Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing

Haack, Tobias B.; Haberberger, Birgit; Frisch, Eva-Maria; Wieland, Thomas; Iuso, Arcangela; Gorza, Matteo; Strecker, Valentina; Graf, Elisabeth; Mayr, Johannes A.; Herberg, Ulrike; Hennermann, Julia B.; Klopstock, Thomas; Kuhn, Klaus A.; Ahting, Uwe; Sperl, Wolfgang; Wilichowski, Ekkehard; Hoffmann, Georg F.; Tesařová, Markéta; Hansı́ková, Hana; Zeman, Jiřı́; Plecko, Barbara; Zeviani, Massimo; Wittig, Ilka; Strom, Tim M.; Schuelke, Markus; Freisinger, Peter; Meitinger, Thomas; Prokisch, Holger

doi:10.1136/jmedgenet-2012-100846

Cited by 161 publications

(150 citation statements)

References 26 publications

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“…The major clinical presentation of this patient was hypertrophic cardiomyopathy, as reported in 10 out of 14 complex I-deficient patients with ACAD9 mutations (Nouws et al 2010;Haack et al 2012;Gerards et al 2011;Haack et al 2012). Additional symptoms among these ten patients included lactic acidosis, failure to thrive, hypotonia, exercise intolerance, encephalomyopathy, cardiorespiratory depression, mild hearing loss, and short stature.…”

Section: Discussionmentioning

confidence: 68%

“…Defects in assembly factors form a new class of disease (Nouws et al 2012), which are probably responsible for 50% of the isolated complex I deficiencies. In 2010, we identified a new complex I assembly factor, ACAD9, and to date 14 patients in 8 families with ACAD9 mutations have been reported (Gerards et al 2011;Haack et al 2010;Haack et al 2012;Nouws et al 2010). …”

Section: Introductionmentioning

confidence: 99%

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A Patient with Complex I Deficiency Caused by a Novel ACAD9 Mutation Not Responding to Riboflavin Treatment

et al. 2013

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Here we report a patient with a new pathogenic mutation in ACAD9. Shortly after birth she presented with respiratory insufficiency and a high lactate level. At age 7 weeks, she was diagnosed with severe hypertrophic cardiomyopathy and she suffered from muscle weakness and hypotonia. Her condition deteriorated during intercurrent illnesses and she died at 6 months of age in cardiogenic shock. Analysis of respiratory chain activities in muscle and fibroblasts revealed an isolated complex I deficiency. A genome-wide screen for homozygosity revealed several homozygous regions. Four candidate genes were found and sequencing revealed a homozygous missense mutation in ACAD9. The mutation results in an Ala220Val amino acid substitution located near the catalytic core of ACAD9. SDS and BN-PAGE analysis showed severely decreased ACAD9 and complex I protein levels, and lentiviral complementation of patient fibroblasts partially rescued the complex I deficiency. Riboflavin supplementation did not ameliorate the complex I deficiency in patient fibroblasts. More than a dozen ACAD9 patients with complex I deficiency have been identified in the last 3 years, indicating that ACAD9 is important for complex I assembly, and that ACAD9 mutations are a relatively frequent cause of complex I deficiency.

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Section: Discussionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

A Patient with Complex I Deficiency Caused by a Novel ACAD9 Mutation Not Responding to Riboflavin Treatment

et al. 2013

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“…By searching the literature we identified eight patients carrying NDUFS8 mutations to date (Table 1); however, the published clinical information was very brief in five cases (Haack et al 2012;Calvo et al 2010;Tuppen et al 2010;Procaccio et al 2004;Loeffen et al 1998). Some patients had a severe disease with feeding difficulties, respiratory problems, epilepsy and hypertrophic cardiomyopathy and died within the first months of life (Tuppen et al 2010;Loeffen et al 1998).…”

Section: Discussionmentioning

confidence: 99%

“…More detailed clinical descriptions of patients carrying mutations in different genes would be highly valuable for clinicians, who need to diagnose and counsel patients with mitochondrial disease. This will be facilitated by next generation sequencing of either large panels of relevant genes (Calvo et al 2010), whole exome (Haack et al 2012) and ultimately whole genome analysis. Our chapter shows the success of this approach.…”

Section: )mentioning

confidence: 99%

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NDUFS8-related Complex I Deficiency Extends Phenotype from “PEO Plus” to Leigh Syndrome

Marina¹,

Schara²,

Pyle

et al. 2012

JIMD Reports

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With over 1,000 nuclear genes that could potentially cause a mitochondrial disorder, the current diagnostic approach requires targeted molecular analysis, guided by a combination of clinical and biochemical features. However, the expanding molecular and clinical spectrum means that this approach does not always yield a result. Here we report the unusual clinical presentation of "Progressive External Ophthalmoplegia (PEO) plus" Leigh syndrome in three children from a consanguineous family where exome sequencing identified mutations in NDUFS8. NDUFS8 is a nuclearencoded structural core protein of complex I, and mutations are expected to cause infantile onset and severe disease. Our patients had a later onset, milder and a clinically distinct phenotype, and this gene would not normally be considered in this context. Being untargeted to specific genes, whole exome analysis has the potential to re-write the phenotype and reveal an unexpected molecular aetiology, as illustrated by this family.

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Use of Whole-Exome Sequencing to Determine the Genetic Basis of Multiple Mitochondrial Respiratory Chain Complex Deficiencies

Taylor

Pyle

Griffin

et al. 2014

JAMA

312

302

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Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing

Cited by 161 publications

References 26 publications

A Patient with Complex I Deficiency Caused by a Novel ACAD9 Mutation Not Responding to Riboflavin Treatment

A Patient with Complex I Deficiency Caused by a Novel ACAD9 Mutation Not Responding to Riboflavin Treatment

NDUFS8-related Complex I Deficiency Extends Phenotype from “PEO Plus” to Leigh Syndrome

Use of Whole-Exome Sequencing to Determine the Genetic Basis of Multiple Mitochondrial Respiratory Chain Complex Deficiencies

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