Reversible infantile respiratory chain deficiency: A clinical and molecular study

Mimaki, Masakazu; Hatakeyama, Hideyuki; Komaki, Hirofumi; Yokoyama, Mina; Arai, Hidee; Kirino, Yohei; Suzuki, Tsutomu; Nishino, Ichizo; Nonaka, Ikuya; Goto, Yu‐ichi

doi:10.1002/ana.22111

Cited by 40 publications

(18 citation statements)

References 35 publications

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“…BN-PAGE showed minor abnormalities in RIRCD myoblasts, similar to a previous study (4), and a defect of complexes I and IV was more pronounced on the ‘in gel’ activity assay. Adding l -cysteine to the culture medium fully reversed this deficiency.…”

Section: Discussionsupporting

confidence: 88%

Altered 2-thiouridylation impairs mitochondrial translation in reversible infantile respiratory chain deficiency

Boczonadi

Smith

Pyle

et al. 2013

Human Molecular Genetics

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Childhood-onset mitochondrial encephalomyopathies are severe, relentlessly progressive conditions. However, reversible infantile respiratory chain deficiency (RIRCD), due to a homoplasmic mt-tRNAGlu mutation, and reversible infantile hepatopathy, due to tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase (TRMU) deficiency, stand out by showing spontaneous recovery, and provide the key to treatments of potential broader relevance. Modification of mt-tRNAGlu is a possible functional link between these two conditions, since TRMU is responsible for 2-thiouridylation of mt-tRNAGlu, mt-tRNALys and mt-tRNAGln. Here we show that down-regulation of TRMU in RIRCD impairs 2-thiouridylation and exacerbates the effect of the mt-tRNAGlu mutation by triggering a mitochondrial translation defect in vitro. Skeletal muscle of RIRCD patients in the symptomatic phase showed significantly reduced 2-thiouridylation. Supplementation with l-cysteine, which is required for optimal TRMU function, rescued respiratory chain enzyme activities in human cell lines of patients with RIRCD as well as deficient TRMU. Our results show that l-cysteine supplementation is a potential treatment for RIRCD and for TRMU deficiency, and is likely to have broader application for the growing group of intra-mitochondrial translation disorders.

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Section: Discussionsupporting

confidence: 88%

Altered 2-thiouridylation impairs mitochondrial translation in reversible infantile respiratory chain deficiency

Boczonadi

Smith

Pyle

et al. 2013

Human Molecular Genetics

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“…27 This homoplasmic mutation (m.14674T>C in tRNA Glu ) was initially considered a neutral polymorphism, but was subsequently found in 17 patients from 12 families of various ethnic origins, 28 and the same mutation (or a T>G mutation at the same site) was confirmed in eight Japanese patients. 29 The pathogenicity of the mutation was established using high-resolution northern blot analysis of muscle biopsies during the symptomatic phase and through biochemical studies of cybrid cell lines, but the mutation by itself does not explain the tissue specificity or reversibility of the biochemical and clinical phenotypes. A role for a developmentally regulated nuclear modifier factor in this disorder has been postulated 28 but not yet identified.…”

Section: Disorders Of Mtdna Defectsmentioning

confidence: 99%

The clinical maze of mitochondrial neurology

et al. 2013

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Mitochondrial diseases involve the respiratory chain, which is under the dual control of nuclear and mitochondrial DNA (mtDNA). The complexity of mitochondrial genetics provides one explanation for the clinical heterogeneity of mitochondrial diseases, but our understanding of disease pathogenesis remains limited. Classification of Mendelian mitochondrial encephalomyopathies has been laborious, but whole-exome sequencing studies have revealed unexpected molecular aetiologies for both typical and atypical mitochondrial disease phenotypes. Mendelian mitochondrial defects can affect five components of mitochondrial biology: subunits of respiratory chain complexes (direct hits); mitochondrial assembly proteins; mtDNA translation; phospholipid composition of the inner mitochondrial membrane; or mitochondrial dynamics. A sixth category—defects of mtDNA maintenance—combines features of Mendelian and mitochondrial genetics. Genetic defects in mitochondrial dynamics are especially important in neurology as they cause optic atrophy, hereditary spastic paraplegia, and Charcot–Marie–Tooth disease. Therapy is inadequate and mostly palliative, but promising new avenues are being identified. Here, we review current knowledge on the genetics and pathogenesis of the six categories of mitochondrial disorders outlined above, focusing on their salient clinical manifestations and highlighting novel clinical entities. An outline of diagnostic clues for the various forms of mitochondrial disease, as well as potential therapeutic strategies, is also discussed.

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“…The infant-onset mitochondrial myopathies have a severe clinical presentation, although it is important to be aware of a subset of patients with infantile cytochrome c oxidase (COX)-deficiency myopathy with reversible disease, whose molecular defect has recently been described (10,11). …”

Section: Clinical Featuresmentioning

confidence: 99%

Diagnosis and treatment of mitochondrial myopathies

2011

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Mitochondrial disorders are a heterogeneous group of disorders resulting from primary dysfunction of the respiratory chain. Muscle tissue is highly metabolically active, and therefore myopathy is a common element of the clinical presentation of these disorders, although this may be overshadowed by central neurological features. This review is aimed at a general medical and neurologist readership and provides a clinical approach to the recognition, investigation, and treatment of mitochondrial myopathies. Emphasis is placed on practical management considerations while including some recent updates in the field.

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Reversible infantile respiratory chain deficiency: A clinical and molecular study

Cited by 40 publications

References 35 publications

Altered 2-thiouridylation impairs mitochondrial translation in reversible infantile respiratory chain deficiency

Altered 2-thiouridylation impairs mitochondrial translation in reversible infantile respiratory chain deficiency

The clinical maze of mitochondrial neurology

Diagnosis and treatment of mitochondrial myopathies

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