SURF1 missense mutations promote a mild Leigh phenotype

Area of Science:

• Genetics and Molecular Biology
• Neuroscience
• Pediatric Neurology

Background:

• Leigh syndrome (LS) is a rare, fatal neurodegenerative disorder in infants.
• SURF1 gene mutations are the primary cause of LS, often leading to premature termination codons.
• Missense mutations in SURF1 are less common but their clinical impact requires further characterization.

Purpose of the Study:

• To investigate the natural history of LS patients with at least one missense mutation in the SURF1 gene.
• To compare the clinical course and survival rates of patients with missense SURF1 mutations versus those with truncating mutations.

Main Methods:

• Retrospective analysis of 19 LS patients with SURF1 missense mutations (8 new, 11 literature cases).
• Comparison with a reference group of 20 LS patients homozygous for c.845_846delCT SURF1 mutation.
• Review of literature data for other LS(SURF-) cases.

Main Results:

• Patients with SURF1 missense mutations exhibited delayed disease onset.
• Acute failure to thrive and hyperventilation were rare; respiratory failure occurred after age 4.
• Dystonia, motor regression, and eye movement dissociation progressed slowly.
• Survival past 7 years was 60% (9/15) in the missense group vs. 4% (1/26) in the truncating mutation group.

Conclusions:

• Missense mutations in the SURF1 gene may be associated with a milder LS phenotype and improved survival.
• Normal MRI, blood lactate, and mild cytochrome c oxidase (COX) activity do not exclude SURF1 mutations.
• SURF1 mutation analysis remains essential for LS diagnosis, irrespective of initial biochemical or imaging findings.