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

ABSTRACT: Leigh syndrome (LS) is a progressive neurodegenerative disorder of infancy and early childhood. It is clinically diagnosed by typical manifestations and characteristic computed tomography (CT) or magnetic resonance imaging (MRI) studies. Unravelling mitochondrial respiratory chain (MRC) dysfunction behind LS is essential for deeper understanding of the disease, which may lead to the development of new therapies and cure. The aim of this study was to evaluate the clinical validity of various diagnostic tools in confirming MRC disorder in LS and Leigh-like syndrome (LL). The results of enzyme assays, molecular analysis, and cellular oxygen consumption rate (OCR) measurements were examined. Of 106 patients, 41 were biochemically and genetically verified, and 34 had reduced MRC activity but no causative mutations. Seven patients with normal MRC complex activities had mutations in the MT-ATP6 gene. Five further patients with normal activity in MRC were identified with causative mutations. Conversely, 12 out of 60 enzyme assays performed for genetically verified patients returned normal results. No biochemical or genetic background was confirmed for 19 patients. OCR was reduced in ten out of 19 patients with negative enzyme assay results. Inconsistent enzyme assay results between fibroblast and skeletal muscle biopsy samples were observed in 33% of 37 simultaneously analyzed cases. These data suggest that highest diagnostic rate is reached using a combined enzymatic and genetic approach, analyzing more than one type of biological materials where suitable. Microscale oxygraphy detected MRC impairment in 50% cases with no defect in MRC complex activities.

SUBMITTER: Ogawa E

PROVIDER: S-EPMC5579154 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

Ogawa Erika E Shimura Masaru M Fushimi Takuya T Tajika Makiko M Ichimoto Keiko K Matsunaga Ayako A Tsuruoka Tomoko T Ishige Mika M Fuchigami Tatsuo T Yamazaki Taro T Mori Masato M Kohda Masakazu M Kishita Yoshihito Y Okazaki Yasushi Y Takahashi Shori S Ohtake Akira A Murayama Kei K

Journal of inherited metabolic disease 20170420 5

Leigh syndrome (LS) is a progressive neurodegenerative disorder of infancy and early childhood. It is clinically diagnosed by typical manifestations and characteristic computed tomography (CT) or magnetic resonance imaging (MRI) studies. Unravelling mitochondrial respiratory chain (MRC) dysfunction behind LS is essential for deeper understanding of the disease, which may lead to the development of new therapies and cure. The aim of this study was to evaluate the clinical validity of various diag ...[more]

PMID: 28429146

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Project description:IntroductionPathogenic variants in SURF1, a nuclear-encoded gene encoding a mitochondrial chaperone involved in COX assembly, are one of the most common causes of Leigh syndrome (LS).Material-methodsSixteen patients diagnosed to have SURF1-related LS between 2012 and 2020 were included in the study. Their clinical, biochemical and molecular findings were recorded. 10/16 patients were diagnosed using whole-exome sequencing (WES), 4/16 by Sanger sequencing of SURF1, 1/16 via targeted exome sequencing and 1/16 patient with whole-genome sequencing (WGS). The pathogenicity of SURF1 variants was evaluated by phylogenetic studies and modelling on the 3D structure of the SURF1 protein.ResultsWe identified 16 patients from 14 unrelated families who were either homozygous or compound heterozygous for SURF1 pathogenic variants. Nine different SURF1 variants were detected The c.769G > A was the most common variant with an allelic frequency of 42.8% (12/28), c.870dupT [(p.Lys291*); (8/28 28.5%)], c.169delG [(p.Glu57Lysfs*15), (2/24; 7.1%)], c.532 T > A [(p.Tyr178Asn); (2/28, 7.1%)], c.653_654delCT [(p.Pro218Argfs*29); (4/28, 14.2%)] c.595_597delGGA [(p.Gly199del); (1/28, 3.5%)], c.751 + 1G > A (2/28, 4.1%), c.356C > T [(p.Pro119Leu); (2/28, 3.5%)] were the other detected variants. Two pathogenic variants, C.595_597delGGA and c.356C > T, were detected for the first time. The c.769 G > A variant detected in 6 patients from 5 families was evaluated in terms of phenotype-genotype correlation. There was no definite genotype - phenotype correlation.ConclusionsTo date, more than 120 patients of LS with SURF1 pathogenic variants have been reported. We shared the clinical, molecular data and natural course of 16 new SURF1 defect patients from our country. This study is the first comprehensive research from Turkey that provides information about disease-causing variants in the SURF1 gene. The identification of common variants and phenotype of the SURF1 gene is important for understanding SURF1 related LS.SynopsisSURF1 gene defects are one of the most important causes of LS; patients have a homogeneous clinical and biochemical phenotype.

Project description:BackgroundRecent studies have revealed relative frequency and characteristic phenotype of two major causative factors for Silver-Russell syndrome (SRS), i.e. epimutation of the H19-differentially methylated region (DMR) and uniparental maternal disomy 7 (upd(7)mat), as well as multilocus methylation abnormalities and positive correlation between methylation index and body and placental sizes in H19-DMR epimutation. Furthermore, rare genomic alterations have been found in a few of patients with idiopathic SRS. Here, we performed molecular and clinical findings in 138 Japanese SRS patients, and examined these matters.Methodology/principal findingsWe identified H19-DMR epimutation in cases 1-43 (group 1), upd(7)mat in cases 44-52 (group 2), and neither H19-DMR epimutation nor upd(7)mat in cases 53-138 (group 3). Multilocus analysis revealed hyper- or hypomethylated DMRs in 2.4% of examined DMRs in group 1; in particular, an extremely hypomethylated ARHI-DMR was identified in case 13. Oligonucleotide array comparative genomic hybridization identified a ?3.86 Mb deletion at chromosome 17q24 in case 73. Epigenotype-phenotype analysis revealed that group 1 had more reduced birth length and weight, more preserved birth occipitofrontal circumference (OFC), more frequent body asymmetry and brachydactyly, and less frequent speech delay than group 2. The degree of placental hypoplasia was similar between the two groups. In group 1, the methylation index for the H19-DMR was positively correlated with birth length and weight, present height and weight, and placental weight, but with neither birth nor present OFC.Conclusions/significanceThe results are grossly consistent with the previously reported data, although the frequency of epimutations is lower in the Japanese SRS patients than in the Western European SRS patients. Furthermore, the results provide useful information regarding placental hypoplasia in SRS, clinical phenotypes of the hypomethylated ARHI-DMR, and underlying causative factors for idiopathic SRS.

Project description:Mitochondrial translation defects are a continuously growing group of disorders showing a large variety of clinical symptoms including a wide range of neurological abnormalities. To date, mutations in PTCD3, encoding a component of the mitochondrial ribosome, have only been reported in a single individual with clinical evidence of Leigh syndrome. Here, we describe three additional PTCD3 individuals from two unrelated families, broadening the genetic and phenotypic spectrum of this disorder, and provide definitive evidence that PTCD3 deficiency is associated with Leigh syndrome. The patients presented in the first months of life with psychomotor delay, respiratory insufficiency and feeding difficulties. The neurologic phenotype included dystonia, optic atrophy, nystagmus and tonic-clonic seizures. Brain MRI showed optic nerve atrophy and thalamic changes, consistent with Leigh syndrome. WES and RNA-seq identified compound heterozygous variants in PTCD3 in both families: c.[1453-1G>C];[1918C>G] and c.[710del];[902C>T]. The functional consequences of the identified variants were determined by a comprehensive characterization of the mitochondrial function. PTCD3 protein levels were significantly reduced in patient fibroblasts and, consistent with a mitochondrial translation defect, a severe reduction in the steady state levels of complexes I and IV subunits was detected. Accordingly, the activity of these complexes was also low, and high-resolution respirometry showed a significant decrease in the mitochondrial respiratory capacity. Functional complementation studies demonstrated the pathogenic effect of the identified variants since the expression of wild-type PTCD3 in immortalized fibroblasts restored the steady-state levels of complexes I and IV subunits as well as the mitochondrial respiratory capacity. Additionally, minigene assays demonstrated that three of the identified variants were pathogenic by altering PTCD3 mRNA processing. The fourth variant was a frameshift leading to a truncated protein. In summary, we provide evidence of PTCD3 involvement in human disease confirming that PTCD3 deficiency is definitively associated with Leigh syndrome.

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

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

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