Respiratory chain deficiency in nonmitochondrial disease

Pyle, Angela; Nightingale, Helen; Griffin, H; Schöser, Benedikt; Kirschner, Janbernd; Barić, Ivo; Ćuk, Mario; Douroudis, Konstantinos; Feder, Lea; Kratz, Markus; Czermin, Birgit; Kleinle, Stephanie; Santibanez‐Koref, Mauro; Karcagi, Veronika; Holinski‐Feder, Elke; Chinnery, Patrick F.; Horvath, Rita

doi:10.1212/nxg.0000000000000006

Cited by 24 publications

(15 citation statements)

References 10 publications

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“…Furthermore, possible identification of patients with respiratory chain defects due to variants involving “non-classical mitochondrial disease” genes should not be overlooked. 6 , 7 Our observations suggest that pathogenic de novo heterozygous variants could be under-recognized in suspected early-onset mitochondrial disease, emphasizing the need to evaluate heterozygous variants with segregation studies in apparently unsolved and prospective cases.…”

Section: Discussionmentioning

confidence: 89%

“…Whole-exome sequencing (WES) has been widely used as a cost-effective tool for the diagnosis of suspected mendelian, early-onset mitochondrial respiratory chain disorders. 2 – 5 However, secondary respiratory chain defects in skeletal muscle have also been described in other neuromuscular and neurologic disorders due to pathogenic variants of genes encoding nonmitochondrial proteins, 6 , 7 providing additional challenges to candidate variant prioritization.…”

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confidence: 99%

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De novo CTBP1 variant is associated with decreased mitochondrial respiratory chain activities

et al. 2017

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Objective:To determine the genetic etiology of a young woman presenting an early-onset, progressive neurodegenerative disorder with evidence of decreased mitochondrial complex I and IV activities in skeletal muscle suggestive of a mitochondrial disorder.Methods:A case report including diagnostic workup, whole-exome sequencing of the affected patient, filtering, and prioritization of candidate variants assuming a suspected autosomal recessive mitochondrial disorder and segregation studies.Results:After excluding candidate variants for an autosomal recessive mitochondrial disorder, re-evaluation of rare and novel heterozygous variants identified a recently reported, recurrent pathogenic heterozygous CTBP1 missense change (c.991C>T, p.Arg331Trp), which was confirmed to have arisen de novo.Conclusions:We report the fifth known patient harboring a recurrent pathogenic de novo c.991C>T p.(Arg331Trp) CTBP1 variant, who was initially suspected to have an autosomal recessive mitochondrial disorder. Inheritance of suspected early-onset mitochondrial disease could wrongly be assumed to be autosomal recessive. Hence, this warrants continued re-evaluation of rare and novel heterozygous variants in patients with apparently unsolved suspected mitochondrial disease investigated using next-generation sequencing.

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Section: Discussionmentioning

confidence: 89%

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confidence: 99%

De novo CTBP1 variant is associated with decreased mitochondrial respiratory chain activities

et al. 2017

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“…Although, mitochondrial disorders are characterized by deficiencies in the oxidative phosphorylation (OXPHOS) and ATP production, biochemical deficiencies are not always detected in the lab. Besides, OXPHOS deficiencies can be a secondary phenomenon in neuromuscular or multi-system disorders with a non-mitochondrial cause (Pyle et al, 2015 ; Niyazov et al, 2016 ). Mitochondrial disorders are also genetically heterogeneous, as different gene defects can result in a similar phenotype and both the nuclear and mitochondrial genomes are involved (Rotig and Munnich, 2003 ; McFarland et al, 2010 ).…”

Section: Introductionmentioning

confidence: 99%

Whole Exome Sequencing Is the Preferred Strategy to Identify the Genetic Defect in Patients With a Probable or Possible Mitochondrial Cause

et al. 2018

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Mitochondrial disorders, characterized by clinical symptoms and/or OXPHOS deficiencies, are caused by pathogenic variants in mitochondrial genes. However, pathogenic variants in some of these genes can lead to clinical manifestations which overlap with other neuromuscular diseases, which can be caused by pathogenic variants in non-mitochondrial genes as well. Mitochondrial pathogenic variants can be found in the mitochondrial DNA (mtDNA) or in any of the 1,500 nuclear genes with a mitochondrial function. We have performed a two-step next-generation sequencing approach in a cohort of 117 patients, mostly children, in whom a mitochondrial disease-cause could likely or possibly explain the phenotype. A total of 86 patients had a mitochondrial disorder, according to established clinical and biochemical criteria. The other 31 patients had neuromuscular symptoms, where in a minority a mitochondrial genetic cause is present, but a non-mitochondrial genetic cause is more likely. All patients were screened for pathogenic variants in the mtDNA and, if excluded, analyzed by whole exome sequencing (WES). Variants were filtered for being pathogenic and compatible with an autosomal or X-linked recessive mode of inheritance in families with multiple affected siblings and/or consanguineous parents. Non-consanguineous families with a single patient were additionally screened for autosomal and X-linked dominant mutations in a predefined gene-set. We identified causative pathogenic variants in the mtDNA in 20% of the patient-cohort, and in nuclear genes in 49%, implying an overall yield of 68%. We identified pathogenic variants in mitochondrial and non-mitochondrial genes in both groups with, obviously, a higher number of mitochondrial genes affected in mitochondrial disease patients. Furthermore, we show that 31% of the disease-causing genes in the mitochondrial patient group were not included in the MitoCarta database, and therefore would have been missed with MitoCarta based gene-panels. We conclude that WES is preferable to panel-based approaches for both groups of patients, as the mitochondrial gene-list is not complete and mitochondrial symptoms can be secondary. Also, clinically and genetically heterogeneous disorders would require sequential use of multiple different gene panels. We conclude that WES is a comprehensive and unbiased approach to establish a genetic diagnosis in these patients, able to resolve multi-genic disease-causes.

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“…This first issue of Neurology ® Genetics is out and it reflects very well the diversity of today's genetics. The approaches employed range from genome-wide association studies 1 to whole-exome sequencing (WES) 2 – 5 and targeted resequencing of a single gene. 6 One study examines the effects of disease-causing mutations on subcellular compartmentalization.…”

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confidence: 99%

“…However, WES revealed a causative homozygous PFKM gene defect in both siblings, which was confirmed by very low residual PFK enzyme activity in biochemical studies. Pyle and colleagues 3 report 5 patients with biochemical evidence of respiratory chain deficiencies and mutations in genes not usually associated with mitochondrial dysfunction. These variants would have been missed by targeted next-generation panels or on MitoExome analysis.…”

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confidence: 99%

Spotlight on the June 2015 issue

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Respiratory chain deficiency in nonmitochondrial disease

Cited by 24 publications

References 10 publications

De novo CTBP1 variant is associated with decreased mitochondrial respiratory chain activities

De novo CTBP1 variant is associated with decreased mitochondrial respiratory chain activities

Whole Exome Sequencing Is the Preferred Strategy to Identify the Genetic Defect in Patients With a Probable or Possible Mitochondrial Cause

Spotlight on the June 2015 issue

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