MT-ND5 Mutation Exhibits Highly Variable Neurological Manifestations at Low Mutant Load

Ng, Yi Shiau; Lax, Nichola Z.; Maddison, Paul; Alston, Charlotte L.; Blakely, Emma L.; Hepplewhite, Philippa D.; Riordan, Gillian; Meldau, Surita; Chinnery, Patrick F.; Pierre, Germaine; Chronopoulou, Efstathia; Du, Ailian; Hughes, Imelda; Morris, Andrew A. M.; Kamakari, Smaragda; Chrousos, Georgia Antonakou; Rodenburg, Richard J.; Saris, Christiaan G J; Feeney, Catherine; Hardy, Steven A.; Sakakibara, Takafumi; Sudo, Akira; Okazaki, Yasushi; Murayama, Kei; Mundy, Helen; Hanna, Michael G.; Ohtake, Akira; Schaefer, Andrew M.; Champion, Mike; Turnbull, Doug M.; Taylor, Robert W.; Pitceathly, Robert D S; McFarland, Robert; Gorman, Gráinne

doi:10.1016/j.ebiom.2018.02.010

Cited by 50 publications

(47 citation statements)

References 29 publications

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“…In our patients with maternally inherited CI deficiency, MRI revealed both the involvement of deep grey matter structures and stroke-like lesions similar to other reports [4]. We also demonstrated the coexistence of LS and stroke-like lesions in 4 of the 13 patients, suggesting that an overlap between the LS and MELAS phenotypes is not rare in patients with maternally inherited CI deficiency.…”

Section: Discussionsupporting

confidence: 89%

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Multisystem mitochondrial diseases due to mutations in mtDNA-encoded subunits of complex I

et al. 2020

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Background: Maternally inherited complex I deficiencies due to mutations in MT-ND genes represent a heterogeneous group of multisystem mitochondrial disorders (MD) with a unfavourable prognosis. The aim of the study was to characterize the impact of the mutations in MT-ND genes, including the novel m.13091 T > C variant, on the course of the disease, and to analyse the activities of respiratory chain complexes, the amount of protein subunits, and the mitochondrial energy-generating system (MEGS) in available muscle biopsies and cultivated fibroblasts. Methods: The respiratory chain complex activities were measured by spectrophotometry, MEGS were analysed using radiolabelled substrates, and protein amount by SDS-PAGE or BN-PAGE in muscle or fibroblasts. Results: In our cohort of 106 unrelated families carrying different mtDNA mutations, we found heteroplasmic mutations in the genes MT-ND1, MT-ND3, and MT-ND5, including the novel variant m.13091 T > C, in 13 patients with MD from 12 families. First symptoms developed between early childhood and adolescence and progressed to multisystem disease with a phenotype of Leigh or MELAS syndromes. MRI revealed bilateral symmetrical involvement of deep grey matter typical of Leigh syndrome in 6 children, cortical/white matter stroke-like lesions suggesting MELAS syndrome in 3 patients, and a combination of cortico-subcortical lesions and grey matter involvement in 4 patients. MEGS indicated mitochondrial disturbances in all available muscle samples, as well as a significantly decreased oxidation of [1-14 C] pyruvate in fibroblasts. Spectrophotometric analyses revealed a low activity of complex I and/or complex I + III in all muscle samples except one, but the activities in fibroblasts were mostly normal. No correlation was found between complex I activities and mtDNA mutation load, but higher levels of heteroplasmy were generally found in more severely affected patients. Conclusions: Maternally inherited complex I deficiencies were found in 11% of families with mitochondrial diseases in our region. Six patients manifested with Leigh, three with MELAS. The remaining four patients presented with an overlap between these two syndromes. MEGS, especially the oxidation of [1-14 C] pyruvate in fibroblasts might serve as a sensitive indicator of functional impairment due to MT-ND mutations. Early onset of the disease and higher level of mtDNA heteroplasmy were associated with a worse prognosis.

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Section: Discussionsupporting

confidence: 89%

“…Leber Hereditary Optic Neuropathy (LHON) syndrome with acute or subacute loss of vision usually starts during the second or third decade of life. In addition, several studies have also documented the LHON/MELAS overlap syndromes [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Multisystem mitochondrial diseases due to mutations in mtDNA-encoded subunits of complex I

et al. 2020

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“…They indicate that metabolic decompensation can also occur in spinal cord in addition to basal ganglia and brainstem, as shown in other mitochondrial genetic defects as well as postmortem spinal cord tissue from patients with LS. 21,22 White matter changes ranging from patchy changes to symmetrical, confluent subcortical white matter signal abnormality (leukodystrophy) were present in 55% of the patients presented here. The underlying neurobiological mechanism remains elusive as no neuropathological study is available to date.…”

Section: Discussionmentioning

confidence: 82%

Leigh syndrome caused by mutations in MTFMT is associated with a better prognosis

Hayhurst

Coo

Piekutowska‐Abramczuk

et al. 2019

Ann Clin Transl Neurol

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Objectives Mitochondrial methionyl‐tRNA formyltransferase (MTFMT) is required for the initiation of translation and elongation of mitochondrial protein synthesis. Pathogenic variants in MTFMT have been associated with Leigh syndrome (LS) and mitochondrial multiple respiratory chain deficiencies. We sought to elucidate the spectrum of clinical, neuroradiological and molecular genetic findings of patients with bi‐allelic pathogenic variants in MTFMT. Methods Retrospective cohort study combining new cases and previously published cases. Results Thirty‐eight patients with pathogenic variants in MTFMT were identified, including eight new cases. The median age of presentation was 14 months (range: birth to 17 years, interquartile range [IQR] 4.5 years), with developmental delay and motor symptoms being the most frequent initial manifestation. Twenty‐nine percent of the patients survived into adulthood. MRI headings in MTFMT pathogenic variants included symmetrical basal ganglia changes (62%), periventricular and subcortical white matter abnormalities (55%), and brainstem lesions (48%). Isolated complex I and combined respiratory chain deficiencies were identified in 31% and 59% of the cases, respectively. Reduction of the mitochondrial complex I and complex IV subunits was identified in the fibroblasts (13/13). Sixteen pathogenic variants were identified, of which c.626C>T was the most common. Seventy‐four percent of the patients were alive at their last clinical review (median 6.8 years, range: 14 months to 31 years, IQR 14.5 years). Interpretation Patients that harbour pathogenic variants in MTFMT have a milder clinical phenotype and disease progression compared to LS caused by other nuclear defects. Fibroblasts may preclude the need for muscle biopsy, to prove causality of any novel variant.

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“…7,8 Individual pathogenic MT-ATP6 variants were screened either by quantitative pyrosequencing or by fluorescent restriction fragment length polymorphism analysis, which permitted the quantitation of mtDNA heteroplasmy at the relevant nucleotide to a level of >3% heteroplasmy. 9,10 Statistical Analysis Descriptive statistical analysis was performed using Minitab (version 17.0; Minitab, State College, PA), SPSS (version 23.0; IBM, Armonk, NY), and R (version 3.5, R Foundation for Statistical Computing, Vienna, Austria). Nonparametric tests were performed to determine if there was any statistically significant difference between the different groups.…”

Section: Molecular Genetics and Measurement Of Mutant Heteroplasmymentioning

confidence: 99%

Pathogenic variants in MT‐ATP6: A United Kingdom–based mitochondrial disease cohort study

Martikainen

Gorman

et al. 2019

Annals of Neurology

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Distinct clinical syndromes have been associated with pathogenic MT‐ATP6 variants. In this cohort study, we identified 125 individuals (60 families) including 88 clinically affected individuals and 37 asymptomatic carriers. Thirty‐one individuals presented with Leigh syndrome and 7 with neuropathy ataxia retinitis pigmentosa. The remaining 50 patients presented with variable nonsyndromic features including ataxia, neuropathy, and learning disability. We confirmed maternal inheritance in 39 families and demonstrated that tissue segregation patterns and phenotypic threshold are variant dependent. Our findings suggest that MT‐ATP6–related mitochondrial DNA disease is best conceptualized as a mitochondrial disease spectrum disorder and should be routinely included in genetic ataxia and neuropathy gene panels. ANN NEUROL 2019;86:310–315

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MT-ND5 Mutation Exhibits Highly Variable Neurological Manifestations at Low Mutant Load

Cited by 50 publications

References 29 publications

Multisystem mitochondrial diseases due to mutations in mtDNA-encoded subunits of complex I

Multisystem mitochondrial diseases due to mutations in mtDNA-encoded subunits of complex I

Leigh syndrome caused by mutations in MTFMT is associated with a better prognosis

Pathogenic variants in MT‐ATP6: A United Kingdom–based mitochondrial disease cohort study

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