Respiratory chain complex I deficiency caused by mitochondrial DNA mutations

Area of Science:

• Biochemistry
• Genetics
• Pediatrics

Background:

• Mitochondrial respiratory chain defects cause varied clinical phenotypes due to nuclear or mitochondrial DNA (mtDNA) mutations.
• Isolated complex I deficiency is the most common mitochondrial disorder in children, often presumed to have nuclear genetic causes.
• Pathogenic mtDNA mutations were historically considered rare in pediatric complex I deficiency.

Purpose of the Study:

• To investigate the prevalence and spectrum of mitochondrial DNA (mtDNA) and nuclear gene defects in pediatric isolated complex I deficiency.
• To compare clinical presentations and onset ages between mtDNA and nuclear genetic defects.
• To establish diagnostic recommendations for complex I deficiency in children.

Main Methods:

• Reviewed clinical and genetic data from 109 pediatric patients with isolated complex I deficiency from 101 families.
• Performed mtDNA sequencing and nuclear gene mutation analysis.
• Utilized cell hybrid studies to infer nuclear gene defects.

Main Results:

• Pathogenic mtDNA mutations identified in 29% of probands (21 in MTND subunit genes, 8 in tRNA genes).
• Nuclear gene defects inferred in 38% of probands (mutations identified in 22).
• Leigh or Leigh-like disease was the most common presentation in both groups; median onset was 12 months for mtDNA vs. 3 months for nuclear defects.

Conclusions:

• Pathogenic mtDNA mutations are a significant cause of complex I deficiency in children.
• Whole mitochondrial genome sequencing is a key diagnostic approach, especially in the absence of parental consanguinity.
• Understanding the genetic basis is crucial for accurate diagnosis and management of pediatric mitochondrial disorders.