether or not the mutation is causing disease. Despite several independent reports linking the m.3291T>C mutation to disease in humans, albeit in association with several different phenotypes, its pathogenicity remains controversial. A lack of conclusive functional evidence and an over-emphasis on the poor evolutionary conservation of the affected nucleotide have contributed to this controversy. Here we describe an adult patient who presented with deafness and lipomas and evidence of mitochondrial abnormalities in his muscle biopsy, who harbours the m.3291T > C mutation, providing conclusive evidence of pathogenicity through analysis of mutation segregation with cytochrome c oxidase (COX) deficiency in single muscle fibres, underlining the importance of performing functional studies when assessing pathogenicity.

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Variable phenotypes in a family with mitochondrial encephalomyopathy harboring a 3291T > C mutation in mitochondrial DNA

Cited by 9 publications

References 8 publications

Mitochondrial epilepsy in pediatric and adult patients

Mitochondrial epilepsy in pediatric and adult patients

A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis

The m.3291T>C mt-tRNALeu(UUR) mutation is definitely pathogenic and causes multisystem mitochondrial disease

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