Clinical validity of biochemical and molecular analysis in diagnosing Leigh syndrome: a study of 106 Japanese patients

Ogawa, Erika; Shimura, Masaru; Fushimi, Takuya; Tajika, Makiko; Ichimoto, Keiko; Matsunaga, Ayako; Tsuruoka, Tomoko; Ishige, Mika; Fuchigami, Tatsuo; Yamazaki, Taro; Mori, Masayuki; Kohda, Masakazu; Kishita, Yoshihito; Okazaki, Yasushi; Takahashi, Shori; Ohtake, Akira; Murayama, Kei

doi:10.1007/s10545-017-0042-6

Cited by 83 publications

(107 citation statements)

References 32 publications

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“…In the present study, the genetic complexity of 17 different nuclear and mitochondrial genes was identified. Genetic defects associated with complex I deficiency were the most frequent, with a total diagnostic yield of 64.5% (40/62 families) . These included six mitochondrial genes in 18 families, including MTATP6 , MTND3 , MTND6 , MTND5 , MTND1 , and MTTK , in descending order of frequency.…”

Section: Discussionmentioning

confidence: 99%

“…However, following the first report on LS, patients with atypical presentations have been noted, expanding the clinical spectrum of the disorder. Likewise, the genetic spectrum has been broadened by advances in genomic technology, such as next‐generation sequencing (NGS) . Along with clinical diversity and overlapping features, genetic heterogeneity complicates the molecular diagnosis of LS.…”

Section: Introductionmentioning

confidence: 99%

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Genetic heterogeneity in Leigh syndrome: Highlighting treatable and novel genetic causes

et al. 2020

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Leigh syndrome (LS), the most common childhood mitochondrial disorder, has characteristic clinical and neuroradiologic features. Mutations in more than 75 genes have been identified in both the mitochondrial and nuclear genome, implicating a high degree of genetic heterogeneity in LS. To profile these genetic signatures and understand the pathophysiology of LS, we recruited 64 patients from 62 families who were clinically diagnosed with LS at Seoul National University Children's Hospital. Mitochondrial genetic analysis followed by whole‐exome sequencing was performed on 61 patients. Pathogenic variants in mitochondrial DNA were identified in 18 families and nuclear DNA mutations in 22. The following 17 genes analyzed in 40 families were found to have genetic complexity: MTATP6, MTND1, MTND3, MTND5, MTND6, MTTK, NDUFS1, NDUFV1, NDUFAF6, SURF1, SLC19A3, ECHS1, PNPT1, IARS2, NARS2, VPS13D, and NAXE. Two treatable cases had biotin‐thiamine responsive basal ganglia disease, and another three were identified as having defects in the newly recognized genes (VPS13D or NAXE). Variants in the nuclear genes that encoded mitochondrial aminoacyl tRNA synthetases were present in 27.3% of cases. Our findings expand the genetic and clinical spectrum of LS, showing genetic heterogeneity and highlighting treatable cases and those with novel genetic causes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetic heterogeneity in Leigh syndrome: Highlighting treatable and novel genetic causes

et al. 2020

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“…All currently identified ECHS1D patients have mutations in both ECHS1 alleles, indicating autosomal recessive inheritance, with many different mutations identified (Table ). Patients who are homozygous for mutations in ECHS1 have all been offspring of consanguineous relationships, resulting in two copies of the same rare mutation .…”

Section: Echs1 Deficiencymentioning

confidence: 99%

“…Short‐chain enoyl‐coA hydratase (ECHS1) is a key enzyme involved in mitochondrial fatty acid β‐oxidation (FAO). Since its initial identification in 2014, 46 patients have been described with ECHS1 deficiency (ECHS1D) . Almost all of these patients have been diagnosed with Leigh syndrome (LS), a lethal form of subacute necrotizing encephalomyelopathy.…”

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confidence: 99%

Understanding the role of OXPHOS dysfunction in the pathogenesis of ECHS1 deficiency

Burgin

McKenzie

2020

FEBS Letters

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Mitochondria provide the main source of energy for eukaryotic cells, oxidizing fatty acids and sugars to generate ATP. Mitochondrial fatty acid β‐oxidation (FAO) and oxidative phosphorylation (OXPHOS) are two key pathways involved in this process. Disruption of FAO can cause human disease, with patients commonly presenting with liver failure, hypoketotic glycaemia and rhabdomyolysis. However, patients with deficiencies in the FAO enzyme short‐chain enoyl‐CoA hydratase 1 (ECHS1) are typically diagnosed with Leigh syndrome, a lethal form of subacute necrotizing encephalomyelopathy that is normally associated with OXPHOS dysfunction. Furthermore, some ECHS1‐deficient patients also exhibit secondary OXPHOS defects. This sequela of FAO disorders has long been thought to be caused by the accumulation of inhibitory fatty acid intermediates. However, new evidence suggests that the mechanisms involved are more complex, and that disruption of OXPHOS protein complex biogenesis and/or stability is also involved. In this review, we examine the clinical, biochemical and genetic features of all ECHS1‐deficient patients described to date. In particular, we consider the secondary OXPHOS defects associated with ECHS1 deficiency and discuss their possible contribution to disease pathogenesis.

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“…We performed targeted gene panel of nuclear genes and mitochondrial genes that are listed in a previous publication 3 using DNA extracted from blood samples obtained from the family with GAIIx and MiSeq (Illumina, San Diego, CA) paired-end reads. 4 Notably, this patient was one of those whose targeted gene panel was sequenced previously using a detailed protocol, including variant calling. 5 The targeted gene panel sequencing detected no previously reported pathogenic variants that were considered as causative for cardiomyopathy.…”

Section: Casementioning

confidence: 99%

Mitochondrial complex deficiency by novel compound heterozygous TMEM70 variants and correlation with developmental delay, undescended testicle, and left ventricular noncompaction in a Japanese patient: A case report

Hirono

Ichida

Nishio

et al. 2019

Clinical Case Reports

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Key Clinical Message We identified novel compound heterozygous TMEM70 variants in a Japanese patient who had hyperlactacidemia, metabolic acidosis, hyperalaninemia, developmental delay, undescended testicle, and left ventricular noncompaction. The urinary organic acids profile revealed elevated levels of 3‐ MGA , and BN ‐ PAGE /Western blotting analysis and ETC. activity confirmed complex V deficiency.

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Clinical validity of biochemical and molecular analysis in diagnosing Leigh syndrome: a study of 106 Japanese patients

Cited by 83 publications

References 32 publications

Genetic heterogeneity in Leigh syndrome: Highlighting treatable and novel genetic causes

Genetic heterogeneity in Leigh syndrome: Highlighting treatable and novel genetic causes

Understanding the role of OXPHOS dysfunction in the pathogenesis of ECHS1 deficiency

Mitochondrial complex deficiency by novel compound heterozygous TMEM70 variants and correlation with developmental delay, undescended testicle, and left ventricular noncompaction in a Japanese patient: A case report

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