Recessive mutations in NDUFA2 cause mitochondrial leukoencephalopathy.

Area of Science:

• Biochemistry
• Genetics
• Neuroscience

Background:

• Mitochondrial respiratory chain complex I (CI) deficiency is a common cause of leukoencephalopathy in children.
• Genetic mutations in CI subunits are continually being identified.

Purpose of the Study:

• To investigate the genetic basis of cystic leukoencephalopathy and complex I deficiency in two patients.
• To identify novel gene mutations associated with these conditions.

Main Methods:

• Biochemical analysis to confirm complex I deficiency.
• Whole-exome sequencing (WES) and whole-genome sequencing (WGS) to identify genetic mutations.
• Review of a biorepository of patients with unsolved genetic leukoencephalopathies.

Main Results:

• Two patients presented with cystic leukoencephalopathy and complex I deficiency.
• Homozygous and compound heterozygous mutations in NDUFA2, encoding an accessory subunit of complex I, were identified.
• This is the first report linking NDUFA2 mutations to cystic leukoencephalopathy.

Conclusions:

• Recessive mutations in NDUFA2 can cause cystic leukoencephalopathy and complex I deficiency.
• NDUFA2 mutations represent a newly discovered genetic cause for this specific leukoencephalopathy phenotype.