Original article
Mitochondrial DNA Depletion is a Prevalent Cause of Multiple Respiratory Chain Deficiency in Childhood

https://doi.org/10.1016/j.jpeds.2007.01.044Get rights and content

Objective

To determine the actual incidence of mitochondrial DNA (mtDNA) depletion syndrome in multiple respiratory chain deficiency.

Study design

We carried out a real-time polymerase chain reaction quantification of mtDNA in liver or muscle tissue of 100 children with unexplained multiple oxidative phosphorylation enzyme deficiency.

Results

A reduction of mtDNA copy number to <35% of control values was found in liver and/or muscle in half of the children (50/100). Most of these patients (32/50; 64%) presented with severe neonatal onset liver involvement; 7 (14%) had Alpers syndrome, and 11 (22%) exhibited various forms of neurologic involvement. Deoxyguanosine kinase or polymerase γ (POLG) mutations could be identified in 11 of 32 patients with liver involvement, and POLG mutations were consistently found in all 7 patients with Alpers syndrome. Homozygous thymidine kinase 2 and MPV17 gene mutations were found in 2 patients.

Conclusions

Our findings show that mtDNA depletion is a prevalent cause of multiple respiratory chain deficiency in infancy.

Section snippets

Patients

Over the past 15 years, we have identified 270 patients with multiple respiratory chain deficiency. Large-scale mtDNA deletions (64/270; 24%) and MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke) mutations were the most common cause of multiple respiratory enzyme chain deficiency (34/270; 12%). Liver and/or muscle DNA was available for 100 cases of unexplained multiple respiratory enzyme chain deficiency. Criteria for inclusion in the present study were multiple

Incidence of mtDNA Depletion

A mtDNA depletion was identified in 50 of the 100 patients (Table II; available at www.jpeds.com) The sex ratio in this series was 1.08 (26 males and 24 females). Some patients were born to consanguineous healthy parents and others had affected siblings, suggesting an autosomal recessive mode of inheritance. Three forms could be recognized on the basis of clinical course and severity. More than half of the patients (32/50; 64%) presented with a severe neonatal-onset liver involvement (liver

Discussion

Here we report on the high incidence of mtDNA depletion (18%) in children with multiple respiratory enzyme chain deficiency. In our series of 270 patients with multiple respiratory enzyme chain deficiency, 24% exhibited large-scale mtDNA rearrangements (64/270 patients) and 12% exhibited a MELAS mutation (34/270 patients). Therefore, mtDNA depletion represents the second most common cause of multiple respiratory enzyme chain deficiency in our series. This incidence is certainly an

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    Supported in part by the Association Française Contre les Myopathies.

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